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WO2015086593A1 - Composés ciblant la protéine bfl-1 anti-apoptotique, et leurs utilisations pour le traitement de cancer - Google Patents

Composés ciblant la protéine bfl-1 anti-apoptotique, et leurs utilisations pour le traitement de cancer Download PDF

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Publication number
WO2015086593A1
WO2015086593A1 PCT/EP2014/077041 EP2014077041W WO2015086593A1 WO 2015086593 A1 WO2015086593 A1 WO 2015086593A1 EP 2014077041 W EP2014077041 W EP 2014077041W WO 2015086593 A1 WO2015086593 A1 WO 2015086593A1
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WIPO (PCT)
Prior art keywords
carcinoma
cancer
bfl
bdm
compounds
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English (en)
Inventor
Nathalie Bonnefoy-Berard
Benoît Deprez
Olivier SPERANDIO
Anne-Laure DEBAUD
Bruno Villoutreix
Florence Leroux
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Universite Lille 2 Droit et Sante
Institut Pasteur de Lille
Institut National de la Sante et de la Recherche Medicale INSERM
Universite Paris Diderot Paris 7
Universite de Montpellier
Institut Regional du Cancer de Montpellier
Universite Claude Bernard Lyon 1
Institut Pasteur
Original Assignee
Universite Lille 2 Droit et Sante
Institut Pasteur de Lille
Institut National de la Sante et de la Recherche Medicale INSERM
Universite Paris Diderot Paris 7
Universite de Montpellier
Institut Regional du Cancer de Montpellier
Universite Claude Bernard Lyon 1
Institut Pasteur
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Publication of WO2015086593A1 publication Critical patent/WO2015086593A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

  • the present invention relates to compounds targeting the Bfl-1 anti-apoptotic protein and uses thereof for the treatment of cancer.
  • ABT-737 a small molecule with high affinity for Bcl-2, Bcl-xl and Bcl-w 1 and more recently the development of ABT-199 a selective inhibitor of Bcl-2 2 .
  • Navitoclax an orally bioavailable derivative of ABT-737 is currently evaluated in phase 2 clinical trials 3"5 .
  • navitoclax Besides a dose- limiting toxicity towards platelets for navitoclax, a limitation for the use of ABT-199 and navitoclax is the expression by tumor cells of Mcl-1 or Bfl-1 (BCL2A1) anti-apoptotic proteins that was shown to confer resistance to ABT-737 6"8 , thus emphasizing the need for BH3 mimetics specific for Mcl-1 or Bfl-1.
  • Bfl-1 Since its discovery in 1995 as a gene overexpressed in stomach cancer 9 , high expression of Bfl-1 has been documented in various types of cancers (for review see 8 ) and particularly in lymphoid malignancies, as a sub-group of diffused large B-cell lymphoma (DLBCL) 10 , mediastinal B cell lymphoma (MLBCL) 11 and mantle cell lymphoma 12 . Bfl-1 was also implicated in the emergence of resistance of B- CLL subjects to fludarabine treatment 13 ' 14 .
  • DLBCL diffused large B-cell lymphoma
  • MLBCL mediastinal B cell lymphoma
  • mantle cell lymphoma 12 mantle cell lymphoma
  • RNA interference strategies demonstrated that inhibition of Bfl-1 sensitize fresh B-CLL or malignant B-cell lymphoma cell lines to chemotherapeutic agents such as Cisplatin and Fludarabine, and therefore validated Bfl-1 as a therapeutic target in B cell malignancies 13 ⁇ 15 .
  • Peptide aptamers that specifically interact with the hydrophobic groove of Bfl-1 were recently identified. Said aptamers disrupt the interaction of Bfl-1 with its pro- apoptotic partners such as the pro-survival protein Bax.
  • RNA interference strategy it was demonstrated that anti-Bfl-1 aptamers sensitize malignant B-cell lymphoma cell lines to chemotherapeutic agents 16 .
  • disrupting interactions of Bfl-1 with pro-apoptotic partners appears to be an efficient strategy to overcome its pro-survival activity in malignant cells.
  • the present invention relates to compounds targeting the Bfl-1 anti-apoptotic protein and uses thereof for the treatment of cancer.
  • the present invention is defined by the claims.
  • the inventors describe the discovery of small molecules targeting Bfl-1 anti- apoptotic protein using high-throughput screening (FITS) approach of a chemical library composed of molecules with relaxed drug-like properties as it is know that modulators of protein-protein interactions usually fall slightly outside well-known rule of thumb such as the Lipinski rule of 5.
  • the inventors found two compounds (BDM 49234, BDM 53787) that display electrophilic functions, specifically interact with Bfl-1, inhibit Bfl-l protective activity and promote cell death of malignant B cells.
  • the inventors observed a synergistic effect of those compounds with ABT-737 in Bfl-1 expressing lymphoma cell lines.
  • the present invention relates to a method of the treatment of cancer in a subject in need thereof comprising administering the subject with a therapeutically effective amount of at least one compound selected from the group consisting of BDM 49234, BDM 53787 and pharmaceutical acceptable salts thereof.
  • BDM 49234" refers to the compound having the general formula (I):
  • BDM_53787 refers to the compound having the general formula (II):
  • Preparing the compounds of the invention is within the skill of the organic chemistry art.
  • the compounds described herein can be conveniently prepared from commercially available starting materials, compounds known in the literature, or readily prepared intermediates, by employing standard synthetic methods and procedures known to those skilled in the art. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be readily obtained from the relevant scientific literature or from standard textbooks in the field. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
  • the prepation methods can be monitored according to any suitable method known in the art.
  • product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., 1H or 13C), infrared spectroscopy (FT -IR), spectrophotometry (e.g., UV -visible), or mass spectrometry (MS), or by chromatography such as high performance liquid chromatograpy (HPLC) or thin layer chromatography (TLC).
  • spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g., 1H or 13C), infrared spectroscopy (FT -IR), spectrophotometry (e.g., UV -visible), or mass spectrometry (MS), or by chromatography such as high performance liquid chromatograpy (HPLC) or thin layer chromatography (TLC).
  • HPLC high performance liquid chromatograpy
  • TLC thin layer chromatography
  • the need for protection and deprotection, and the selection of appropriate protecting groups can be readily determined by one skilled in the art.
  • the reactions of the processes can be carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis. Suitable solvents can be substantially nonreactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, i.e., temperatures which can range from the solvent's freezing temperature to the solvent's boiling temperature.
  • a given reaction can be carried out in one solvent or a mixture of solvents.
  • suitable solvents for a particular reaction step can be selected.
  • Pharmaceutically acceptable salts of the compounds of formula (I) or (II) include the acid addition and base salts thereof.
  • Suitable acid addition salts are formed from acids, which form non-toxic salts. Examples include the acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate and triflu
  • the pharmaceutically acceptable salts of compounds of formula (I) or (II) may be prepared by one or more of three methods by reacting the compound of formula (I) or (II) with the desired acid or base.
  • the resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent.
  • the degree of ionization in the resulting salt may vary from completely ionized to almost non- ionized.
  • the compounds of the invention may also exist in both unsolvated and solvated forms.
  • solvate is used herein to describe a molecular complex comprising the compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, for example, ethanol.
  • solvent molecules for example, ethanol.
  • hydrate is employed when said solvent is water.
  • references to compounds of formula (I) or (II) include references to salts, solvates and complexes thereof and to solvates and complexes of salts thereof.
  • the compounds of the invention include compounds of formula (I) or (II) as hereinbefore defined, including all polymorphs and crystal habits thereof, prodrugs and isomers thereof whenever relevant. So-called “pro-drugs" of the compounds of formula (I) or (II) are also within the scope of the invention. Thus certain derivatives of compounds of formula (I) or (II) which may have little or no pharmacological activity themselves can, when administered into or onto the body, be converted into compounds of formula (I) or (II) having the desired activity, for example, by hydrolytic cleavage. Such derivatives are referred to as "prodrugs".
  • Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the compounds of formula (I) or (II) with certain moieties known to those skilled in the art as "pro-moieties” as described, for example, in “Design of Prodrugs” by H. Bundgaard (Elsevier, 1985).
  • the subject suffers from a cancer selected from the group consisting of breast cancer, prostate cancer, lymphoma, skin cancer, pancreatic cancer, colon cancer, melanoma, malignant melanoma, ovarian cancer, brain cancer, primary brain carcinoma, head-neck cancer, glioma, glioblastoma, liver cancer, bladder cancer, non-small cell lung cancer, head or neck carcinoma, breast carcinoma, ovarian carcinoma, lung carcinoma, small-cell lung carcinoma, Wilms' tumor, cervical carcinoma, testicular carcinoma, bladder carcinoma, pancreatic carcinoma, stomach carcinoma, colon carcinoma, prostatic carcinoma, genitourinary carcinoma, thyroid carcinoma, esophageal carcinoma, myeloma, multiple myeloma, adrenal carcinoma, renal cell carcinoma, endometrial carcinoma, adrenal cortex carcinoma, malignant pancreatic insulinoma, malignant carcinoid carcinoma, choriocarcinoma, mycosis fungoides, malignant hypercalcemia, cervical hyperplasia, leukemia
  • the subject suffers from a haemato logical malignancy selected from the group consisting of leukemia, lymphoma or myeloma.
  • the lymphoma is a mature (peripheral) B-cell neoplasm.
  • the mature B-cell neoplasm is selected from the group consisting of B- cell chronic lymphocytic leukemia/small lymphocytic lymphoma; B-cell prolymphocytic leukemia; Lymphoplasmacytic lymphoma; Marginal zone lymphoma, such as Splenic marginal zone B-cell lymphoma (+/-villous lymphocytes), Nodal marginal zone lymphoma (+/-monocytoid B-cells), and Extranodal marginal zone B-cell lymphoma of mucosa- associated lymphoid tissue (MALT) type; Hairy cell leukemia; Plasma cell myeloma/plasmacytoma; Follicular lymphoma, follicle center; Mantle cell lymphoma; Diffuse large cell B-cell lymphoma (including Mediastinal large B-cell lymph
  • the lymphoma is selected from the group consisting of multiple myeloma (MM) and non Hodgkin's lymphoma (NHL), mantle cell lymphoma (MCL), follicular lymphoma, Waldenstrom's macroglobulinemia (WM) or B-cell lymphoma and diffuse large B-cell lymphoma (DLBCL).
  • NHL Non-Hodgkin's Lymphoma
  • Aggressive NHL is fast growing and may lead to a subject's death relatively quickly. Untreated survival may be measured in months or even weeks.
  • Examples of aggressive NHL includes B-cell neoplasms, diffuse large B-cell lymphoma, T/NK cell neoplasms, anaplastic large cell lymphoma, peripheral T-cell lymphomas, precursor B-lymphoblastic leukemia/lymphoma, precursor T- lymphoblastic leukemia/lymphoma, Burkitt's lymphoma, Adult T-cell lymphoma/leukemia (HTLV1+), primary CNS lymphoma, mantle cell lymphoma, polymorphic post- transplantation lymphoproliferative disorder (PTLD), AIDS-related lymphoma, true histiocytic lymphoma, and blastic NK-cell lymphoma.
  • HTLV1+ Adult T-cell lymphoma/leukemia
  • PTLD polymorphic post- transplantation lymphoproliferative disorder
  • AIDS-related lymphoma true histiocytic lymphoma
  • lymphoplasmacytic lymphoma Waldenstrom's macroglobulinemialn some cases, histologic transformation may occur, e.g., indolent NHL in subjects may convert to aggressive NHL.
  • the leukemia is selected from the group consisting of acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), and small lymphocytic lymphoma (SLL).
  • ALL acute lymphocytic leukemia
  • AML acute myeloid leukemia
  • CLL chronic lymphocytic leukemia
  • SLL small lymphocytic lymphoma
  • Acute lymphocytic leukemia is also known as acute lymphoblastic leukemia and may be used interchangeably herein. Both terms describe a type of cancer that starts from the white blood cells, lymphocytes, in the bone marrow.
  • the compounds of the invention are used in combination with a chemotherapeutic agent.
  • Chemotherapeutic agents include, but are not limited to alkylating agents such as thiotepa and cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethiylenethiophosphoramide and trimethylolomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including the synthetic analogue topotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); dolastatin; du
  • calicheamicin especially calicheamicin gammall and calicheamicin omegall ; dynemicin, including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antiobiotic chromophores, aclacinomysins, actinomycin, authrarnycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin (including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino- doxorubicin and deoxy dox
  • the compounds of the invention are administered to the subject in combination with a compound which targets a member of Bcl-2 family.
  • said compound is selected from the group consisting of ABT-199, ABT-263 and ABT-737.
  • ABT-737 has its general meaning in the art and refers to 4-
  • ABT-199 has its general meaning in the art and refers to 4- [4-[[2-(4-Chlorophenyl)-4,4-dimethylcyclohex- 1 -en- 1 - yl]methyl]piperazin- 1 -yl]-N-[[3-nitro- 4- [ [(tetrahydro-2H- pyran-4-yl)methyl]amino ]phenyl] sulfonyl] -2- [( 1 H- pyrrolo [2,3 - b]pyridin-5-yl)oxy]benzamide.
  • ABT-263 or “Navitoclax” has its general meaning in the art and refers to R)-4-(4-((4'-chloro-4,4-dimethyl-3,4,5,6-tetrahydro-[l,r-biphenyl]-2- yl)methyl)piperazin- 1 -yl)-N-((4-((4-morpholino- 1 -(phenylthio)butan-2-yl)amino)-3- ((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide.
  • compounds of the invention are administered to a subject having a refractory cancer, i.e. a cancer that is resistant to chemotherapeutic agents.
  • a subject having a refractory cancer i.e. a cancer that is resistant to chemotherapeutic agents.
  • the subject suffers from a cancer which is resistant to a fludarabine or cisplatine treatment.
  • the subject suffers from a cancer that is resistant toa BCL-2 inhibitor (e.g. ABT-737, ABT-199 or ABT-263).
  • a "therapeutically effective amount” is meant a sufficient amount of the compound to treat cancer at a reasonable benefit/risk ratio applicable to any medical treatment.
  • the total daily usage of the compounds of the present invention will be decided by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically effective dose level for any particular subject will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed, the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidential with the specific compound employed; and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of the compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
  • the daily dosage of the products may be varied over a wide range from 0.01 to 1,000 mg per adult per day.
  • the compositions contain 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 250 and 500 mg of the active ingredient for the symptomatic adjustment of the dosage to the subject to be treated.
  • a medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, preferably from 1 mg to about 100 mg of the active ingredient.
  • An effective amount of the drug is ordinarily supplied at a dosage level from 0.0002 mg/kg to about 20 mg/kg of body weight per day, especially from about 0.001 mg/kg to 7 mg/kg of body weight per day.
  • the compounds of the invention are administered as a formulation in association with one or more pharmaceutically acceptable excipients to form pharmaceutical composition.
  • the term “Pharmaceutically” or “pharmaceutically acceptable” refers to molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to a mammal, especially a human, as appropriate.
  • a pharmaceutically acceptable carrier or excipient refers to a non-toxic solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
  • compositions suitable for the delivery of compounds of the present invention and methods for their preparation will be readily apparent to those skilled in the art.
  • the active principle i.e. a compound of the invention
  • Suitable unit administration forms comprise oral-route forms such as tablets, gel capsules, powders, granules and oral suspensions or solutions, sublingual and buccal administration forms, aerosols, implants, subcutaneous, transdermal, topical, intraperitoneal, intramuscular, intravenous, subdermal, transdermal, intrathecal and intranasal administration forms and rectal administration forms.
  • the pharmaceutical compositions contain vehicles which are pharmaceutically acceptable for a formulation capable of being injected.
  • vehicles which are pharmaceutically acceptable for a formulation capable of being injected.
  • These may be in particular isotonic, sterile, saline solutions (monosodium or disodium phosphate, sodium, potassium, calcium or magnesium chloride and the like or mixtures of such salts), or dry, especially freeze-dried compositions which upon addition, depending on the case, of sterilized water or physiological saline, permit the constitution of injectable solutions.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations including sesame oil, peanut oil or aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi.
  • Solutions comprising compounds as free base or pharmacologically acceptable salts can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • a surfactant such as hydroxypropylcellulose
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • Compounds of the invention can be formulated into a composition in a neutral or salt form as above described.
  • the carrier can also be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetables oils.
  • the proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars or sodium chloride.
  • Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminium monostearate and gelatin.
  • Sterile injectable solutions are prepared by incorporating the compounds of the invention in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
  • the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile- filtered solution thereof.
  • solutions Upon formulation, solutions will be administered in a manner compatible with the dosage formulation and in such amount as is therapeutically effective.
  • the formulations are easily administered in a variety of dosage forms, such as the type of injectable solutions described above, but drug release capsules and the like can also be employed.
  • aqueous solutions For parenteral administration in an aqueous solution, for example, the solution should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose.
  • aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration.
  • sterile aqueous media which can be employed will be known to those of skill in the art in light of the present disclosure.
  • one dosage could be dissolved in 1 ml of isotonic NaCl solution and either added to 1000 ml of hypodermoclysis fluid or injected at the proposed site of infusion. Some variation in dosage will necessarily occur depending on the condition of the subject being treated. The person responsible for administration will, in any event, determine the appropriate dose for the individual subject.
  • Compounds of the invention may be formulated within a therapeutic mixture to comprise about 0.0001 to 1.0 milligrams, or about 0.001 to 0.1 milligrams, or about 0.1 to 1.0 or even about 10 milligrams per dose or so. Multiple doses can also be administered.
  • other pharmaceutically acceptable forms include, e.g. tablets or other solids for oral administration; liposomal formulations; time release capsules ; and any other form currently used.
  • FIGURES are a diagrammatic representation of FIGURES.
  • Figure 1 Chemical library selection.
  • Figure 2. Screening to identify molecules targeting Bfl-1 and displaying cytotoxic properties. 25 000 compounds were screened at 30 ⁇ to find inhibitors of Bfl-1 (30 nM) binding to Bim BH3 (15 nM).
  • FIG. 3 Inhibitory effect of BDM 49234 and BDM 53787 in FP assays against other apoptotic and anti-apoptotic proteins of the Bcl-2 family.
  • BDM 49234 (A) and BDM 53787 (B) effect on Bfl-1 binding to Bim BH3 or to other pro-apoptotic peptides (Bax and Bak).
  • FP was measured after 15 minutes. Data are mean of 2 incubates.
  • FIG. 4 Pro-apoptotic effect of BDM 49234 and BDM 53787 compounds towards lymphoma cell lines.
  • BP3 and IM9 cells were treated 24h with increasing concentrations of BDM 49234 (A) and BDM 53787 (B) molecules. Percent of viable cells was evaluated by propidium iodide / Annexin V double staining and flow cytometry analysis.
  • IM9 (C, D) and BP3 (E, F) cells were incubated in the presence of ABT-737 and BDM 49234 or BDM 53787 at the indicated concentrations. Percent of viable cells was evaluated as in A. Data are presented as mean +/-SEM of 3 independent experiments.
  • the compounds used in the experimental screening were selected from the Enamine HTS collection (Sept 2009) and processed with the program Pipeline Pilot v7.5.
  • the selection is based on a hierarchical procedure combining the compliance with physicochemical thresholds (molecular weight, logP, etc.) and the absence of chemical moieties commonly associated with toxicity and an increase in false positive rates.
  • the physicochemical thresholds used for the compound selection are the following: number of Hydrogen bonds acceptors ⁇ 13; number of Hydrogen bonds donors ⁇ 8; 150 ⁇ molecular weight ⁇ 700; logP ⁇ 6; TPSA ⁇ 160; and number of rotatable bonds ⁇ 13.
  • the chemical library was formatted in barcoded racks of 96 tubes and stored at ambient temperature or -20°C for dried or 10 mM DMSO-dissolved copies, respectively.
  • the workstation to dilute and aliquot the library was a CyBI-Well® (CyBio, Savigny Le Temple, France) liquid handler.
  • the sample management system avoids repeated freeze thaw cycles and ensures the longest possible lifetime for all the samples. Structures, compound ID and library manipulations were recorded in Isis and access bases.
  • GST fusion proteins containing ⁇ -Cter-Bfl-l, A-Cter-Bcl-2, ⁇ -Cter-Bcl-XL or ⁇ -Cter- Mcl-1 were expressed from pGEX4T-l plasmid in XL 1 -Blue cells (Stratagene). The cells were grown in 1 liter of TY media (1.6% (w/v) tryptone, 1% (w/v) yeast extract, and 85 mM NaCl) with 50 ⁇ g/mL ampicillin at 37 °C to an A600 nm of 0.8 followed by the addition of isopropyl-B-D-thiogalactopyranoside (0.4 mM) and incubated at 25 °C for 7 h.
  • TY media (1.6% (w/v) tryptone, 1% (w/v) yeast extract, and 85 mM NaCl
  • ampicillin 50 ⁇ g/mL ampicillin at 37 °C to an A600 nm of 0.8
  • the cells were recovered in 10 ml lysis buffer (50 mM Tris-HCl, pH 8.0, 150 mM NaCl, 1% Tween 20, 0.1% 2-B-mercaptoethanolsupplemented with protease inhibitor mixture (RocheDiagnostics), 0.5 mg/rnL lysozyme and benzonase (250 units ⁇ L)) 30 min at 30 °C, followed by three freezing cycles.
  • the cellular debris were removed by centrifugation at 6,000 x g for 20 min, and the resulting supernatants were incubated with 2mL of glutathione-Sepharose (GE Healthcare) at 4 °C for 3 h.
  • the resin was washed three times with buffer (20mM Tris- HCLpH 8.0, 150mM NaCl, 0.1% Tween 20, and 0.1% 2-B-mercaptoethanol) followed by elution of GST fusion proteins in 10 mM of reduced glutathione dissolved in 50 mM Tris- HCl, pH 8.0.
  • Recombinant proteins in solutions were thereafter dialyzed in PBS buffer containing ImM DTT using Amicon Ultra-4 10K columns (Millipore) and glycerol was added to a final concentration of 10% to stabilize proteins.
  • FP assays were performed in 10 mM PBS pH 7.4, 100 mM NaCl, 2.7 mM KC1, 0.01% Triton XI 00 and 1% DMSO in black 96-well microplates (Corning, Amsterdam, The Netherlands). Twenty five Bcl-2 family proteins were incubated with 25 test compound at room temperature for 30 minutes. Then, 25 ⁇ , FITC-BH3 peptide were added.
  • FITC-Bim FITC-DMRPEIWIAQELRRIGDEFNAYYAR
  • FITC-Bax FITC-VPQDASTKKLSECLKRIGDELDSNMELQR
  • FITC-Bak FITC- KGGGQVGRQLAIIGDDINRRYDS
  • the polarization signal was defined in equation (1) where Sc and Pc were the signals corrected in plan S and P by subtracting the buffer (without labeled-ligand in the well) signal.
  • the « g factor » was a correction factor depending on plate reader and fluorophore used.
  • Plates were validated if their respective Z' factors were > 0.5 and if PPI inhibition with 100 ⁇ or 2 ⁇ gambogic acid were > 80% and > 40%, respectively.
  • IC 50 values were calculated from concentration-response curves by a nonlinear regression analysis at four parameters (3) using XL fitTM 5.2.0.0. from IDBS (Guilford, United Kingdom) or GraphPad Prism 5.02 (San Diego, USA).
  • A minimum y value
  • B maximum y value
  • C LoglCso value
  • D slope factor
  • TR-FRET Time-Resolved Fluorescence Resonance Energy Transfer Assay
  • the TR-FRET assay was conducted in black 384-well microplates (Corning, Amsterdam, The Netherlands). Five recombinant human Bfl-l protein (120 nM) were incubated with 5 compounds at room temperature for 30 minutes. Then, 5 ⁇ LanthaScreenTM Tb-anti-GST_Tag Antibody (Invitrogen) and 5 ⁇ ⁇ FITC-Bim peptide were added at 20 nM and 40 nM, respectively. Buffer was PBS pH 7.4 with 0.01% Triton XI 00 and 1% DMSO.
  • the mobile phase solvents used were: (A) H 2 0 5mM ammonium formate buffer pH 3,8; (B) CH 3 CN 5mM ammonium formate buffer pH 3,8.
  • the following mobile phase gradient was applied: 2% B during 30s, 2- 98% (B) in 6'; hold at 98% (B) for 2'; 98%-2% B in 10s; 2% B hold for ⁇ 20.
  • the injection volume was 20 and the flow rate of 1 mL/min.
  • PBMCs peripheral blood mononuclear cells
  • BP3, IM9, and peripheral blood mononuclear cells were cultured in RPMI supplemented with 10% fetal bovine serum, 2mM glutamine, lOmM Hepes and 40 ⁇ g/mL gentamycin.
  • PBMCs were collected from healthy donors (Etablatorium Francais du Sang). Separation of PBMCs was obtained by standard Ficoll density gradient centrifugation. After 2 washes in phosphate- buffered saline, PBMCs were cultured in RPMI with molecules as indicated.
  • Mouse embryonic fibroblasts either wild-type (WT) or bak-/- bax-/- double knock-out (DKO) were cultured in Dulbecco's modified Eagle's medium supplemented with 10%> fetal bovine serum, 2 mM glutamine, 10 mM Hepes and 40 ⁇ g/mL gentamycin. All cells were cultured at 37°C in humidified atmosphere with 5% C0 2 .
  • ABT-737 and Obatoclax were purchased from Euromedex and Gambogic acid from
  • ATP monitoring was performed 24h after treatment using ATPlite assay (Perkin Elmer) according to manufacturer instructions. This assay is based on ATP measurement that is a marker for cell viability. Briefly, cells are lysed using buffer provided by the kit and incubated 5 minutes with shaking. Then substrate solution containing Luciferase and D-luciferin (reacting with ATP to produce light) is added to the wells and plate is incubated 10 min in the dark. Luminescence is thereafter measured on a Tecan Infinite M200 plate reader. Luminescent signal is proportional to viable cell number in each well.
  • Cells were treated with molecules for 24 h. Cell death was evaluated by propidium iodide / Annexin V double staining (BD Pharmingen) and analyzed by flow cytometry with FlowJo software (TreeStar). Viable cells are gated as propidium iodide/ Annexin V double negative cells.
  • the selected complex proposed by Autodock was also investigated within MOE 2012.10 and a full minimization of the complex was carried out. Then, the molecular surface of the protein in the vicinity of the binding site and the electrostatic map were calculated to picture the pocket of Bfl-1 and the polarity of the favored interacting regions with BDM53787.
  • the hierarchical protocol used for compound selection allowed us to prioritize the purchase of 25,000 compounds among the 1,100,307 compounds of the Enamine HTS collection (Sept 2009). The number of compounds along the selection process and the distribution of some major physicochemical properties for the resulting database are shown in Fig. 1.
  • a FP assay was set up to follow the interaction of the recombinant human GST-Bfl-1- ACter protein with FITC-Bim BH3.
  • Preliminary experiments with various concentrations of Bim BH3 incubated in PBS buffer showed that reproducible and similar polarization values could be obtained with concentrations going from 15 nM to 50 nM (106 ⁇ 8 mP at 15 nM to 99 ⁇ 2 mP at 50nM). Consequently we chose to use Bim BH3 peptide at 15 nM which is the lowest concentration giving a low and stable polarization value.
  • addition of the Bfl-1 protein to Bim BH3 peptide increased the polarization value.
  • FITC-Bim BH3 was synthesized by GeneCust (Luxembourg) (FITC- DMRPEIWIAQELRRIGDEFNAYYAR).
  • IC 50 values were calculated from concentration-response curves by a nonlinear regression analysis using XL fit from I DBS or GraphPad Prim 5.
  • the 25,000 compounds of the library were screened at the concentration of 30 ⁇ for their capacity to disrupt Bfl-l/Bim interaction (Fig. 2).
  • the FP assay-based HTS demonstrated robust performance with an average Z' factor of 0.81 ⁇ 0.08 and an average percentage inhibition value of 68 ⁇ 9 for gambogic acid at 2 ⁇ used as positive reference compound.
  • fluorescence of compounds could interfere with the FP assay, we take into account only data associated with a fluorescence value below 3800 UF, a limit that corresponded to the mean fluorescence of all negative controls ⁇ 3 SD.
  • Fourty one compounds were found to inhibit more than 60% of the Bfl-l/Bim interaction (Fig. 2B).
  • TR-FRET secondary assay investigated the same molecular interaction between GST-Bfl-1- ACter protein and FITC-Bim BH3, but in this assay FITC fluorescence is excited by the long- life time terbium-conjugated anti-GST when brought into proximity. This assay is less prone to interference with fluorescent tested compounds.
  • BDM 53787 and BDM 49234 Two prototypes of the indole series, BDM 53787 and BDM 49234 with respective IC 50 of 1.4 ⁇ and 2.5 ⁇ in TR-FRET (Fig. 2C), one compound from the phenol series, BDM 56776 (IC 50 of 4.8 ⁇ ), and the benzimidazole compound, BDM 57859 (IC 50 of 5.8 ⁇ ) were resupplied and evaluated for their cytotoxic activity towards B cell lines by using ATPlite metabolic assay.
  • DLBCL diffused large B cell lymphoma
  • BDM_ 49234 and BDM_ 53787 demonstrated strong activity against BP3 and IM9 cell lines as less than 10% treated cells are still viable following 24h treatment with 25 ⁇ compound.
  • Bfl-l interacts with multiple pro-apoptotic proteins, potentially through the same BH3 domain binding site.
  • BDM_ 49234 and BDM_ 53787 displaced Bfl-l from its interaction with FITC-Bax or FITC-Bak BH3 peptides.
  • IC 50 values are in the same range for BDM 49234 (6 ⁇ , 16 ⁇ and 8 ⁇ , for Bfl-l/Bim, Bfl-l/Bax and Bfl-l/Bak, respectively).
  • BDM_ 53787 is ten fold more potent to displace Bim BH3 (IC 50 of 0.8 ⁇ ) than Bax (IC 50 of 10 ⁇ ) or Bak BH3 peptides (IC 50 of 8 ⁇ ) from their complex with Bfl-l .
  • BDM_ 49234 and BDM_ 53787 were not significant with estimated IC 50 > 100 ⁇ .
  • Anti-apoptotic Bcl-2 members suppress apoptosis by inhibiting Bax and Bak pro- apoptotic Bcl-2 members, and cells lacking both Bax and Bak proteins are resistant to apoptotic stimuli that act through Bax/Bak-dependent disruption of mitochondrial function 19 .
  • murine embryonic fibroblasts MEF
  • WT or Bax/Bak DKO murine embryonic fibroblasts
  • compound BDM 49234 did not induce death of WT or DKO MEFs for concentrations up to 6.25 ⁇ , a dose that efficiently induced apoptosis of IM9 B lymphoma.
  • the crystal structure of Bfl-l in complex with the interacting alpha-helix of Bim (pdb code 2VM6) was used to predict the hot spot residues of Bim interacting with the binding pocket of Bfl-l using the virtual alanine scanning DrugscorePPI server 21 .
  • Several hot spot residues were predicted including Bim-Ilel48, Bim- Leul52, and Bim-Argl53 with predicted ⁇ superior to 1.5 kcal.mol "1 .
  • the selection of the BDM 53787 docking pose was therefore made with the attempt to mimic the binding mode of BIM with regards to these three hot spot residues.
  • the proposed binding mode of BDM 53787 was selected among the Autodock poses of the docked ligand and corresponds to the enantiomer R of BDM 53787.
  • the phenyl moiety of BDM 53787 occupies the hydrophobic sub-pocket of BIM- Leul52
  • the 4-methoxyphenyl moiety occupies the hydrophobic sub-pocket of BIM-Ilel48
  • the piperazine moiety occupies a region of the Bfl-l binding pocket compatible with the type of interaction that Bim-Argl53 makes with Bfl-l including a salt-bridge with residue Glu80 of Bfl-l .
  • Novel small compounds targeting Bcl-2 and/or Bcl-xl anti-apoptotic protein of the Bcl-2 family such as Navitoclax, an orally bioavailable derivative of ABT-737, or ABT-199 are now in clinical trials 3 5 .
  • ABT-737 result in increased levels of Bfl-l and Mcl-1 and development of resistance in lymphoma cell lines that were initially sensitive 6 .
  • Bfl-l inhibitors Based on the strong characterization of Bfl-l in chemoresistance associated with its over-expression in DBCL and B-CLL where it stands as an innovative target 13 ⁇ 16 , we focused on the identification of Bfl-l inhibitors. We described here 2 compounds that specifically target the Bfl-l hydrophobic BH3 -binding groove, and thereby efficiently disrupt its interaction with pro-apoptotic partners, such as Bim but also Bax and Bak. Both compounds inhibit Bfl-l protective activity and promote cell death of malignant B cells, either alone or in combination with ABT-737. The synergistic effect of those compounds with ABT-737 is of particular interest since Bfl-l overexpression was clearly identified as a limit to its efficacy.
  • Bfl-l/Bim inhibitors Screening of such a library with "relaxed” drug like properties provides 3 structurally different series of Bfl-l/Bim inhibitors, amongst which 2 contain Mannich base function.(Ar- CHR-NR 1 R 2 ), where the amine fragment can be substituted by a sulfur nucleophile. Bfl-1 contains at position 55 a Cys residue close to the binding groove, that could explain why we and others described electrophilic Bfl-1 inhibitors 26-28 . The indol series was progressed and tested in different cell lines.
  • Positioning of the ligand in the groove is a prerequisite for activity: in the Mannich base family described here, one of the compounds is not thiol reactive and a reversible inhibitor, while its close analogue is thiol reactive and a partial reversible binder.
  • the reversible compound (BDM 53787) was more potent in the cell-free and cell based assays, and molecular modeling clearly supports the experimental work and proposes a likely binding mode of Bfl-1.
  • the partially reversible compound (BDM 49234) was less potent, but it was also less toxic, suggesting that chemical reactivity and irreversibility does not imply a non-specific cell toxicity.
  • the thiol reactivity should not be by itself a reason to discard a hit before medicinal chemistry efforts to improve potency and explore chemical reactivity are done.
  • a great care to incubation times should be given when measuring activities on target and comparing compounds with very different kinetic properties.
  • binding kinetics and pharmacokinetics should be jointly analyzed: slow tight binders may be of interest if the Cmax and elimination rates are high. Therefore having in hand compounds with various binding kinetics early in the drug discovery is favorable.

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Abstract

La présente invention concerne des composés ciblant la protéine Bfl-1 anti-apoptotique, et leurs utilisations pour le traitement de cancer. En particulier, la présente invention concerne au moins un composé, choisi parmi le groupe constitué de BDM-49234, de BDM 53787 et de sels pharmaceutiques acceptables de ceux-ci, destiné à être utilisé dans un procédé de traitement de cancer chez un sujet en ayant besoin.
PCT/EP2014/077041 2013-12-09 2014-12-09 Composés ciblant la protéine bfl-1 anti-apoptotique, et leurs utilisations pour le traitement de cancer Ceased WO2015086593A1 (fr)

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Citations (2)

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Publication number Priority date Publication date Assignee Title
WO2013032960A2 (fr) * 2011-08-26 2013-03-07 Uwm Research Foundation, Inc. Inhibiteurs de récepteur de vitamine d - co-régulateur
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Patent Citations (2)

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Publication number Priority date Publication date Assignee Title
WO2013032960A2 (fr) * 2011-08-26 2013-03-07 Uwm Research Foundation, Inc. Inhibiteurs de récepteur de vitamine d - co-régulateur
WO2013142281A1 (fr) * 2012-03-20 2013-09-26 Dana Farber Cancer Institute, Inc. Inhibition de mcl-1 et/ou de bfl-1/a1

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