Discovery of S64315, a Potent and Selective Mcl-1 Inhibitor

被引：58

作者：

Szlavik, Zoltan ^{[1
]}

Csekei, Marton ^{[1
]}

Paczal, Attila ^{[1
]}

Szabo, Zoltan B. ^{[1
]}

Sipos, Szabolcs ^{[1
]}

Radics, Gabor ^{[1
]}

Proszenyak, Agnes ^{[1
]}

Balint, Balazs ^{[1
]}

Murray, James ^{[2
]}

Davidson, James ^{[2
]}

Chen, Ijen ^{[2
]}

Dokurno, Pawel ^{[2
]}

Surgenor, Allan E. ^{[2
]}

Daniels, Zoe Marie ^{[2
]}

Hubbard, Roderick E. ^{[2
]}

Le Toumelin-Braizat, Gaetane ^{[3
]}

Claperon, Audrey ^{[3
]}

Lysiak-Auvity, Gaelle ^{[3
]}

Girard, Anne-Marie ^{[3
]}

Bruno, Alain ^{[3
]}

Chanrion, Maia ^{[3
]}

Colland, Frederic ^{[3
]}

Maragno, Ana-Leticia ^{[3
]}

Demarles, Didier ^{[4
]}

Geneste, Olivier ^{[3
]}

Kotschy, Andras ^{[1
]}

机构：

[1] Servier Res Inst Med Chem, H-1031 Budapest, Hungary

[2] Vernalis R&D Ltd, Cambridge CB21 6GB, England

[3] Inst Rech Servier, F-78290 Croissy Sur Seine, France

[4] Technol Servier, F-45000 Orleans, France

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2020年 / 63卷 / 22期

关键词：

CANCER; SURVIVAL; SERIES; BCL-2;

D O I：

10.1021/acs.jmedchem.0c01234

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：13762 / 13795

页数：34

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