The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models

被引：789

作者：

Kotschy, Andras ^{[1
]}

Szlavik, Zoltan ^{[1
]}

Murray, James ^{[2
]}

Davidson, James ^{[2
]}

Maragno, Ana Leticia ^{[3
]}

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

Chanrion, Maia ^{[3
]}

Kelly, Gemma L. ^{[4
,5
]}

Gong, Jia-Nan ^{[4
,5
]}

Moujalled, Donia M. ^{[6
]}

Bruno, Alain ^{[3
]}

Sekei, Marton C. ^{[1
]}

Paczal, Attila ^{[1
]}

Szabo, Zoltan B. ^{[1
]}

Sipos, Szabolcs ^{[1
]}

Radics, Gabor ^{[1
]}

Proszenyak, Agnes ^{[1
]}

Balint, Balazs ^{[1
]}

Ondi, Levente ^{[1
]}

Blasko, Gabor ^{[1
]}

Robertson, Alan ^{[2
]}

Surgenor, Allan ^{[2
]}

Dokurno, Pawel ^{[2
]}

Chen, Ijen ^{[2
]}

Matassova, Natalia ^{[2
]}

Smith, Julia ^{[2
]}

Pedder, Christopher ^{[2
]}

Graham, Christopher ^{[2
]}

Studeny, Aurelie ^{[3
]}

Lysiak-Auvity, Gaelle ^{[3
]}

Girard, Anne-Marie ^{[3
]}

Grave, Fabienne ^{[3
]}

Segal, David ^{[4
,5
]}

Riffkin, Chris D. ^{[4
,5
]}

Pomilio, Giovanna ^{[6
]}

Galbraith, Laura C. A. ^{[4
,5
]}

Aubrey, Brandon J. ^{[4
,5
,7
]}

Brennan, Margs S. ^{[4
,5
]}

Herold, Marco J. ^{[4
,5
]}

Chang, Catherine ^{[4
,5
]}

Guasconi, Ghislaine ^{[3
]}

Auquil, Nicolas C. ^{[3
]}

Melchiore, Fabien ^{[8
]}

Guigal-Stephan, Nolwen ^{[8
]}

Lockhart, Brian ^{[8
]}

Colland, Frederic ^{[3
]}

Hickman, John A. ^{[3
]}

Roberts, Andrew W. ^{[4
,5
,9
]}

Huang, David C. S. ^{[4
,5
]}

Wei, Andrew H. ^{[6
,10
]}

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 Oncol, R&D Unit, F-78290 Croissy Sur Seine, France

[4] Walter & Eliza Hall Inst Med Res, Melbourne, Vic 3052, Australia

[5] Univ Melbourne, Dept Med Biol, Melbourne, Vic 3010, Australia

[6] Monash Univ, Australian Ctr Blood Dis, Melbourne, Vic 3004, Australia

[7] Royal Melbourne Hosp, Victorian Comprehens Canc Ctr, Dept Clin Haematol & Bone Marrow Transplantat, Melbourne, Vic 3050, Australia

[8] Inst Rech Servier, Biomarker Res Div, F-78290 Croissy Sur Seine, France

[9] Univ Melbourne, Fac Med, Melbourne, Vic 3010, Australia

[10] Alfred Hosp, Dept Clin Haematol, Melbourne, Vic 3004, Australia

[11] Univ Melbourne, Dept Pharmacol & Pharmaceut, Melbourne, Vic 3010, Australia

来源：

NATURE | 2016年 / 538卷 / 7626期

基金：

英国医学研究理事会;

关键词：

ANTI-APOPTOTIC MCL-1; BCL-XL; MULTIPLE-MYELOMA; HIGH-AFFINITY; TUMOR-CELLS; SURVIVAL; PROTEIN; COMBINATION; DEPENDENCY; NAVITOCLAX;

D O I：

10.1038/nature19830

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Avoidance of apoptosis is critical for the development and sustained growth of tumours. The pro-survival protein myeloid cell leukemia 1 (MCL1) is overexpressed in many cancers, but the development of small molecules targeting this protein that are amenable for clinical testing has been challenging. Here we describe S63845, a small molecule that specifically binds with high affinity to the BH3-binding groove of MCL1. Our mechanistic studies demonstrate that S63845 potently kills MCL1-dependent cancer cells, including multiple myeloma, leukaemia and lymphoma cells, by activating the BAX/BAK-dependent mitochondrial apoptotic pathway. In vivo, S63845 shows potent anti-tumour activity with an acceptable safety margin as a single agent in several cancers. Moreover, MCL1 inhibition, either alone or in combination with other anti-cancer drugs, proved effective against several solid cancer-derived cell lines. These results point towards MCL1 as a target for the treatment of a wide range of tumours.

引用

页码：477 / +

页数：20

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