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Research Articles

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

Sean Caenepeel, Sean P. Brown, Brian Belmontes, Gordon Moody, Kathleen S. Keegan, Danny Chui, Douglas A. Whittington, Xin Huang, Leszek Poppe, Alan C. Cheng, Mario Cardozo, Jonathan Houze, Yunxiao Li, Brian Lucas, Nick A. Paras, Xianghong Wang, Joshua P. Taygerly, Marc Vimolratana, Manuel Zancanella, Liusheng Zhu, Elaina Cajulis, Tao Osgood, Jan Sun, Leah Damon, Regina K. Egan, Patricia Greninger, Joseph D. McClanaghan, Jianan Gong, Donia Moujalled, Giovanna Pomilio, Pedro Beltran, Cyril H. Benes, Andrew W. Roberts, David C. Huang, Andrew Wei, Jude Canon, Angela Coxon and Paul E. Hughes
Sean Caenepeel
1Oncology Research, Amgen Inc., Thousand Oaks, California.
2Amgen Research, Amgen Inc., Thousand Oaks, California.
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  • ORCID record for Sean Caenepeel
Sean P. Brown
2Amgen Research, Amgen Inc., Thousand Oaks, California.
3Medicinal Chemistry, Amgen Inc., Thousand Oaks, California.
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  • ORCID record for Sean P. Brown
  • For correspondence: phughes@amgen.com seanpomeroy@yahoo.com
Brian Belmontes
1Oncology Research, Amgen Inc., Thousand Oaks, California.
2Amgen Research, Amgen Inc., Thousand Oaks, California.
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Gordon Moody
1Oncology Research, Amgen Inc., Thousand Oaks, California.
2Amgen Research, Amgen Inc., Thousand Oaks, California.
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Kathleen S. Keegan
4Oncology Research, Amgen Inc., Seattle, Washington.
5Amgen Research, Amgen Inc., Seattle, Washington.
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Danny Chui
2Amgen Research, Amgen Inc., Thousand Oaks, California.
6Genome Analysis Unit, Amgen Inc., Thousand Oaks, California.
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Douglas A. Whittington
7Molecular Engineering, Amgen Inc., Cambridge, Massachusetts.
8Amgen Research, Amgen Inc., Cambridge, Massachusetts.
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Xin Huang
7Molecular Engineering, Amgen Inc., Cambridge, Massachusetts.
8Amgen Research, Amgen Inc., Cambridge, Massachusetts.
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  • ORCID record for Xin Huang
Leszek Poppe
2Amgen Research, Amgen Inc., Thousand Oaks, California.
9Discovery Attribute Sciences, Amgen Inc., Thousand Oaks, California.
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Alan C. Cheng
10Molecular Engineering, Amgen Inc., South San Francisco, California.
11Amgen Research, Amgen Inc., South San Francisco, California.
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Mario Cardozo
10Molecular Engineering, Amgen Inc., South San Francisco, California.
11Amgen Research, Amgen Inc., South San Francisco, California.
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Jonathan Houze
8Amgen Research, Amgen Inc., Cambridge, Massachusetts.
12Medicinal Chemistry, Amgen Inc., Cambridge, Massachusetts.
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Yunxiao Li
11Amgen Research, Amgen Inc., South San Francisco, California.
13Medicinal Chemistry, Amgen Inc., South San Francisco, California.
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Brian Lucas
11Amgen Research, Amgen Inc., South San Francisco, California.
13Medicinal Chemistry, Amgen Inc., South San Francisco, California.
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Nick A. Paras
11Amgen Research, Amgen Inc., South San Francisco, California.
13Medicinal Chemistry, Amgen Inc., South San Francisco, California.
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  • ORCID record for Nick A. Paras
Xianghong Wang
11Amgen Research, Amgen Inc., South San Francisco, California.
13Medicinal Chemistry, Amgen Inc., South San Francisco, California.
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Joshua P. Taygerly
11Amgen Research, Amgen Inc., South San Francisco, California.
13Medicinal Chemistry, Amgen Inc., South San Francisco, California.
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Marc Vimolratana
11Amgen Research, Amgen Inc., South San Francisco, California.
13Medicinal Chemistry, Amgen Inc., South San Francisco, California.
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Manuel Zancanella
11Amgen Research, Amgen Inc., South San Francisco, California.
13Medicinal Chemistry, Amgen Inc., South San Francisco, California.
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Liusheng Zhu
11Amgen Research, Amgen Inc., South San Francisco, California.
13Medicinal Chemistry, Amgen Inc., South San Francisco, California.
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Elaina Cajulis
1Oncology Research, Amgen Inc., Thousand Oaks, California.
2Amgen Research, Amgen Inc., Thousand Oaks, California.
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Tao Osgood
1Oncology Research, Amgen Inc., Thousand Oaks, California.
2Amgen Research, Amgen Inc., Thousand Oaks, California.
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Jan Sun
1Oncology Research, Amgen Inc., Thousand Oaks, California.
2Amgen Research, Amgen Inc., Thousand Oaks, California.
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Leah Damon
14Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.
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Regina K. Egan
14Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.
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Patricia Greninger
14Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.
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Joseph D. McClanaghan
14Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.
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Jianan Gong
15The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.
16Department of Medical Biology, University of Melbourne, Melbourne, Australia.
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Donia Moujalled
17Malignant Haematology and Stem Cell Transplantation Service, Alfred Hospital, Melbourne, Australia; and Australian Centre for Blood Diseases, Monash University, Melbourne, Australia.
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Giovanna Pomilio
17Malignant Haematology and Stem Cell Transplantation Service, Alfred Hospital, Melbourne, Australia; and Australian Centre for Blood Diseases, Monash University, Melbourne, Australia.
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Pedro Beltran
1Oncology Research, Amgen Inc., Thousand Oaks, California.
2Amgen Research, Amgen Inc., Thousand Oaks, California.
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Cyril H. Benes
14Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.
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Andrew W. Roberts
15The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.
16Department of Medical Biology, University of Melbourne, Melbourne, Australia.
18Department of Clinical Haematology and Bone Marrow Transplantation, The Royal Melbourne Hospital, Melbourne, Australia.
19Victorian Comprehensive Cancer Centre, Parkville, Australia.
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David C. Huang
15The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.
16Department of Medical Biology, University of Melbourne, Melbourne, Australia.
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Andrew Wei
17Malignant Haematology and Stem Cell Transplantation Service, Alfred Hospital, Melbourne, Australia; and Australian Centre for Blood Diseases, Monash University, Melbourne, Australia.
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Jude Canon
1Oncology Research, Amgen Inc., Thousand Oaks, California.
2Amgen Research, Amgen Inc., Thousand Oaks, California.
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Angela Coxon
1Oncology Research, Amgen Inc., Thousand Oaks, California.
2Amgen Research, Amgen Inc., Thousand Oaks, California.
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Paul E. Hughes
1Oncology Research, Amgen Inc., Thousand Oaks, California.
2Amgen Research, Amgen Inc., Thousand Oaks, California.
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  • For correspondence: phughes@amgen.com seanpomeroy@yahoo.com
DOI: 10.1158/2159-8290.CD-18-0387 Published December 2018
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This article has a correction. Please see:

  • Correction: AMG 176, a Selective MCL1 Inhibitor, Is Effective in Hematologic Cancer Models Alone and in Combination with Established Therapies - July 1, 2019

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

Footnotes

  • Note: Supplementary data for this article are available at Cancer Discovery Online (http://cancerdiscovery.aacrjournals.org/).

  • Affiliations of G. Moody, K.S. Keegan, D. Chui, D.A. Whittington, A.C. Cheng, M. Cardozo, B. Lucas, N.A. Paras, X. Wang, J.P. Taygerly, M. Vimolratana, M. Zancanella, L. Zhu, and P. Beltran at the time the research was conducted.

  • Received April 9, 2018.
  • Revision received August 29, 2018.
  • Accepted September 24, 2018.
  • Published first September 25, 2018.
  • Corrected online May 29, 2019.
  • ©2018 American Association for Cancer Research.
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Cancer Discovery: 8 (12)
December 2018
Volume 8, Issue 12
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AMG 176, a Selective MCL1 Inhibitor, Is Effective in Hematologic Cancer Models Alone and in Combination with Established Therapies
Sean Caenepeel, Sean P. Brown, Brian Belmontes, Gordon Moody, Kathleen S. Keegan, Danny Chui, Douglas A. Whittington, Xin Huang, Leszek Poppe, Alan C. Cheng, Mario Cardozo, Jonathan Houze, Yunxiao Li, Brian Lucas, Nick A. Paras, Xianghong Wang, Joshua P. Taygerly, Marc Vimolratana, Manuel Zancanella, Liusheng Zhu, Elaina Cajulis, Tao Osgood, Jan Sun, Leah Damon, Regina K. Egan, Patricia Greninger, Joseph D. McClanaghan, Jianan Gong, Donia Moujalled, Giovanna Pomilio, Pedro Beltran, Cyril H. Benes, Andrew W. Roberts, David C. Huang, Andrew Wei, Jude Canon, Angela Coxon and Paul E. Hughes
Cancer Discov December 1 2018 (8) (12) 1582-1597; DOI: 10.1158/2159-8290.CD-18-0387

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AMG 176, a Selective MCL1 Inhibitor, Is Effective in Hematologic Cancer Models Alone and in Combination with Established Therapies
Sean Caenepeel, Sean P. Brown, Brian Belmontes, Gordon Moody, Kathleen S. Keegan, Danny Chui, Douglas A. Whittington, Xin Huang, Leszek Poppe, Alan C. Cheng, Mario Cardozo, Jonathan Houze, Yunxiao Li, Brian Lucas, Nick A. Paras, Xianghong Wang, Joshua P. Taygerly, Marc Vimolratana, Manuel Zancanella, Liusheng Zhu, Elaina Cajulis, Tao Osgood, Jan Sun, Leah Damon, Regina K. Egan, Patricia Greninger, Joseph D. McClanaghan, Jianan Gong, Donia Moujalled, Giovanna Pomilio, Pedro Beltran, Cyril H. Benes, Andrew W. Roberts, David C. Huang, Andrew Wei, Jude Canon, Angela Coxon and Paul E. Hughes
Cancer Discov December 1 2018 (8) (12) 1582-1597; DOI: 10.1158/2159-8290.CD-18-0387
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