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Cancer Discov. 2018 Dec;8(12):1582-1597. doi: 10.1158/2159-8290.CD-18-0387. Epub 2018 Sep 25.

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

Caenepeel S1,2, Brown SP3,4, Belmontes B1,2, Moody G1,2, Keegan KS5,6, Chui D2,7, Whittington DA8,9, Huang X8,9, Poppe L2,10, Cheng AC11,12, Cardozo M11,12, Houze J9,13, Li Y12,14, Lucas B12,14, Paras NA12,14, Wang X12,14, Taygerly JP12,14, Vimolratana M12,14, Zancanella M12,14, Zhu L12,14, Cajulis E1,2, Osgood T1,2, Sun J1,2, Damon L15, Egan RK15, Greninger P15, McClanaghan JD15, Gong J16,17, Moujalled D18, Pomilio G18, Beltran P1,2, Benes CH15, Roberts AW16,17,19,20, Huang DC16,17, Wei A18, Canon J1,2, Coxon A1,2, Hughes PE21,2.

Author information

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.

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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