1. AMG 176, a Selective MCL1 Inhibitor, Is Effective in Hematologic Cancer Models Alone and in Combination with Established Therapies
- Author
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Jia-Nan Gong, Angela Coxon, Sean Caenepeel, Cyril H. Benes, Andrew W. Roberts, Tao Osgood, Donia M Moujalled, Elaina Cajulis, Andrew H. Wei, Regina K. Egan, Mario G. Cardozo, Pedro J. Beltran, Liusheng Zhu, Marc Vimolratana, Sean P. Brown, Brian Lucas, Xin Huang, Gordon Moody, Paul E. Hughes, David C.S. Huang, Giovanna Pomilio, Joshua Taygerly, Jan Sun, Danny Chui, Leszek Poppe, Jude Canon, Douglas A. Whittington, Yunxiao Li, Manuel Zancanella, Nick A. Paras, Joseph McClanaghan, Xianghong Wang, Alan C. Cheng, Kathleen S. Keegan, Jonathan B. Houze, Leah J. Damon, Patricia Greninger, and Brian Belmontes
- Subjects
0301 basic medicine ,Apoptosis Inhibitor ,Venetoclax ,business.industry ,Cancer ,Myeloid leukemia ,medicine.disease ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,Oncology ,chemistry ,Apoptosis ,Cell culture ,Pharmacodynamics ,Cancer research ,medicine ,MCL1 ,business - Abstract
The prosurvival BCL2 family member MCL1 is frequently dysregulated in cancer. To overcome the significant challenges associated with inhibition of MCL1 protein–protein 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 pharmacodynamic effects, demonstrated by reductions in B cells, monocytes, and neutrophils. Furthermore, the combination of AMG 176 and venetoclax is synergistic in acute myeloid leukemia (AML) tumor models and in primary patient samples at tolerated doses. These results highlight the therapeutic promise of AMG 176 and the potential for combinations with other BH3 mimetics. Significance: AMG 176 is a potent, selective, and orally bioavailable MCL1 inhibitor that induces a rapid commitment to apoptosis in models of hematologic malignancies. The synergistic combination of AMG 176 and venetoclax demonstrates robust activity in models of AML at tolerated doses, highlighting the promise of BH3-mimetic combinations in hematologic cancers. See related commentary by Leber et al., p. 1511. This article is highlighted in the In This Issue feature, p. 1494
- Published
- 2018