2. Academic Validation
  3. AMG 176, a Selective MCL1 Inhibitor, Is Effective in Hematologic Cancer Models Alone and in Combination with Established Therapies

AMG 176, a Selective MCL1 Inhibitor, Is Effective in Hematologic Cancer Models Alone and in Combination with Established Therapies

  • Cancer Discov. 2018 Dec;8(12):1582-1597. doi: 10.1158/2159-8290.CD-18-0387.
Sean Caenepeel 1 2,  Sean P Brown 3 4,  Brian Belmontes 1 2,  Gordon Moody 1 2,  Kathleen S Keegan 5 6,  Danny Chui 2 7,  Douglas A Whittington 8 9,  Xin Huang 8 9,  Leszek Poppe 2 10,  Alan C Cheng 11 12,  Mario Cardozo 11 12,  Jonathan Houze 9 13,  Yunxiao Li 12 14,  Brian Lucas 12 14,  Nick A Paras 12 14,  Xianghong Wang 12 14,  Joshua P Taygerly 12 14,  Marc Vimolratana 12 14,  Manuel Zancanella 12 14,  Liusheng Zhu 12 14,  Elaina Cajulis 1 2,  Tao Osgood 1 2,  Jan Sun 1 2,  Leah Damon 15,  Regina K Egan 15,  Patricia Greninger 15,  Joseph D McClanaghan 15,  Jianan Gong 16 17,  Donia Moujalled 18,  Giovanna Pomilio 18,  Pedro Beltran 1 2,  Cyril H Benes 15,  Andrew W Roberts 16 17 19 20,  David C Huang 16 17,  Andrew Wei 18,  Jude Canon 1 2,  Angela Coxon 1 2,  Paul E Hughes 21 2
Affiliations

Affiliations

  • 1 Oncology Research, Amgen Inc., Thousand Oaks, California.
  • 2 Amgen Research, Amgen Inc., Thousand Oaks, California.
  • 3 Amgen Research, Amgen Inc., Thousand Oaks, California. phughes@amgen.com seanpomeroy@yahoo.com.
  • 4 Medicinal Chemistry, Amgen Inc., Thousand Oaks, California.
  • 5 Oncology Research, Amgen Inc., Seattle, Washington.
  • 6 Amgen Research, Amgen Inc., Seattle, Washington.
  • 7 Genome Analysis Unit, Amgen Inc., Thousand Oaks, California.
  • 8 Molecular Engineering, Amgen Inc., Cambridge, Massachusetts.
  • 9 Amgen Research, Amgen Inc., Cambridge, Massachusetts.
  • 10 Discovery Attribute Sciences, Amgen Inc., Thousand Oaks, California.
  • 11 Molecular Engineering, Amgen Inc., South San Francisco, California.
  • 12 Amgen Research, Amgen Inc., South San Francisco, California.
  • 13 Medicinal Chemistry, Amgen Inc., Cambridge, Massachusetts.
  • 14 Medicinal Chemistry, Amgen Inc., South San Francisco, California.
  • 15 Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.
  • 16 The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.
  • 17 Department of Medical Biology, University of Melbourne, Melbourne, Australia.
  • 18 Malignant Haematology and Stem Cell Transplantation Service, Alfred Hospital, Melbourne, Australia; and Australian Centre for Blood Diseases, Monash University, Melbourne, Australia.
  • 19 Department of Clinical Haematology and Bone Marrow Transplantation, The Royal Melbourne Hospital, Melbourne, Australia.
  • 20 Victorian Comprehensive Cancer Centre, Parkville, Australia.
  • 21 Oncology Research, Amgen Inc., Thousand Oaks, California. phughes@amgen.com seanpomeroy@yahoo.com.
PMID: 30254093 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-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.

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