AMG 176, a selective MCL1 inhibitor, is effective in hematologic cancer models alone and in combination with established therapies

S Caenepeel; SP Brown; B Belmontes; G Moody; KS Keegan; D Chui; DA Whittington; X Huang; L Poppe; AC Cheng; M Cardozo; J Houze; Y Li; B Lucas; NA Paras; X Wang; JP Taygerly; M Vimolratana; M Zancanella; L Zhu; E Cajulis; T Osgood; J Sun; L Damon; RK Egan; P Greninger; JD McClanaghan; J Gong; D Moujalled; G Pomilio; P Beltran; CH Benes; AW Roberts; DC Huang; A Wei; J Canon; A Coxon; PE Hughes

Journal article

AMG 176, a selective MCL1 inhibitor, is effective in hematologic cancer models alone and in combination with established therapies

S Caenepeel, SP Brown, B Belmontes, G Moody, KS Keegan, D Chui, DA Whittington, X Huang, L Poppe, AC Cheng, M Cardozo, J Houze, Y Li, B Lucas, NA Paras, X Wang, JP Taygerly, M Vimolratana, M Zancanella, L Zhu Show all

Cancer Discovery | Published : 2018

DOI: 10.1158/2159-8290.CD-18-0387

Abstract

The prosurvival BCL2 family member MCL1 is frequently dysregulated in cancer. To overcome the significant challenges associated with inhibition of MCL1 protein–pro-tein interactions, we rigorously applied small-molecule conformational restriction, which culminated in the discovery of AMG 176, the first selective MCL1 inhibitor to be studied in humans. We demonstrate that MCL1 inhibition induces a rapid and committed step toward apoptosis in subsets of hematologic cancer cell lines, tumor xenograft models, and primary patient samples. With the use of a human MCL1 knock-in mouse, we demonstrate that MCL1 inhibition at active doses of AMG 176 is tolerated and correlates with clear pharmacodynam..

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University of Melbourne Researchers

Andrew Roberts Author

David Huang Author

Andrew Wei Author

Grants

Awarded by Amgen

Funding Acknowledgements

This work was supported by Amgen Inc. BAK<SUP>-/-</SUP>BAX<SUP>-/-</SUP> cell line experiments were supported by scholarships, fellowships, and grants from the Australian National Health and Medical Research Council [NHMRC; Research Fellowships to A.W. Roberts and the Department of Community Services and Health (DCSH); Project Grants to DCSH 1057742; Program Grants 1016647, 1016701; Independent Research Institutes Infrastructure Support Scheme grant 9000220], the Cancer Council Victoria (grant-in-aid to A.W. Roberts and DCSH), the Leukemia and Lymphoma Society (SCOR grants 7001-13), the Australian Cancer Research Foundation, and a Victorian State Government Operational Infrastructure Support grant. The authors thank Jin Tang for assistance with protein purification and Victor Cee for critical evaluation of the manuscript. Ben Scott, PhD (Scott Medical Communications, LLC), and Beate Quednau, PhD (Amgen Inc.), provided medical writing assistance funded by Amgen Inc.