- Discovery of S64315, a Potent and Selective Mcl-1 Inhibitor
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Myeloid cell leukemia 1 (Mcl-1) has emerged as an attractive target for cancer therapy. It is an antiapoptotic member of the Bcl-2 family of proteins, whose upregulation in human cancers is associated with high tumor grade, poor survival, and resistance to chemotherapy. Here we report the discovery of our clinical candidate S64315, a selective small molecule inhibitor of Mcl-1. Starting from a fragment derived lead compound, we have conducted structure guided optimization that has led to a significant (3 log) improvement of target affinity as well as cellular potency. The presence of hindered rotation along a biaryl axis has conferred high selectivity to the compounds against other members of the Bcl-2 family. During optimization, we have also established predictive PD markers of Mcl-1 inhibition and achieved both efficient in vitro cell killing and tumor regression in Mcl-1 dependent cancer models. The preclinical candidate has drug-like properties that have enabled its development and entry into clinical trials.
- Szlavik, Zoltan,Csekei, Marton,Paczal, Attila,Szabo, Zoltan B.,Sipos, Szabolcs,Radics, Gabor,Proszenyak, Agnes,Balint, Balazs,Murray, James,Davidson, James,Chen, Ijen,Dokurno, Pawel,Surgenor, Allan E,Daniels, Zoe Marie,Hubbard, Roderick E.,Le Toumelin-Braizat, Ga?tane,Claperon, Audrey,Lysiak-Auvity, Ga?lle,Girard, Anne-Marie,Bruno, Alain,Chanrion, Maia,Colland, Frédéric,Maragno, Ana-Leticia,Demarles, Didier,Geneste, Olivier,Kotschy, Andras
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p. 13762 - 13795
(2020/12/02)
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- MACROCYCLIC MCL-1 INHIBITORS AND METHODS OF USE
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The present disclosure provides for compounds of Formula (I) wherein A2, A3, A4, A6, A7, A8, A15, RA, R5, R9, R10A, R10B, R11, R12, R13, R14, R16, W, X, and Y have any of the values defined in the specification, and pharmaceutically acceptable salts thereof, that are useful as agents in the treatment of diseases and conditions, including cancer. Also provided are pharmaceutical compositions comprising compounds of Formula (I).
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- Macrocyclic MCL-1 inhibitors and methods of use
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The present disclosure provides for compounds of Formula (I) wherein A2, A3, A4, A6, A7, A8, A15, RA, R5, R9, R10A, R10B, R11, R12, R13, R14, R16, W, X, and Y have any of the values defined in the specification, and pharmaceutically acceptable salts thereof, that are useful as agents for the treatment of diseases and conditions, including cancer. Also provided are pharmaceutical compositions comprising compounds of Formula (I).
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- NEW AMINOACID DERIVATIVES, A PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
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Compounds of formula (I): wherein R1, R2, R5, R6, R7, R12, X, Y, A, E and n are as defined in the description. Medicaments.
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- NEW THIENOPYRIMIDINE DERIVATIVES, A PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
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Compounds of formula (I): wherein R1, R2, R3, R4, R5, R6, R7, R12, X, A and n are as defined in the description.
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- Benzimidazole Thiophene Compounds
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The present invention provides benzimidazole thiophene compounds pharmaceutical compositions containing the same, processes for preparing the same and their use as pharmaceutical agents.
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Page/Page column 114
(2009/01/20)
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- BENZIMIDAZOLE THIOPHENE COMPOUNDS
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The present invention provides benzimidazole thiophene compounds pharmaceutical compositions containing the same, processes for preparing the same and their use as pharmaceutical agents.
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Page/Page column 248-249
(2008/06/13)
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