WO2018127575A1 - Combinaison d'un inhibiteur de mcl-1 et d'un composé de taxane, ses utilisations et compositions pharmaceutiques la comprenant - Google Patents

Combinaison d'un inhibiteur de mcl-1 et d'un composé de taxane, ses utilisations et compositions pharmaceutiques la comprenant Download PDF

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WO2018127575A1
WO2018127575A1 PCT/EP2018/050298 EP2018050298W WO2018127575A1 WO 2018127575 A1 WO2018127575 A1 WO 2018127575A1 EP 2018050298 W EP2018050298 W EP 2018050298W WO 2018127575 A1 WO2018127575 A1 WO 2018127575A1
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Prior art keywords
group
alkyl
branched
linear
hydrogen atom
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PCT/EP2018/050298
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English (en)
Inventor
Dale Porter
Ensar HALILOVIC
Maïa CHANRION
Ana Leticia MARAGNO
Olivier Geneste
Delphine MERINO
James WHITTLE
François VAILLANT
Jane Visvader
Geoffrey Lindeman
Guillaume Lessene
Elisabetta Marangoni
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Les Laboratoires Servier
Novartis Ag
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Priority to JOP/2019/0159A priority Critical patent/JOP20190159B1/ar
Priority to UAA201907499A priority patent/UA125142C2/uk
Priority to EA201991623A priority patent/EA201991623A1/ru
Priority to MX2019008109A priority patent/MX2019008109A/es
Priority to CN201880015906.7A priority patent/CN110381937A/zh
Priority to AU2018205735A priority patent/AU2018205735B2/en
Priority to KR1020197022996A priority patent/KR102576567B1/ko
Application filed by Les Laboratoires Servier, Novartis Ag filed Critical Les Laboratoires Servier
Priority to EP18700861.0A priority patent/EP3565547B1/fr
Priority to CA3049095A priority patent/CA3049095C/fr
Priority to JP2019536593A priority patent/JP7179733B2/ja
Priority to US16/475,389 priority patent/US10765680B2/en
Priority to RU2019123982A priority patent/RU2763544C2/ru
Priority to CU2019000064A priority patent/CU20190064A7/es
Priority to BR112019013907A priority patent/BR112019013907A2/pt
Publication of WO2018127575A1 publication Critical patent/WO2018127575A1/fr
Priority to PH12019501451A priority patent/PH12019501451A1/en
Priority to ZA2019/04280A priority patent/ZA201904280B/en
Priority to IL267791A priority patent/IL267791B/en
Priority to CONC2019/0007261A priority patent/CO2019007261A2/es

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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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a combination of a MCL-1 inhibitor and a taxane compound.
  • the invention also relates to the use of said combination in the treatment of cancer, in particular breast, lung, ovarian, bladder and prostate cancers, more particularly breast and lung cancers.
  • pharmaceutical formulations suitable for the administration of such combinations are also provided.
  • Antimitotic agents and antimicrotubule agents have been explored for cancer therapy because of their important effect in the cell division. Inhibition of the mitotic machinery results in a diverse array of outcomes, primarily leading to cell cycle arrest and cell death.
  • Antimicrotubule agents such as taxanes are currently being used in clinical setting. For example, paclitaxel and docetaxel have a similar spectrum of clinical activity including ovarian, lung, breast, bladder, and prostate cancers. Taxanes are anti-mitotic agents that bind to tubulin and inhibit microtubule depolymerization thereby disrupting the normal equilibrium involved in microtubule assembly and deconstruction and therefore impair microtubule functioning.
  • Microtubules are essential to cell division and cells exposed to taxanes can fail to divide. Cell cycle arrest after treatment with taxanes may eventually result in cell death due to unsuccessful mitosis.
  • the toxicities associated with paclitaxel and docetaxel include neutropenia as the major dose limiting toxicity, along with significant peripheral neuropathy. In fact, dose reductions are frequent in heavily pretreated patients to mitigate the severity of these toxicities.
  • the development of resistance to taxanes also limits its use in the clinic.
  • Apoptosis is a highly regulated cell death pathway that is initiated by various cytotoxic stimuli, including oncogenic stress and chemotherapeutic agents.
  • Breast cancer is a heterogeneous disease and can be stratified into at least five major subgroups based on gene expression profiling: Luminal A, Luminal B (estrogen positive, ER + ), HER2-amplified, basal-like (predominantly triple negative breast cancer or TNBC) and normal-like (Curtis et al., Nature 2012, 486, 346-352; Perou et al., Nature 2000, 406, 747-752). These subtypes generally predict clinical behavior with respect to response and resistance to therapy, patterns of metastasis, and overall survival.
  • Lung cancer is classified into non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), and carcinoid. Approximately 80 % of all lung cancers correspond to NSCLC, which can be further classified into adenocarcinoma, squamous cell carcinoma, and large cell carcinoma. Lung cancer is the most common cause of cancer-related death in men and second most common in women after breast cancer. Although lung cancer therapy has evolved significantly with the appearance of targeted therapy, there is still a strong need to develop novel therapies in order to improve treatment efficacy, reduce side effects and avoid appearance of resistance (Rothschild Cancers 2015, 7(2), 930-949).
  • the present invention provides a novel combination of a MCL-1 inhibitor and a taxane compound.
  • the results show that with the association of potent small molecules targeting MCL-1 with antimicrotubule agents is highly synergistic in breast and lung cancer cell lines ( Figures 1 to 7; Tables 1 and 4).
  • D represents a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group,
  • E represents a furyl, thienyl or pyrrolyl ring
  • Xi, X3, X 4 and X5 independently of one another represent a carbon atom or a nitrogen atom
  • X 2 represents a C-R 2 6 group or a nitrogen atom
  • Y represents a nitrogen atom or a C-R 3 group
  • Z represents a nitrogen atom or a C-R4 group
  • Ri represents a halogen atom, a linear or branched (Ci-Cg)alkyl group, a linear or branched (C2-Ce)alkenyl group, a linear or branched (C2-C6)alkynyl group, a linear or branched (Ci-C6)polyhaloalkyl group, a hydroxy group, a hydroxy(Ci-C6)alkyl group, a linear or branched (Ci-Ce)alkoxy group, -S-(Ci-Ce)alkyl group, a cyano group, a nitro group, -Cy 8 , -alkyl(Co-C 6 )-NRi 1 11 ' , -0-alkyl(Ci-C6)-NRnRn ' , -0-alkyl(Ci-C 6 )-Ri2, -C(0)-OR thoughts, -0-C(0)-Rnam, -C(0)-NR fetchR cache line,
  • R2, R 3 , R4 and R5 independently of one another represent a hydrogen atom, a halogen atom, a linear or branched (Ci-C6)alkyl group, a linear or branched (C 2 -Ce)alkenyl group, a linear or branched (C 2 -Ce)alkynyl group, a linear or branched (Ci-C6)polyhaloalkyl, a hydroxy group, a hydroxy(Ci-C6)alkyl group, a linear or branched (Ci-Ce)alkoxy group, a -S-(Ci-Ce)alkyl group, a cyano group, a nitro group, -alkyl(C 0 -C 6 )-NRi iRii ⁇ -O-Cyi, -alkyl(C 0 -C 6 )-Cyi, -alkenyl(C 2 -C 6 )-Ci
  • ⁇ Re and R7 independently of one another represent a hydrogen atom, a halogen atom, a linear or branched (Ci-C6)alkyl group, a linear or branched (C 2 -C6)alkenyl group, a linear or branched (C 2 -Ce)alkynyl group, a linear or branched (Ci-C6)polyhaloalkyl, a hydroxy group, a linear or branched (Ci-Ce)alkoxy group, a -S-(Ci-Ce)alkyl group, a cyano group, a nitro group, -alkyl(Co-C6)-NRnRn ', ', -0-C yi , -alkyl(C 0 -C 6 )-C yi , -alkenyl(C 2 -C 6 )-C yi , -alkynyl(C 2 -C 6 )-C
  • ⁇ W represents a -CH 2 - group, a -NH- group or an oxygen atom
  • ⁇ Rs represents a hydrogen atom, a linear or branched (Ci-C8)alkyl group, a -CHR a R group, an aryl group, a heteroaryl group, an arylalkyl(Ci-C6) group, or a heteroarylalkyl(Ci-C6) group,
  • ⁇ R represents a hydrogen atom, a linear or branched (Ci-Ce)alkyl group, a linear or branched (C 2 -Ce)alkenyl group, a linear or branched (C 2 -Ce)alkynyl group, -Cy 2 , -alkyl(C 1 -C 6 )-Cy 2 , -alkenyl(C 2 -C 6 )-Cy 2 , -alkynyl(C 2 -C 6 )-Cy 2 , -Cy 2 -Cy 3 , -alkynyl(C 2 -C( 5 )-0-Cy 2 , -Cy 2 -alkyl(Co-C6)-0-alkyl(Co-C6)-Cy 3 , a halogen atom, a cyano group, -C(0)-Ri4, or -C(0)-NRHRI4',
  • ⁇ Rio represents a hydrogen atom, a linear or branched (Ci-Ce)alkyl group, a linear or branched (C 2 -Ce)alkenyl group, a linear or branched (C 2 -Ce)alkynyl group, an arylalkyl(Ci-Ce) group, a cycloalkylalkyl(Ci-C6) group, a linear or branched (Ci-C 6 )polyhaloalkyl, or -alkyl(Ci-C 6 )-0-Cy 4 ,
  • Ri 1 and Ri 1 ' independently of one another represent a hydrogen atom, an optionally substituted linear or branched (Ci-Ce)alkyl group, or -alkyl(Co-C6)-Cyi , or the substituents of the pair (Rn, Rn') form together with the nitrogen atom carrying them an aromatic or non-aromatic ring composed of from 5 to 7 ring members, which may contain in addition to the nitrogen atom from 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen, it being understood that the nitrogen in question may be substituted by from 1 to 2 groups representing a hydrogen atom, or a linear or branched (Ci-C ⁇ 5 )alkyl group and it being understood that one or more of the carbon atoms of the possible substituents, may be deuterated,
  • Ri 2 represents -Cy 5 , -Cy 5 -alkyl(Co-C6)-0-alkyl(Co-C 6 )-Cy6, -Cy 5 -alkyl(Co-C 6 )-Cy 6 , -Cy5-alkyl(Co-C6)-NRii-alkyl(Co-C 6 )-Cy6, -Cy5-Cy6-0-alkyl(Co-C 6 )-Cy7, -Cy 5 -alkyl(Co-C6)-0-alkyl(Co-C 6 )-Cy9, -Cy 5 -alkyl(Co-C 6 )-Cy9, -NH-C(0)-NH-R literally, -Cy 5 -alkyl(Co-C 6 )-NRii-alkyl(Co-C 6 )-Cy 9 , -C(0)-NRiiR n ⁇ -NR n R protest', -OR worship,
  • ammonium so defined it being possible for the ammonium so defined to exist as a zwitterionic form or to have a monovalent anionic counterion,
  • R 1 3 ', Ri 4 and R1 ' independently of one another represent a hydrogen atom, or an optionally substituted linear or branched (Ci-C6)alkyl group,
  • ⁇ R a represents a hydrogen atom or a linear or branched (Ci-Ce)alkyl group
  • R b represents a -0-C(0)-0-Rc group, a -0-C(0)-NR c R c ' group, or a -0-P(0)(ORe) 2 group,
  • R c and R c ' independently of one another represent a hydrogen atom, a linear or branched (Ci-Cs)alkyl group, a cycloalkyl group, a (Ci-C6)alkoxy(Ci-C6)alkyl group, or a (Ci-C6)alkoxycarbonyl(Ci-Ce)alkyl group,
  • Cy9 represents a heteroaryl group which is substituted by a group selected from -O-P(O)(OR 20 ) 2 ; -0-P(0)(O M + ) 2 ; -(CH 2 ) p -O-(CHR 18 -CHR 19 -O) q -R 20 ; hydroxy; hydroxy(Ci-C 6 )alkyl; -(CH 2 ) r -U-(CH 2 ) s -heterocycloalkyl; or -U-(CH 2 ) q -NR 2 iR 2 i ', ⁇ Ri5 represents a hydrogen atom; a -(CH 2 ) p -0-(CHRi8-CHRi9-0) q -R 2 o group; a linear or branched (Ci-C6)alkoxy(Ci-C6)alkyl group; a -U-(CH 2 ) q -NR 2 iR 2 i
  • Ri 6 represents a hydrogen atom; a hydroxy group; a hydroxy(Ci-C6)alkyl group; a -(CH 2 )r-U-(CH 2 )s-heterocycloalkyl group; a (CH 2 ) r -U-V-0-P(0)(OR 2 o)2 group; a -0-P(0)(0 " M + ) 2 group; a -(CH 2 ) p -O-(CHR 18 -CHR 19 -O) q -R 20 group; a -(CH 2 )p-0-C(0)-NR 22 R 23 group; or a -U-(CH 2 ) q -NR 2 iR 2 group,
  • ⁇ Ri7 represents a hydrogen atom; a -(CH 2 ) p -0-(CHRi8-CHRi9-0) q -R 2 o group; a -0-P(0)(OR 2 o) 2 group; a -0-P(0)(0 " M + ) 2 group; a hydroxy group; a hydroxy(Ci-C6)alkyl group; a -(CH 2 ) r -U-(CH 2 ) s -heterocycloalkyl group; a -U-(CH 2 ) q -NR 2 iR 2 i ' group; or an aldonic acid,
  • ⁇ M + represents a pharmaceutically acceptable monovalent cation
  • ⁇ U represents a bond or an oxygen atom
  • ⁇ V represents a -(CH 2 ) S - group or a -C(O)- group
  • ⁇ Ri 8 represents a hydrogen atom or a (Ci-C6)alkoxy(Ci-Ce)alkyl group
  • ⁇ Ri 9 represents a hydrogen atom or a hydroxy(Ci-Ce)alkyl group
  • R 2 o represents a hydrogen atom or a linear or branched (Ci-Ce)alkyl group
  • R 2 i and R 2 i' independently of one another represent a hydrogen atom, a linear or branched (Ci-C6)alkyl group, or a hydroxy(Ci-C6)alkyl group,
  • the substituents of the pair (R 2 i, R 2 i') form together with the nitrogen atom carrying them an aromatic or non-aromatic ring composed of from 5 to 7 ring members, which may contain in addition to the nitrogen atom from 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen, it being understood that the resulting ring may be substituted by a group representing a hydrogen atom or a linear or branched (Ci-Ce)alkyl group,
  • ⁇ R 22 represents a (Ci-C6)alkoxy(Ci-C6)alkyl group, a -(CH 2 ) P - R 2 4R 2 4 ' group, or a -(CH 2 ) p -O-(CHR 18 -CHR 19 -O) q -R 20 group,
  • ⁇ R 2 3 represents a hydrogen atom or a (Ci-C6)alkoxy(Ci-C6)alkyl group
  • R 22 , R 23 form together with the nitrogen atom carrying them an aromatic or non-aromatic ring composed of from 5 to 18 ring members, which may contain in addition to the nitrogen atom from 1 to 5 heteroatoms selected from oxygen, sulphur and nitrogen, it being understood that the resulting ring may be substituted by a group representing a hydrogen atom, a linear or branched (Ci-Ce)alkyl group or a heterocycloalkyl group, ⁇ R24 and R24' independently of one another represent a hydrogen atom or a linear or branched (Ci-C6)alkyl group,
  • R 24 , R24' form together with the nitrogen atom carrying them an aromatic or non-aromatic ring composed of from 5 to 7 ring members, which may contain in addition to the nitrogen atom from 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen, it being understood that the resulting ring may be substituted by a group representing a hydrogen atom or a linear or branched (Ci-Ce)alkyl group,
  • ⁇ R25 represents a hydrogen atom, a hydroxy group, or a hydroxy(Ci-C6)alkyl group
  • ⁇ R26 represents a hydrogen atom, a halogen atom, a linear or branched (Ci-Ce)alkyl group, or a cyano group,
  • ⁇ R27 represents a hydrogen atom or a linear or branched (Ci-Ce)alkyl group
  • ⁇ R 28 represents a -0-P(0)(0 " )(0 " ) group, a -O-P(O)(O ⁇ )(OR 30 ) group, a -0-P(0)(OR 30 )(OR 3 o') group, a -0-S0 2 -0 " group, a -O-SO 2 -OR 30 group, -Cyio, a -0-C(0)-R 2 9 group, a -0-C(0)-OR 29 group or a -0-C(0)-NR 2 9R 2 9 ' group;
  • R2 and R 2 9 ' independently of one another represent a hydrogen atom, a linear or branched (Ci-C6)alkyl group or a linear or branched amino(Ci-C6)alkyl group,
  • R 3 o and R 3 o' independently of one another represent a hydrogen atom, a linear or branched (Ci-C6)alkyl group or an arylalkyl(Ci-C6) group,
  • ⁇ n is an integer equal to 0 or 1 ,
  • ⁇ p is an integer equal to 0, 1 or 2
  • ⁇ q is an integer equal to 1 , 2, 3 or 4,
  • ⁇ r and s are independently an integer equal to 0 or 1 , ing understood that:
  • aryl means a phenyl, naphthyl, biphenyl, indanyl or indenyl group
  • heteroaryl means any mono- or bi-cyclic group composed of from 5 to 10 ring members, having at least one aromatic moiety and containing from 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen,
  • cycloalkyl means any mono- or bi-cyclic non-aromatic carbocyclic group containing from 3 to 10 ring members,
  • heterocycloalkyl means any mono- or bi-cyclic non-aromatic carbocyclic group containing from 3 to 10 ring members, and containing from 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen, which may include fused, bridged or spiro ring systems, it being possible for the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups so defined and the alkyl, alkenyl, alkynyl, alkoxy, to be substituted by from 1 to 4 groups selected from optionally substituted linear or branched (Ci-C6)alkyl, optionally substituted linear or branched (C2-C6)alkenyl group, optionally substituted linear or branched (C2-C6)alkynyl group, optionally substituted linear or branched (Ci-Ce)alkoxy, optionally substituted (Ci-C6)alkyl-S-, hydroxy, oxo (or N-oxide where appropriate), nitro,
  • the taxane compound is selected from paclitaxel, docetaxel, cabazitaxel, tesetaxel, Opaxio® (paclitaxel poliglumex), Abraxane® (nab-paclitaxel) larotaxel, taxoprexin, BMS-184476, hongdoushan A, hongdoushan B, and hongdoushan C, and others.
  • a MCL-1 inhibitor of formula (II) a particular case of MCL-1 inhibitor of formula (I):
  • ⁇ Z represents a nitrogen atom or a C-R4 group
  • ⁇ Ri represents a linear or branched (Ci-C6)alkyl group, a linear or branched (C2-C6)alkenyl group, a linear or branched (C2-C6)alkynyl group, a linear or branched (Ci-C6)alkoxy group, -S-(Ci-Cs)alkyl group, a linear or branched (Ci-C6)polyhaloalkyl, a hydroxy group, a cyano, -NRnRn ', -Cys or a halogen atom,
  • R2, R 3 and R4 independently of one another represent a hydrogen atom, a halogen atom, a linear or branched (Ci-C6)alkyl group, a linear or branched (C2-Ce)alkenyl group, a linear or branched (C 2 -C6)alkynyl group, a linear or branched (Ci-C6)polyhaloalkyl, a hydroxy group, a linear or branched (Ci-C6)alkoxy group, -S-(Ci-C6)alkyl group, a cyano group, a nitro group, -alkyl(Co-C6)-NRnRn ' , -0-C yi , -alkyl(Co-C 6 )-Cyi, -alkenyl(C2-C 6 )-C yi , -alkynyl(C 2 -C 6 )-C yi , -0-alkyl(Ci
  • ⁇ Re and R 7 independently of one another represent a hydrogen atom, a halogen atom, a linear or branched (Ci-Ce)alkyl group, a linear or branched (C 2 -Ce)alkenyl group, a linear or branched (C 2 -Ce)alkynyl group, a linear or branched (Ci-C6)polyhaloalkyl, a hydroxy group, a linear or branched (Ci-Ce)alkoxy group, a -S-(Ci-C(5)alkyl group, a cyano group, a nitro group, -alkyl(Co-C6)-NRnRn', -O-Cyi, -alkyl(C 0 -C 6 )-Cyi, -alkenyl(C2-C6)-Cyi, -alkynyl(C 2 -C6)-C yi , -0-alkyl(Ci
  • ⁇ R represents a hydrogen atom, a linear or branched (Ci-Cs)alkyl group, an aryl group, a heteroaryl group, an arylalkyl(Ci-C ⁇ 5) group, or a heteroarylalkyl(Ci-Ce) group,
  • ⁇ R9 represents a linear or branched (Ci-Ce)alkyl group, a linear or branched (C 2 -C6)alkenyl group, a linear or branched (C 2 -C6)alkynyl group, -Cy 2 , -alkyl(C 1 -C 6 )-Cy 2 , -alkenyl(C 2 -C 6 )-Cy 2 , -alkynyl(C 2 -C 6 )-Cy 2 , -Cy 2 -Cy 3 , -alkynyl(C 2 -C ⁇ 5)-0-Cy 2 , -Cy 2 -alkyl(Co-C6)-0-alkyl(Co-C6)-Cy 3 , a halogen atom, a cyano group, -C(0)-Ri4, or -C(0)- Ri4 i4',
  • Ri 1 and Ri 1 ' independently of one another represent a hydrogen atom, an optionally substituted linear or branched (Ci-Ce)alkyl group, or -alkyl(Co-Cs)-Cyi , or the substituents of the pair (Rn, R11 ') form together with the nitrogen atom carrying them an aromatic or non-aromatic ring composed of from 5 to 7 ring members, which may contain in addition to the nitrogen atom from 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen, it being understood that the nitrogen in question may be substituted by a group representing a hydrogen atom, or a linear or branched (Ci-Ce)alkyl group and it being understood that one or more of the carbon atoms of the possible substituents, may be deuterated,
  • Ri2 represents -Cy 5 , -Cy 5 -alkyl(Co-C6)-Cy 6 , -Cy 5 -alkyl(Co-C6)-0-alkyl(Co-C6)-Cy 6 , -Cy 5 -alkyl(Co-C 6 )-NR 11 -alkyl(Co-C 6 )-Cy 6 , -Cy 5 -Cy 6 -O-alkyl(C 0 -C 6 )-Cy 7 , -C(0)-NRi iRi i ', -NRnRi i ', -ORn , -NRn-C(0)-Rn ⁇ -0-alkyl(Ci-C 6 )-ORn, -SO2-R11, -C(0)-ORi i , or -NH-C(0)-NH-R n ,
  • Ri 3 , R1 3 ', Ri4 and R14' independently of one another represent a hydrogen atom, or an optionally substituted linear or branched (Ci-C6)alkyl group,
  • ⁇ R25 represents a hydrogen atom, a hydroxy group, or a hydroxy(Ci-C ⁇ 5)alkyl group
  • Cyi, Cy2, Cy 3 , Cys, Cy 6 , Cy 7 and Cy 8 independently of one another, represent a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group,
  • ⁇ n is an integer equal to 0 or 1 , it being understood that:
  • aryl means a phenyl, naphthyl, biphenyl, indanyl or indenyl group
  • heteroaryl means any mono- or bi-cyclic group composed of from 5 to 10 ring members, having at least one aromatic moiety and containing from 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen,
  • cycloalkyl means any mono- or bi-cyclic non-aromatic carbocyclic group containing from 3 to 10 ring members,
  • heterocycloalkyl means any mono- or bi-cyclic non-aromatic carbocyclic group containing from 3 to 10 ring members, and containing from 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen, which may include fused, bridged or spiro ring systems, it being possible for the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups so defined and the alkyl, alkenyl, alkynyl, alkoxy, to be substituted by from 1 to 4 groups selected from optionally substituted linear or branched (Ci-C6)alkyl, optionally substituted linear or branched (C2-Ce)alkenyl group, optionally substituted linear or branched (C2-Ce)alkynyl group, optionally substituted linear or branched (Ci-Ce)alkoxy, optionally substituted (Ci-C6)alkyl-S-, hydroxy, oxo (or N-oxide where appropriate),
  • the invention provides a combination comprising:
  • the invention provides a combination comprising:
  • the invention provides a combination comprising:
  • the invention provides a combination as described herein, for use in the treatment of cancer.
  • the invention provides the use of a combination as described herein, in the manufacture of a medicament for the treatment of cancer.
  • the invention provides a medicament containing, separately or together,
  • MCL-1 inhibitor and the taxane compound are provided in effective amounts for the treatment of cancer.
  • the invention provides a method of treating cancer, comprising administering a jointly therapeutically effective amount of:
  • the MCL-1 inhibitor is (2i?)-2- ⁇ [(5&)-5- ⁇ 3-chloro-2-methyl-4-[2- (4-methylpiperazin- 1 -yl)ethoxy]phenyl ⁇ -6-(4-fluorophenyl)thieno[2,3-ii]pyrimidin-4-yl] oxy ⁇ -3-(2- ⁇ [2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy ⁇ phenyl)propanoic acid (Compound 1).
  • the MCL-1 inhibitor is (2 ⁇ )-2- ⁇ [(53 ⁇ 4)-5- ⁇ 3- ⁇ -2 ⁇ 1-4-[2- (4-methylpiperazin-l-yl)ethoxy]phenyl ⁇ -6-(5-fluorofuran-2-yl)thieno[2,3-Jjpyrimidin-4- yl]oxy ⁇ -3-(2- ⁇ [l-(2,2,2-trifluoroethyl)-lH-pyrazol-5-yl]methoxy ⁇ phenyl)propanoic acid (Compound 2).
  • the taxane compound is paclitaxel. In another embodiment, the taxane compound is docetaxel.
  • Figure 1 illustrates matrices for inhibition, Loewe excess inhibition and growth inhibition for paclitaxel combinations with Compound 1 in representative MDA-MB-453 breast cancer cell line.
  • Figure 2 illustrates matrices for inhibition, Loewe excess inhibition and growth inhibition for paclitaxel combinations with Compound 1 in representative MDA-MB-468 breast cancer cell line.
  • Figure 3 illustrates matrices for inhibition, Loewe excess inhibition and growth inhibition for paclitaxel combinations with Compound 1 in representative H522 lung cancer cell line.
  • Figure 4 illustrates exemplary cell growth inhibition effect and synergy combination matrices for inhibition of cell growth (left) and Loewe excess inhibition (right) afforded by Compound 2 in combination with paclitaxel in the breast cancer cell line MDA-MB-453 in two independent experiments.
  • Values in the effect matrix range from 0 (no inhibition) to 100 (total inhibition).
  • Values in the synergy matrix represent the extent of growth inhibition in excess of the theoretical additivity calculated based on the single agent activities of Compound 2 and paclitaxel at the concentrations tested.
  • Figure 5 illustrates exemplary cell growth inhibition effect and synergy combination matrices for inhibition of cell growth (left) and Loewe excess inhibition (right) afforded by Compound 2 in combination with paclitaxel in the lung cancer cell line H522 in two independent experiments.
  • Values in the effect matrix range from 0 (no inhibition) to 100 (total inhibition).
  • Values in the synergy matrix represent the extent of growth inhibition in excess of the theoretical additivity calculated based on the single agent activities of Compound 2 and Paclitaxel at the concentrations tested.
  • Figure 6 illustrates synergistic effect of Compound 2 with docetaxel.
  • SK-BR-3 cells were treated with docetaxel (2 nM), or left untreated in the presence of Compound 2 (30 nM), with or without QVD (10 ⁇ ) for 72 hours before viability analysis with propidium iodide (PI) staining. Results are presented as a percent of untreated cells and represent 3-5 independent experiments.
  • Figure 7 illustrates synergistic effect of Compound 2 with docetaxel.
  • SK-BR-3 cells were treated with increasing concentrations of Compound 2 and docetaxel for 72 hours, then subjected to viability assays using Cell Titer Glo followed by BLISS score analysis.
  • BLISS synergy values are > 0.0 on vertical axis.
  • Figure 8 illustrates efficacy of Compound 2 with docetaxel in improving of animal survival in TNBC PDX models.
  • the PDX 838T model was terminated at 120 days due to age related illness, independent of therapy. Log rank (Mantel-Cox) p value is showing for combination therapy versus docetaxel alone.
  • Figure 9 illustrates the maintaining of normal body weight during therapy.
  • NOD SCID IL2 gamma receptor knockout mice were treated with docetaxel (15 mg/kg, once i.p.) and Compound 2 at 25 or 50 mg/kg (3 mice per group, i.v. injections, once per week for 3 weeks). Their body weight was monitored three times per week for 3 weeks. Compound 2 therapy as single agent or combined with docetaxel was well tolerated.
  • FIG 10 illustrates efficacy of paclitaxel and Compound 1 (named as Compound A in the Figure) alone and in combination in female nude rats bearing MDA-MB-231 xenografts, a model of TNBC.
  • Tumor volumes were estimated using the two largest diameters according to (L x W 2 x ⁇ /6) and body weights were measured 2-3 times per week. Data are presented as means ⁇ SEM or as individual tumor volumes. * p ⁇ 0.05, compared with vehicle group (one way ANOVA with post hoc Dunnett's test).
  • FIG 11 illustrates tolerability of paclitaxel and Compound 1 (named as Compound A in the Figure) alone and in combination in female nude rats bearing MDA-MB-231 xenografts, a model of TNBC.
  • Figure 12 illustrates efficacy of paclitaxel and Compound 1 (named as Compound A in the Figure) alone and in combination at different doses schedules in female nude rats bearing MDA-MB-231 xenografts, a model of TNBC.
  • Tumor volumes were estimated using the two largest diameters according to (L x W 2 x ⁇ /6) and body weights were measured 2-3 times per week. Data are presented as means ⁇ SEM or as individual tumor volumes. * p ⁇ 0.05, compared with vehicle group (one way ANOVA with post hoc Dunnett's test).
  • Figure 13 illustrates tolerability of paclitaxel and Compound 1 (named as Compound A in the Figure) alone and in combination at different doses schedules in female nude rats bearing MDA-MB-231 xenografts, a model of TNBC.
  • Figure 14 illustrates synergistic effect of Compound 1 with docetaxel.
  • Figure 15 illustrates antitumor activity of docetaxel and Compound 1 administrated IV alone and in combination in female SCID mice bearing patient derived TNBC model. Docetaxel was administrated first followed either 30 minutes or 72 hours later with Compound 1.
  • Embodiment El a combination comprising:
  • D represents a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group,
  • E represents a furyl, thienyl or pyrrolyl ring
  • Xi, X3, X 4 and X5 independently of one another represent a carbon atom or a nitrogen atom
  • X 2 represents a C-R 2 6 group or a nitrogen atom
  • Y represents a nitrogen atom or a C-R 3 group
  • Z represents a nitrogen atom or a C-R4 group
  • Ri represents a halogen atom, a linear or branched (Ci-C6)alkyl group, a linear or branched (C2-Ce)alkenyl group, a linear or branched (C2-C6)alkynyl group, a linear or branched (Ci-C6)polyhaloalkyl group, a hydroxy group, a hydroxy(Ci-C6)alkyl group, a linear or branched (Ci-Ce)alkoxy group, -S-(Ci-Ce)alkyl group, a cyano group, a nitro group, -Cy 8 , -alkyl(Co-C6)-NRnRn ', -0-alkyl(Ci-C6)-NRnRn ', -0-alkyl(Ci-C 6 )-Ri2, -C(0)-OR thoughts, -0-C(0)-Rnam, -C(0)-NR fetchR
  • R2, R 3 , R4 and R5 independently of one another represent a hydrogen atom, a halogen atom, a linear or branched (Ci-C6)alkyl group, a linear or branched (C 2 -Ce)alkenyl group, a linear or branched (C 2 -Ce)alkynyl group, a linear or branched (Ci-C6)polyhaloalkyl, a hydroxy group, a hydroxy(Ci-C6)alkyl group, a linear or branched (Ci-Ce)alkoxy group, a -S-(Ci-Ce)alkyl group, a cyano group, a nitro group, -alkyl(C 0 -C 6 )-NRi iRii ⁇ -O-Cyi, -alkyl(C 0 -C 6 )-Cyi , -alkenyl(C 2 -C 6 )-
  • ⁇ Re and R7 independently of one another represent a hydrogen atom, a halogen atom, a linear or branched (Ci-C6)alkyl group, a linear or branched (C 2 -C6)alkenyl group, a linear or branched (C 2 -Ce)alkynyl group, a linear or branched (Ci-C6)polyhaloalkyl, a hydroxy group, a linear or branched (Ci-Ce)alkoxy group, a -S-(Ci-Ce)alkyl group, a cyano group, a nitro group, -alkyl(Co-C6)-NRnRn ', ', -0-C yi , -alkyl(C 0 -C 6 )-C yi , -alkenyl(C 2 -C 6 )-C yi , -alkynyl(C 2 -C 6 )-C
  • ⁇ W represents a -CH 2 - group, a -NH- group or an oxygen atom
  • ⁇ s represents a hydrogen atom, a linear or branched (Ci-C8)alkyl group, a -CHR a R group, an aryl group, a heteroaryl group, an arylalkyl(Ci-Ce) group, or a heteroarylalkyl(Ci-C6) group,
  • ⁇ R represents a hydrogen atom, a linear or branched (Ci-Ce)alkyl group, a linear or branched (C 2 -Ce)alkenyl group, a linear or branched (C 2 -Ce)alkynyl group, -Cy 2 , -alkyl(C 1 -C 6 )-Cy 2 , -alkenyl(C 2 -C 6 )-Cy 2 , -alkynyl(C 2 -C 6 )-Cy 2 , -Cy 2 -Cy 3 , -alkynyl(C 2 -C( 5 )-0-Cy 2 , -Cy 2 -alkyl(Co-C6)-0-alkyl(Co-Ce)-Cy 3 , a halogen atom, a cyano group, -C(0)-Ri4, or -C(0)-NRHRI4',
  • ⁇ Rio represents a hydrogen atom, a linear or branched (Ci-Ce)alkyl group, a linear or branched (C 2 -C6)alkenyl group, a linear or branched (C 2 -C6)alkynyl group, an arylalkyl(Ci-Ce) group, a cycloalkylalkyl(Ci-C6) group, a linear or branched (Ci-C 6 )polyhaloalkyl, or -alkyl(Ci-C 6 )-0-Cy 4 ,
  • Ri 1 and Ri 1 ' independently of one another represent a hydrogen atom, an optionally substituted linear or branched (Ci-Ce)alkyl group, or -alkyl(Co-C6)-Cyi , or the substituents of the pair (Rn, Rn') form together with the nitrogen atom carrying them an aromatic or non-aromatic ring composed of from 5 to 7 ring members, which may contain in addition to the nitrogen atom from 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen, it being understood that the nitrogen in question may be substituted by from 1 to 2 groups representing a hydrogen atom, or a linear or branched (Ci-C ⁇ 5 )alkyl group and it being understood that one or more of the carbon atoms of the possible substituents, may be deuterated,
  • Ri 2 represents -Cy 5 , -Cy 5 -alkyl(Co-C6)-0-alkyl(Co-C 6 )-Cy6, -Cy 5 -alkyl(Co-C 6 )-Cy 6 , -Cy5-alkyl(Co-C6)-NRii-alkyl(Co-C 6 )-Cy6, -Cy5-Cy6-0-alkyl(Co-C 6 )-Cy7, -Cy 5 -alkyl(Co-C6)-0-alkyl(Co-C 6 )-Cy9, -Cy 5 -alkyl(Co-C 6 )-Cy9, -NH-C(0)-NH-R literally, -Cy 5 -alkyl(Co-C 6 )-NRii-alkyl(Co-C 6 )-Cy 9 , -C(0)-NRiiR n ⁇ -NR n R protest', -OR worship,
  • ammonium so defined it being possible for the ammonium so defined to exist as a zwitterionic form or to have a monovalent anionic counterion,
  • Rn', R-14 and R14' independently of one another represent a hydrogen atom, or an optionally substituted linear or branched (Ci-C6)alkyl group,
  • ⁇ R a represents a hydrogen atom or a linear or branched (Ci-Ce)alkyl group
  • R b represents a -0-C(0)-0-Rc group, a -0-C(0)-NR c R c ' group, or a -0-P(0)(ORe) 2 group,
  • Rc and R c ' independently of one another represent a hydrogen atom, a linear or branched (Ci-C 8 )alkyl group, a cycloalkyl group, a (Ci-C6)alkoxy(Ci-C6)alkyl group, or a (Ci-C6)alkoxycarbonyl(Ci-C6)alkyl group,
  • Cy9 represents a heteroaryl group which is substituted by a group selected from -O-P(O)(OR 20 ) 2 ; -0-P(0)(O M + ) 2 ; -(CH 2 ) p -O-(CHR 18 -CHR 19 -O) q -R 20 ; hydroxy; hydroxy(Ci-C 6 )alkyl; -(CH 2 ) r -U-(CH 2 ) s -heterocycloalkyl; or -U-(CH 2 ) q -NR 2 iR 2 i ', ⁇ Ri5 represents a hydrogen atom; a -(CH 2 ) p -0-(CHRi8-CHRi9-0) q -R 2 o group; a linear or branched (Ci-C6)alkoxy(Ci-C6)alkyl group; a -U-(CH 2 ) q -NR 2 iR 2 i
  • Ri 6 represents a hydrogen atom; a hydroxy group; a hydroxy(Ci-C6)alkyl group; a -(CH 2 )r-U-(CH 2 )s-heterocycloalkyl group; a (CH 2 ) r -U-V-0-P(0)(OR 2 o)2 group; a -0-P(0)(0 " M + ) 2 group; a -(CH 2 ) p -O-(CHR 18 -CHR 19 -O) q -R 20 group; a -(CH 2 )p-0-C(0)-NR 22 R 23 group; or a -U-(CH 2 ) q -NR 2 iR 2 group,
  • ⁇ Ri7 represents a hydrogen atom; a -(CH 2 ) p -0-(CHRi8-CHRi9-0) q -R 2 o group; a -0-P(0)(OR 2 o) 2 group; a -0-P(0)(0 " M + ) 2 group; a hydroxy group; a hydroxy(Ci-C6)alkyl group; a -(CH 2 ) r -U-(CH 2 ) s -heterocycloalkyl group; a -U-(CH 2 ) q -NR 2 iR 2 i ' group; or an aldonic acid,
  • ⁇ M + represents a pharmaceutically acceptable monovalent cation
  • ⁇ U represents a bond or an oxygen atom
  • ⁇ V represents a -(CH 2 ) S - group or a -C(O)- group
  • ⁇ Ri 8 represents a hydrogen atom or a (Ci-C6)alkoxy(Ci-Ce)alkyl group
  • ⁇ Ri 9 represents a hydrogen atom or a hydroxy(Ci-Ce)alkyl group
  • R 2 o represents a hydrogen atom or a linear or branched (Ci-Ce)alkyl group
  • R 2 i and R 21 ' independently of one another represent a hydrogen atom, a linear or branched (Ci-C6)alkyl group, or a hydroxy(Ci-C6)alkyl group,
  • the substituents of the pair (R 2 i, R 2 i') form together with the nitrogen atom carrying them an aromatic or non-aromatic ring composed of from 5 to 7 ring members, which may contain in addition to the nitrogen atom from 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen, it being understood that the resulting ring may be substituted by a group representing a hydrogen atom or a linear or branched (Ci-Ce)alkyl group,
  • ⁇ R 22 represents a (Ci-C6)alkoxy(Ci-C6)alkyl group, a -(CH 2 ) P - R 2 4R 2 4 ' group, or a -(CH 2 ) p -O-(CHR 18 -CHR 19 -O) q -R 20 group,
  • ⁇ R 2 3 represents a hydrogen atom or a (Ci-C6)alkoxy(Ci-Ce)alkyl group
  • R 22 , R 23 form together with the nitrogen atom carrying them an aromatic or non-aromatic ring composed of from 5 to 18 ring members, which may contain in addition to the nitrogen atom from 1 to 5 heteroatoms selected from oxygen, sulphur and nitrogen, it being understood that the resulting ring may be substituted by a group representing a hydrogen atom, a linear or branched (Ci-Ce)alkyl group or a heterocycloalkyl group, ⁇ R24 and R24' independently of one another represent a hydrogen atom or a linear or branched (Ci-C6)alkyl group,
  • R 24 , R24' form together with the nitrogen atom carrying them an aromatic or non-aromatic ring composed of from 5 to 7 ring members, which may contain in addition to the nitrogen atom from 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen, it being understood that the resulting ring may be substituted by a group representing a hydrogen atom or a linear or branched (Ci-Ce)alkyl group,
  • ⁇ R25 represents a hydrogen atom, a hydroxy group, or a hydroxy(Ci-C6)alkyl group
  • ⁇ R26 represents a hydrogen atom, a halogen atom, a linear or branched (Ci-Ce)alkyl group, or a cyano group,
  • ⁇ R27 represents a hydrogen atom or a linear or branched (Ci-Ce)alkyl group
  • ⁇ R 28 represents a -0-P(0)(0 " )(0 " ) group, a -O-P(O)(O ⁇ )(OR 30 ) group, a -0-P(0)(OR 30 )(OR 3 o') group, a -0-S0 2 -0 " group, a -O-SO 2 -OR 30 group, -Cyio, a -0-C(0)-R 2 9 group, a -0-C(0)-OR 29 group or a -0-C(0)-NR 2 9R 2 9 ' group;
  • R2 and R 2 9 ' independently of one another represent a hydrogen atom, a linear or branched (Ci-C6)alkyl group or a linear or branched amino(Ci-C6)alkyl group,
  • R 3 o and R 3 o' independently of one another represent a hydrogen atom, a linear or branched (Ci-C6)alkyl group or an arylalkyl(Ci-C6) group,
  • ⁇ n is an integer equal to 0 or 1 ,
  • ⁇ p is an integer equal to 0, 1 or 2
  • ⁇ q is an integer equal to 1 , 2, 3 or 4,
  • ⁇ r and s are independently an integer equal to 0 or 1 , ing understood that:
  • aryl means a phenyl, naphthyl, biphenyl, indanyl or indenyl group
  • heteroaryl means any mono- or bi-cyclic group composed of from 5 to 10 ring members, having at least one aromatic moiety and containing from 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen,
  • cycloalkyl means any mono- or bi-cyclic non-aromatic carbocyclic group containing from 3 to 10 ring members,
  • heterocycloalkyl means any mono- or bi-cyclic non-aromatic carbocyclic group containing from 3 to 10 ring members, and containing from 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen, which may include fused, bridged or spiro ring systems, it being possible for the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups so defined and the alkyl, alkenyl, alkynyl, alkoxy, to be substituted by from 1 to 4 groups selected from optionally substituted linear or branched (Ci-C6)alkyl, optionally substituted linear or branched (C2-C6)alkenyl group, optionally substituted linear or branched (C2-C6)alkynyl group, optionally substituted linear or branched (Ci-Ce)alkoxy, optionally substituted (Ci-C6)alkyl-S-, hydroxy, oxo (or N-oxide where appropriate), nitro,
  • ⁇ Z represents a nitrogen atom or a C-R4 group
  • ⁇ Ri represents a linear or branched (Ci-Ce)alkyl group, a linear or branched (C 2 -Ce)alkenyl group, a linear or branched (C 2 -Ce)alkynyl group, a linear or branched (Ci-Ce)alkoxy group, -S-(Ci-Ce)arkyl group, a linear or branched (Ci-C6)polyhaloalkyl, a hydroxy group, a cyano, -NRnRn ', -Cys or a halogen atom,
  • R2, R 3 and R4 independently of one another represent a hydrogen atom, a halogen atom, a linear or branched (Ci-C6)alkyl group, a linear or branched (C2-Ce)alkenyl group, a linear or branched (C 2 -C6)alkynyl group, a linear or branched (Ci-C6)polyhaloalkyl, a hydroxy group, a linear or branched (Ci-Ce)alkoxy group, -S-(Ci-Ce)alkyl group, a cyano group, a nitro group, -alkyl(Co-C6)-NRnRn', -O-Cyi, -alkyl(C 0 -C 6 )-Cyi, -alkynyl(C 2 -C6)-C yi , -0-alkyl(Ci-C 6 )-R 12 , -C(0)-OR intersect, a
  • ⁇ 3 ⁇ 4 and R 7 independently of one another represent a hydrogen atom, a halogen atom, a linear or branched (Ci-C6)alkyl group, a linear or branched (C 2 -C6)alkenyl group, a linear or branched (C2-C6)alkynyl group, a linear or branched (Ci-Ce)polyhaloalkyl, a hydroxy group, a linear or branched (Ci-Ce)alkoxy group, a -S-(Ci-Ce)alkyl group, a cyano group, a nitro group, -alkyl(Co-C6)-NRnRn', -0-C yi , -alkyl(C 0 -C 6 )-C yi , -alkenyl(C 2 -C 6 )-C yi , -alkynyl(C 2 -C 6 )-C yi
  • ⁇ Rs represents a hydrogen atom, a linear or branched (Ci-Cs)alkyl group, an aryl group, a heteroaryl group, an arylalkyl(Ci-Ce) group, or a heteroarylalkyl(Ci-C6) group,
  • ⁇ R9 represents a linear or branched (Ci-Ce)alkyl group, a linear or branched (C 2 -C6)alkenyl group, a linear or branched (C 2 -C6)alkynyl group, -Cy 2 , -alkyl(Ci-C 6 )-Cy2, -alkenyl(C 2 -C 6 )-Cy 2 , -alkynyl(C 2 -C 6 )-Cy 2 , -Cy 2 -Cy 3 , -alkynyl(C 2 -C6)-0-Cy 2 , -Cy 2 -alkyl(Co-C6)-0-alkyl(Co-C6)-Cy3, a halogen atom, a cyano group, -C(0)-RH, or -C(0)-NRi 4 Ri4 ⁇
  • Ri 1 and Ri 1 ' independently of one another represent a hydrogen atom, an optionally substituted linear or branched (Ci-Ce)alkyl group, or -alkyl(Co-Ce)-Cyi, or the substituents of the pair (Rn, Rn') form together with the nitrogen atom carrying them an aromatic or non-aromatic ring composed of from 5 to 7 ring members, which may contain in addition to the nitrogen atom from 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen, it being understood that the nitrogen in question may be substituted by a group representing a hydrogen atom, or a linear or branched (C 1 -Ce)alkyl group and it being understood that one or more of the carbon atoms of the possible substituents, may be deuterated,
  • ⁇ Ri2 represents -Cy 5 , -Cy 5 -alkyl(Co-C 6 )-Cy 6 , -Cy 5 -alkyl(Co-C 6 )-0-alkyl(Co-C 6 )-Cy 6 , -Cy 5 -alkyl(Co-C6)-NRi i-alkyl(Co-C 6 )-Cy6, -Cy5-Cy6-0-alkyl(Co-C 6 )-Cy 7 , -C(0)-NR n Ri , - Ri iRn ' , -OR theory, -NR purpose-C(0)-R thinking', -0-alkyl(C 1 -C 6 )-OR queue, -SO2-R11, -C(0)-ORi i , or -NH-C(0)-NH-R n ,
  • Ri 3 , R1 3 ', Ri4 and R1 ' independently of one another represent a hydrogen atom, or an optionally substituted linear or branched (Ci-C6)alkyl group,
  • ⁇ R25 represents a hydrogen atom, a hydroxy group, or a hydroxy(Ci-C6)alkyl group
  • Cyi , Cy2, Cy 3 , Cys, Cy 6 , Cy 7 and Cyg independently of one another, represent a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group,
  • ⁇ n is an integer equal to 0 or 1 , it being understood that:
  • aryl means a phenyl, naphthyl, biphenyl, indanyl or indenyl group
  • heteroaryl means any mono- or bi-cyclic group composed of from 5 to 10 ring members, having at least one aromatic moiety and containing from 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen,
  • cycloalkyl means any mono- or bi-cyclic non-aromatic carbocyclic group containing from 3 to 10 ring members,
  • heterocycloalkyl means any mono- or bi-cyclic non-aromatic carbocyclic group containing from 3 to 10 ring members, and containing from 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen, which may include fused, bridged or spiro ring systems, it being possible for the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups so defined and the alkyl, alkenyl, alkynyl, alkoxy, to be substituted by from 1 to 4 groups selected from optionally substituted linear or branched (Ci-Ce)alkyl, optionally substituted linear or branched (C2-Ce)alkenyl group, optionally substituted linear or branched (C2-Ce)alkynyl group, optionally substituted linear or branched (Ci-Ce)alkoxy, optionally substituted (Ci-C6)alkyl-S-, hydroxy, oxo (or N-oxide where appropriate),
  • MCL-1 inhibitor is (2R)-2- ⁇ [(5S a )- 5- ⁇ 3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl ⁇ -6-(5-fluorofuran-2-yl) thieno[2,3-rf]pyrimidin-4-yl]oxy ⁇ -3-(2- ⁇ [l-(2,2,2-trifluoroethyl)-lH-pyrazol-5-yl] methoxy ⁇ phenyl)propanoic acid.
  • E5. A combination according to E l or E2, wherein the MCL-1 inhibitor is (2R)-2- ⁇ [(5S a )- 5- ⁇ 3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl ⁇ -6-(4-fluorophenyl) thieno[2,3-(i]pyrimidin-4-yl]oxy ⁇ -3-(2- ⁇ [2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy ⁇ phenyl)propanoic acid.
  • MCL-1 inhibitor is (2R)-2- ⁇ [(5S a )-5- (3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl ⁇ -6-(4-fiuorophenyl) thieno[2,3-(i]pyrimidin-4-yl]oxy ⁇ -3-(2- ⁇ [2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy ⁇ phenyl)propanoic acid and the taxane compound is paclitaxel.
  • MCL-1 inhibitor is (2R)-2- ⁇ [(5S a )-5- (3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl ⁇ -6-(4-fiuorophenyl) thieno[2,3-(i]pyrimidin-4-yl]oxy ⁇ -3-(2- ⁇ [2-(2-methoxyphenyl)pyrimidin
  • MCL-1 inhibitor is (2R)-2- ⁇ [(5S a )-5- ⁇ 3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl ⁇ -6-(5-fluorofuran-2-yl) thieno[2,3-JJpyrimidin-4-yl]oxy ⁇ -3-(2- ⁇ [l-(2,2,2-trifluoroethyl)-lH-pyrazol-5-yl] methoxy ⁇ phenyl)propanoic acid and the taxane compound is paclitaxel.
  • MCL-1 inhibitor is (2R)-2- ⁇ [(5S a )-5- ⁇ 3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl ⁇ -6-(5-fluorofuran-2-yl) thieno[2,3-JJpyrimidin-4-yl]oxy ⁇ -3-(2- ⁇ [l
  • MCL-1 inhibitor is (2R)-2- ⁇ [(5S a )-5- ⁇ 3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl ⁇ -6-(4-fluorophenyl) thieno[2,3-ii]pyrimidin-4-yl]oxy ⁇ -3-(2- ⁇ [2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy ⁇ phenyl)propanoic acid and the taxane compound is docetaxel.
  • MCL-1 inhibitor is (2R)-2- ⁇ [(5S a )-5- ⁇ 3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl ⁇ -6-(5-fluorofuran-2-yl) thieno[2,3-ti]pyrimidin-4-yl]oxy ⁇ -3-(2- ⁇ [l-(2,2,2-trifluoroethyl)-lH-pyrazol-5-yl] methoxy ⁇ phenyl)propanoic acid and the taxane compound is docetaxel.
  • E12 A combination according to E5, wherein the dose of (2i?)-2- ⁇ [(56 , a )-5- ⁇ 3-chloro-2- methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl ⁇ -6-(4-fluorophenyl)thieno[2,3-JJ pyrimidin-4-yl]oxy ⁇ -3 -(2- ⁇ [2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy ⁇ phenyl) propanoic acid during the combination treatment is from 25 mg to 1500 mg.
  • E20 The combination for use according to any of E16 to El 9, wherein the cancer is breast cancer.
  • E21 The combination for use according to E20, wherein the cancer is triple negative breast cancer, particularly chemoresistant triple negative breast cancer, more particularly, triple negative breast cancer resistant to taxane therapy.
  • E22 The combination for use according to any of E16 to E19, wherein the cancer is lung cancer, particularly non-small cell lung cancer or small cell lung cancer.
  • compositions comprising a combination according to any of El to El 5, in combination with one or more pharmaceutically acceptable excipients.
  • E25 Pharmaceutical compositions according to E24, for use in the treatment of cancer.
  • E26 Pharmaceutical compositions for use according to E25, wherein the cancer is breast cancer.
  • compositions for use according to E26, wherein the cancer is triple negative breast cancer, particularly chemoresistant triple negative breast cancer, more particularly, triple negative breast cancer resistant to taxane therapy.
  • compositions for use according to E25, wherein the cancer is lung cancer, particularly non-small cell lung cancer or small cell lung cancer.
  • E30 The use according to E29, wherein the cancer is breast cancer.
  • E31 The use according to E30, wherein the cancer is triple negative breast cancer, particularly chemoresistant triple negative breast cancer, more particularly, triple negative breast cancer resistant to taxane therapy.
  • E32 The use according to E29, wherein the cancer is lung cancer, particularly non-small cell lung cancer or small cell lung cancer.
  • MCL-1 inhibitor and the taxane compound are provided in effective amounts for the treatment of cancer.
  • a taxane compound for simultaneous, sequential or separate administration, and wherein the MCL-1 inhibitor and the taxane compound are provided in effective amounts for the treatment of cancer.
  • a method of treating cancer comprising administering a jointly therapeutically effective amount of:
  • E36 A method of treating cancer, comprising administering a jointly therapeutically effective amount of:
  • 'Combination' refers to either a fixed dose combination in one unit dosage form (e.g., capsule, tablet, or sachet), non-fixed dose combination, or a kit of parts for the combined administration where a compound of the present invention and one or more combination partners (e.g. another drug as explained below, also referred to as 'therapeutic agent' or ' co-agent') may be administered independently at the same time or separately within time intervals, especially where these time intervals allow that the combination partners show a cooperative, e.g. synergistic effect.
  • a compound of the present invention and one or more combination partners e.g. another drug as explained below, also referred to as 'therapeutic agent' or ' co-agent'
  • 'co-administration' or 'combined administration' or the like as utilized herein are meant to encompass administration of the selected combination partner to a single subject in need thereof (e.g. a patient), and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time.
  • the term 'fixed dose combination means that the active ingredients, e.g. a compound of formula (I) and one or more combination partners, are both administered to a patient simultaneously in the form of a single entity or dosage.
  • non-fixed dose combination means that the active ingredients, e.g. a compound of the present invention and one or more combination partners, are both administered to a patient as separate entities either simultaneously or sequentially, with no specific time limits, wherein such administration provides therapeutically effective levels of the two compounds in the body of the patient.
  • cocktail therapy e.g. the administration of three or more active ingredients.
  • 'Cancer' means a class of disease in which a group of cells display uncontrolled growth. Cancer types include solid tumors including carcinoma, sarcoma, or blastoma. In particular 'cancer' refers to breast and lung cancer.
  • 'jointly therapeutically effective means that the therapeutic agents may be given separately (in a chronologically staggered manner, especially a sequence-specific manner) in such time intervals that they prefer, in the warm-blooded animal, especially human, to be treated, still show a (preferably synergistic) interaction (joint therapeutic effect). Whether this is the case can, inter alia, be determined by following the blood levels, showing that both compounds are present in the blood of the human to be treated at least during certain time intervals.
  • 'Synergistically effective' or 'synergy' means that the therapeutic effect observed following administration of two or more agents is greater than the sum of the therapeutic effects observed following the administration of each single agent.
  • the term 'treat', 'treating' or 'treatment' of any disease or disorder refers in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof).
  • 'treat', 'treating' or 'treatment' refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient.
  • 'treat', 'treating' or 'treatment' refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both.
  • a subject is 'in need of a treatment if such subject would benefit biologically, medically or in quality of life from such treatment.
  • a patient who is sensitized is a patient who is responsive to the treatment involving administration of a MCL-1 inhibitor of formula (I) or formula (II) in combination with a taxane compound, as described herein, or who has not developed resistance to such treatment.
  • 'Medicament' means a pharmaceutical composition, or a combination of several pharmaceutical compositions, which contains one or more active ingredients in the presence of one or more excipients.
  • the proportion of active ingredients by weight is from 5 to 50 %.
  • compositions according to the invention there will be more especially used those which are suitable for administration by the oral, parenteral and especially intravenous, per- or trans-cutaneous, nasal, rectal, perlingual, ocular or respiratory route, more specifically tablets, dragees, sublingual tablets, hard gelatin capsules, glossettes, capsules, lozenges, injectable preparations, aerosols, eye or nose drops, suppositories, creams, ointments, dermal gels etc.
  • compositions according to the invention comprise one or more pharmaceutically acceptable excipients or carriers selected from diluents, lubricants, binders, disintegration agents, stabilizers, preservatives, absorbents, colorants, sweeteners, flavorings etc.
  • ⁇ as diluents: lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycerol,
  • ⁇ as lubricants silica, talc, stearic acid and its magnesium and calcium salts, polyethylene glycol,
  • binders magnesium aluminium silicate, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and polyvinylpyrrolidone,
  • ⁇ as disintegrants agar, alginic acid and its sodium salt, effervescent mixtures.
  • the compounds of the combination may be administered simultaneously or sequentially.
  • the administration route is preferably the intravenous infusion or injection, and the corresponding pharmaceutical compositions may allow the instantaneous or delayed release of the active ingredients.
  • the compounds of the combination may moreover be administered in the form of two separate pharmaceutical compositions, each containing one of the active ingredients, or in the form of a single pharmaceutical composition, in which the active ingredients are in admixture.
  • the useful dosage regimen varies according to the sex, age and weight of the patient, the administration route, the nature of the cancer and of any associated treatments and ranges from 25 mg to 1500 mg of MCL-1 inhibitor per week, more preferably from 50 mg to 1400 mg per week.
  • the dose of the taxane compound will be the same as that used when it is administered on its own.
  • EXAMPLE 1 In vitro effect on proliferation of combining MCL-l inhibitor (Compound 1) with paclitaxel in breast and lung cancer cell lines
  • the effect on proliferation of combining MCL-l inhibitor (Compound 1) with paclitaxel was assessed in a panel of 19 breast cancer cell lines (BT-20, BT-474, BT-549, Cal-148, HCC1143, HCC1395, HCC1500, HCC1937, HCC1954, HCC38, HCC70, Hs 578T, MCF7, MDA-MB-157, MDA-MB-231, MDA-MB-436, MDA-MB-453, MDA-MB-468 and SK-BR-3) and 3 lung cancer cell line (H522, H23 and A549).
  • Compounds were dissolved in 100 % DMSO (Sigma, Catalog #D2438-50ML) at a stock concentration of 10 mM and stored at -20 °C until use. Compounds were arrayed in 2 ml deep 96-well plates (Greiner bio-one, catalog number 780271) serially diluted 3-fold. Compound 1 was used over a concentration range of 0.0 - 10.0 ⁇ . Paclitaxel was used over a concentration range of 0.0 - 1.0 ⁇ in breast cancer cells and 0.0 - 2.0 ⁇ range in lung cancer cells.
  • All cell lines were purchased from the American Type Culture Collection and cultured according to vendor recommendations. All lines were supplemented with 10 % FBS (GIBCO, Catalog number 10099-141). All cell lines were determined to be free of mycoplasma contamination by a PCR detection assay performed at Idexx Radii (Columbia, MO, USA) and authenticated by SNP analysis. Cells were thawed from frozen stocks, expanded through > 1 passage and grown at 37 °C in 5 % CO 2 . Cells were expanded to T-75 flasks and assessed for viability using a Beckman-Coulter ViCell counter prior to plating.
  • cells were dislodged from flasks using 0.25 % Trypsin-EDTA (Corning Costar, Catalog #25-053-CL). Cell proliferation was measured in 72 hours CellTiter-GloTM (CTG) assays and all results shown are the result of at least triplicate measurements.
  • CCG CellTiter-GloTM
  • the cells were dispensed into tissue culture treated 96-well plates (Costar, catalog number 3904) with a final volume of 80 of medium and at density of 3000 cells per well. 16 to 24 hours after plating, 20 of each compound dilution series were transferred to plates containing the cells, resulting in compound concentration ranges stated above and a final DMSO concentration of 0.16 %.
  • the percent growth inhibition, excess inhibition and growth inhibition were calculated using Combo Module software using the Loewe synergy model (as described in Lehar et al., Nature Biotechnology 2009, 27(7), 659-66), which measures the effect on growth above what would be expected if two drugs behaved in a dose additive manner. Positive numbers represent areas of increasing synergy.
  • the percentage of growth inhibition relative to DMSO is displayed in the panel labelled “Inhibition” .
  • the amount of inhibition in excess of the expected amount is in the panel labelled “Loewe Excess Inhibition”.
  • the amount of inhibition normalized to day zero is displayed in the panel labelled "Growth Inhibition”.
  • Concentrations of Compound 1 are shown along the bottom row from left to right and increasing concentrations of paclitaxel along the left most column from bottom to top. All remaining points in the grids display results from a combination of the two inhibitors that correspond to the single agent concentrations denoted on the two axes. Absolute IC5 0 was determined by finding the compound concentration where the calculated curve crosses the 50 % activity mark. Absolute IC50 and synergy score were calculated in Combo module software as described in Lehar et al. 2009. Synergy Score
  • Compound 1 as single agent inhibit the growth of 7/19 breast cancer cell lines and 2/3 lung cancer cell lines, with IC5 0 below 1000 nM (Table 1).
  • Paclitaxel as single agent inhibited the growth of the 17/19 breast cancer cell lines and 3/3 lung cancer cell lines, with IC50 below 1000 nM.
  • EXAMPLE 2 In vitro effect on proliferation of combining MCL-1 inhibitor (Compound 2) with paclitaxel in breast and lung cancer cell lines
  • Cell lines were sourced and maintained in the basic media supplemented with fetal bovine serum as indicated in Table 2. In addition, all media contained penicillin (100 IU/ml), streptomycin (100 ⁇ g/ml) and L-glutamine (2 mM).
  • Cell lines were cultured at 37 °C in a humidified atmosphere containing 5 % CO2 and expanded in T-150 flasks. In all cases cells were thawed from frozen stocks, expanded through > 1 passage using appropriate dilutions, counted and assessed for viability using a CASY cell counter prior to plating 150 ⁇ well at the densities indicated in Table 2 into 96-well plates. All cell lines were determined to be free of mycoplasma contamination in- house.
  • the doubling time indicated in Table 2 is the mean of the doubling time obtained in the different passages (in T-150 flasks) performed from the thawing of the cells to their seeding in the 96-weel plates.
  • Paclitaxel as single agent inhibited the growth of the 2/3 lines tested, with IC5 0 below 1 nM.
  • MCL-1 inhibitor (Compound 2) elicited synergistic activity with agents currently used in the treatment of TNBC.
  • Compound 2 was combined with docetaxel in S -B -3 cells. Material and method
  • the breast cancer cell line SK-BR-3 was maintained in RPMI-1640 plus GlutaMAX-1 (Gibco) supplemented with 10 % fetal calf serum (FCS) and 10 ⁇ g/ml insulin.
  • GlutaMAX-1 GlutaMAX-1
  • FCS fetal calf serum
  • cells were plated at 2 x 10 5 cells/ml in 96 well plates, in RPMI-1640 medium (Gibco) supplemented with 10 % FCS and 10 ⁇ g/ml insulin, and treated with increasing concentrations of Compound 2.
  • Cell viability was assessed using the Cell Titer Glo Luminescent Assay (Promega) as per the manufacturer's instructions.
  • the broad-spectrum caspase inhibitor QVD-OPh hydrate (Sigma- Aldrich) was used at 10 ⁇ .
  • Propidium iodide exclusion (5 ⁇ / ⁇ ) was analyzed by flow cytometry.
  • combination effects were determined using the Bliss independence method (Prichard et al., Antimicrobial Agents and Chemotherapy 1991, 35, 1060-5).
  • Docetaxel and MCL-1 inhibitors showed marked synergy at very low concentrations of both components. Particularly, docetaxel and Compound 2 showed marked synergy at very low concentrations of docetaxel (2 nM) and Compound 2 (31 nM) ( Figures 6 and 7). Inhibition of caspases with the pan-caspase inhibitor QVD-OPH efficiently blocked cell death, confirming that cell death was triggered via apoptosis ( Figure 6).
  • EXAMPLE 4 MCL-1 inhibition sensitizes PDX tumors to taxane treatment in vivo
  • Compound 2 (25 mg/kg) or its vehicle was injected i.v. weekly for six weeks. Compound 2 was dissolved in 20 % (2-hydroxypropyl)-P-cyclodextrin and 25 mM hydrochloric acid. Docetaxel (10 mg/kg i.p.) or its vehicle was prepared as previously described (Oakes et al, Proceedings of the National Academy of Sciences of the USA 2012, 109, 2766-71) and injected i.p. weekly one day prior to Compound 2. Mice were monitored for tumor development three times weekly and tumor size measured using electronic vernier calipers. Tumor volume was estimated by measuring the minimum and maximum tumor diameters using the formula: (minimum diameter) 2 (maximum diameter)/2.
  • mice were randomized into treatment arms. Treatment was initiated when the tumor volume reached 80-120 mm 3 . Randomization and tumor measurements were managed using the Study Director software (v 3.0, studylog). Mice were sacrificed at the first measurement for which tumor volume exceeded 600 mm 3 or animal health deterioration that are not due to disease progression or drug toxicity (mice censored).
  • EXAMPLE 5 MCL-1 inhibitor combined with docetaxel is well tolerated in vivo
  • NOD SCID IL2 gamma receptor knockout mice were treated with docetaxel (15 mg/kg, once i.p.) and Compound 2 at 25 or 50 mg kg (3 mice per group, i.v. injections, once per week for 3 weeks). Their body weight was monitored three times per week for 3 weeks. Compound 2 combined with docetaxel was well-tolerated and did not induce significant body weight loss (Figure 9).
  • EXAMPLE 6 Efficacy of Compound 1 in combination with paclitaxel in MDA-MB- 231 breast xenograft model in nude rats
  • Compound 1 (free base) and paclitaxel (Sandoz) was used in these studies.
  • Paclitaxel was diluted as per manufacturer's instruction with sterile 5 % (w/v) glucose solution to 1.5 mg/ml to administer 7.5 mg/kg in 5 ml/kg dose volume [final ethanol and Cremophor EL concentration was 10 and 15 %, respectively in 5 % (w/v) glucose solution].
  • Compound 1 was formulated in a liposomal formulation (Novartis) at 5 mg/ml to administer 50 mg kg dose in 10 ml/kg dose volume.
  • MDA-MB-231 a triple negative breast cancer cell line, was obtained from ATCC cell bank.
  • the cells were cultured at 37 °C in an atmosphere of 5 % C0 2 in air in DMEM high glucose medium (BioConcept Ltd. Amimed) supplemented with 10 % FCS (BioConcept Ltd. Amimed, # 2-01F36-I) and 4 mM L-glutamine (BioConcept Ltd. Amimed, #5-10K00-H).
  • xenografts To establish MDA-MB-231 xenografts cells were harvested and re- suspended in HBSS (Gibco, #14175) and mixed with Matrigel (BD Bioscience, #354234) (1 : 1 v/v) before injecting 200 containing 1 x 10 7 cells subcutaneously in the right flanks of animals which were anesthetized with isoflurane. Twenty four hours prior to cell inoculation all animals were irradiated with 5 Gy over 2 minutes using a ⁇ -irradiator.
  • the vehicle for paclitaxel or paclitaxel was administered once a week (QW) as a slow bolus dose via a caudal vein 0.5 h or 16 h before the vehicle for Compound 1 or Compound 1 itself in liposomal formulation and these were administered by iv infusion over 15 minutes in a caudal vein.
  • QW a slow bolus dose
  • Tumor volumes were measured using calipers 2-3 times per week.
  • Tumor and body weight change data were analyzed statistically using GraphPad Prism 7.00 (GraphPad Software). If the variances in the data were normally distributed, the data were analyzed using one-way ANOVA with post hoc Dunnett's test for comparison of treatment versus control group. The post hoc Tukey's test was used for intragroup comparison. Otherwise, the Kruskal-Wallis ranked test post hoc Dunn's was used. When applicable, results are presented as mean ⁇ SEM.
  • Tumor regression was calculated according to:
  • Atumor volumes represent the mean tumor volume on the evaluation day minus the mean tumor volume at the start of the experiment.
  • Compound 1 50 mg/kg dosed 0.5 h or 16 h after vehicle for paclitaxel [ethanol : Cremophor EL : 5 % (w/v) glucose (10 : 15 : 75 %)] is well tolerated.
  • Compound 1 (50 mg/kg QW) in liposomal formulation exhibited no efficacy in the MDA- MB-231 xenograft model after QWx7 iv infusion administration ( Figures 10 and 12).
  • EXAMPLE 7 MCL-1 inhibition sensitizes PDX tumors to taxane treatment in vivo
  • TNBC PDXl lO early passage human breast tumors
  • 100,000 cells were resuspended in 10 ⁇ of transplantation buffer (50 % fetal calf serum, 10 % of a 0.04 % trypan blue solution and 40 % PBS) and growth- factor-reduced Matrigel [BD] at a ratio of 3:1, and injected into the cleared mammary fat pads of 3- or 4-week-old NOD-SCID-IL2Ry c ' female mice.
  • Mice were monitored for tumor development three times weekly and tumor size measured using electronic vernier calipers.
  • EXEMPLE 8 Antitumor activity of docetaxel and Compound 1 in female SCID mice bearing patient derived TNBC model
  • Docetaxel was formulated in 5 % ethanol, 5 % PS80 and 90 % Glucose at 0.67 mg/ml to administer 10 mg/kg.
  • Compound 1 was formulated in a liposomal formulation (Novartis) at 7.5 mg/ml to administer 70 mg/kg.
  • Tumor volumes were measured using calipers 2-3 times per week. Tumor volume was calculated using the formula: length x width 2 /2. Animals were also weighed 2-3 times per week and examined frequently for overt signs of any adverse effects.
  • PDX models whose resistance to docetaxel has been confirmed in vivo were tested.
  • Each treatment group included 5 female Swiss Nude mice, aged from 6 to 8 weeks old. The treatment started when xenografts reached a mean tumor volume of ⁇ 120-150 mm 3 . Groups of mice were then randomly affected to the different treatments. The number of grafted animals depended on the homogeneity of the tumor growth.
  • Compound 1 was administered intravenously at 70 mg/kg once a week.
  • the formulation had to be prepared extemporaneously.
  • Paclitaxel diluted in 0.9 % NaCl was given ip at 25 mg/kg.
  • Paclitaxel was given QW 16 hours before the administration of Compound 1.
  • the administration schedule of the different treatments is defined as follows:
  • Tumor sizes were measured twice a week and weights of individual mice were measured once a week. Treatments were done until the median tumor volume of the most responsive group started to regrow. Mice were followed after the stop of the treatment to compare the time to relapse between the groups.
  • tumor volume and/or relative tumor volume ratio of the volume at the time t divided by the initial volume at day 1 and multiplied by 100
  • optimal growth inhibition ratio of RTV (x 100) in the treated group divided by the RTV in the controls
  • growth delay the time in days necessary to multiply by 4 an initial tumor volume of 200 mm 3 in treated group and control group
  • body weight change were compared.
  • mice were rechallenged with the Compound 1 + paclitaxel combination. This was done either by including 10 mice in the paclitaxel treated group and then treated tumor relapsing mice with paclitaxel alone (5 animals) or in combination (5 animals), or by using not randomized mice from the efficacy study. If initial response to paclitaxel was observed, additional animals left after randomization were included for this study. Results Compound 1 alone was insufficient in inhibiting tumor growth. However, we observed a superior activity in combination with paclitaxel as compared to paclitaxel administered as a single agent, resulting in significantly improved antitumor activity in the PDX model resistant to a taxane compound.

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Abstract

L'invention concerne une combinaison comprenant un inhibiteur de MCL-1 et un composé de taxane, ainsi que des compositions la comprenant et ses utilisations.
PCT/EP2018/050298 2017-01-06 2018-01-05 Combinaison d'un inhibiteur de mcl-1 et d'un composé de taxane, ses utilisations et compositions pharmaceutiques la comprenant WO2018127575A1 (fr)

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CU2019000064A CU20190064A7 (es) 2017-01-06 2018-01-05 Combinación de un inhibidor de mcl-1 y un compuesto taxano, y composiciones farmacéuticas de ésta
EA201991623A EA201991623A1 (ru) 2017-06-30 2018-01-05 Комбинация mcl-1 ингибитора и таксанового соединения, их применения и фармацевтические композиции
MX2019008109A MX2019008109A (es) 2017-01-06 2018-01-05 Combinacion de un inhibidor de mcl-1 y un compuesto taxano, usos y composiciones farmaceuticas de esta.
CN201880015906.7A CN110381937A (zh) 2017-01-06 2018-01-05 Mcl-1抑制剂和紫杉烷化合物的组合及其用途和药物组合物
AU2018205735A AU2018205735B2 (en) 2017-01-06 2018-01-05 Combination of a MCL-1 inhibitor and a taxane compound, uses and pharmaceutical compositions thereof
KR1020197022996A KR102576567B1 (ko) 2017-01-06 2018-01-05 Mcl-1 억제제와 탁산 화합물의 조합물, 이의 용도 및 약학적 조성물
JP2019536593A JP7179733B2 (ja) 2017-01-06 2018-01-05 Ｍｃｌ－１阻害剤及びタキサン化合物の組み合わせ物、その使用及び医薬組成物
EP18700861.0A EP3565547B1 (fr) 2017-01-06 2018-01-05 Combinaison d'un inhibiteur de mcl-1 avec compose du taxane, utilisations et compositions pharmaceutiques associées
CA3049095A CA3049095C (fr) 2017-01-06 2018-01-05 Combinaison d'un inhibiteur de mcl-1 et d'un compose de taxane, ses utilisations et compositions pharmaceutiques la comprenant
JOP/2019/0159A JOP20190159B1 (ar) 2017-01-06 2018-01-05 توليفة من مثبط mcl-1 ومركب تاكسان، استخداماتها وتركيباتها الصيدلانية
US16/475,389 US10765680B2 (en) 2017-01-06 2018-01-05 Combination of a MCL-1 inhibitor and a taxane compound, uses and pharmaceutical compositions thereof
RU2019123982A RU2763544C2 (ru) 2017-01-06 2018-01-05 Комбинация mcl-1 ингибитора и таксанового соединения, их применения и фармацевтические композиции
UAA201907499A UA125142C2 (uk) 2017-01-06 2018-01-05 Комбінація інгібітору mcl-1 і таксанової сполуки, її застосування та фармацевтична композиція
BR112019013907A BR112019013907A2 (pt) 2017-01-06 2018-01-05 combinação de um inibidor de mcl-1 e um composto de taxano, usos e composições farmacêuticas dos mesmos
PH12019501451A PH12019501451A1 (en) 2017-01-06 2019-06-21 Combination of a mcl-1 inhibitor and a taxane compound, uses and pharmaceuitcal compositions thereof
ZA2019/04280A ZA201904280B (en) 2017-01-06 2019-06-28 Combination of a mcl-1 inhibitor and a taxane compound, uses and pharmaceutical compositions thereof
IL267791A IL267791B (en) 2017-01-06 2019-07-02 Combination of mcl-1 inhibitor and taxane compound, its uses and pharmaceutical preparations
CONC2019/0007261A CO2019007261A2 (es) 2017-01-06 2019-07-05 Combinación de un inhibidor de mcl-1 y un compuesto taxano, usos y composiciones farmacéuticas de ésta

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WO2020123994A1 (fr) * 2018-12-14 2020-06-18 Prelude Therapeutics, Incorporated Dérivés d'acide 2-((5-(phényl)-pyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)-3-(phényl)propanoïque et composés apparentés servant d'inhibiteurs d'enzyme mcl-1 pour le traitement du cancer
WO2020254299A1 (fr) * 2019-06-17 2020-12-24 Les Laboratoires Servier Combinaison d'un inhibiteur de mcl-1 et d'un standard de traitement de soin pour cancers du sein, utilisations et compositions pharmaceutiques associées
WO2022261301A1 (fr) 2021-06-11 2022-12-15 Gilead Sciences, Inc. Inhibiteurs de mcl-1 en combinaison avec des agents anticancéreux
WO2022261310A1 (fr) 2021-06-11 2022-12-15 Gilead Sciences, Inc. Inhibiteurs de mcl-1 en combinaison avec des conjugués anti-corps-médicament
US11931424B2 (en) 2021-06-11 2024-03-19 Gilead Sciences, Inc. Combination MCL-1 inhibitors with anti-body drug conjugates
US11957693B2 (en) 2021-06-11 2024-04-16 Gilead Sciences, Inc. Combination MCL-1 inhibitors with anti-cancer agents

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