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

A Kotschy; Z Szlavik; J Murray; J Davidson; AL Maragno; G Le Toumelin-Braizat; M Chanrion; GL Kelly; JN Gong; DM Moujalled; A Bruno; M Csekei; A Paczal; ZB Szabo; S Sipos; G Radics; A Proszenyak; B Balint; L Ondi; G Blasko; A Robertson; A Surgenor; P Dokurno; I Chen; N Matassova; J Smith; C Pedder; C Graham; A Studeny; G Lysiak-Auvity; AM Girard; F Gravé; D Segal; CD Riffkin; G Pomilio; LCA Galbraith; BJ Aubrey; MS Brennan; MJ Herold; C Chang; G Guasconi; N Cauquil; F Melchiore; N Guigal-Stephan; B Lockhart; F Colland; JA Hickman; AW Roberts; DCS Huang; AH Wei; A Strasser; G Lessene; O Geneste

Journal article

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

A Kotschy, Z Szlavik, J Murray, J Davidson, AL Maragno, G Le Toumelin-Braizat, M Chanrion, GL Kelly, JN Gong, DM Moujalled, A Bruno, M Csekei, A Paczal, ZB Szabo, S Sipos, G Radics, A Proszenyak, B Balint, L Ondi, G Blasko Show all

Nature | Published : 2016

DOI: 10.1038/nature19830

Abstract

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 ac..

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University of Melbourne Researchers

Gemma Kelly Author

Marco Herold Author

Andrew Roberts Author

David Huang Author

Grants

Awarded by Australian Cancer Research Foundation

Funding Acknowledgements

We thank S. Courtade-Gaiani and D. Valour for bioinformatics support, E. Borges for assistance on manuscript formatting, E. Schneider and C. Wagner-Legrand, H. Johnson, G. Siciliano and K. Hughes for technical help for in vivo studies, N. Whitehead for protein production support, P. Bouillet and L. A. O'Reilly for assistance with histology, M. Fallowfield, J. D'Alessandro, L. Terry, V. Lemesre, J.-P. Galizzi and C. de la Moureyre for in vitro assay support, H. Simmonite for analytical support and L. Andrieu, L. Montane and A. Schmutz for biostatistical support. Research at WEHI is supported by the National Health and Medical Research Council Australia (NHMRC, GNT1016647, GNT1016701, GNT1020363, GNT1086291, GNT1049720, GNT1057742, GNT1079560), the Leukemia and Lymphoma Society (SCOR grant 7001-03), The Cancer Council (1086157 GLK, grant in aid to A.W.R. and D. C. S. H.), The Kay Kendall Leukemia Fund Intermediate Fellowship (KKL331 to G. L. K.), the Victoria Cancer Agency, the Australian Cancer Research Foundation, a Victorian State Government Operational Infrastructure Support (OIS) grant and the estate of Anthony (Toni) Redstone OAM.