AMG 176, a Selective MCL1 Inhibitor, Is Effective in Hematologic Cancer Models Alone and in Combination with Established Therapies
Open accessAbstract
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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Sensitivity of cancer cells to MCL-1 inhibition is inversely related to BCL-XL expression level and the capacity for BCL-XL to neutralize pro-apoptotic BH3 proteins such as BIM.
“Prior studies have demonstrated that sensitivity of cancer cells to MCL-1 inhibition is inversely related to BCL-XL expression level and the capacity for BCL-XL to neutralize pro-apoptotic BH3 proteins such as BIM60,61.”
From LKB1 regulates JNK-dependent stress signaling and apoptotic dependency of KRAS-mutant lung cancers (2025) · cites this paper as [61]
The biomarker analysis (p. 7) identifies high BCL-xL expression as the strongest predictor of resistance to MCL1 inhibition, supporting the inverse relationship with sensitivity. The Introduction (p. 2) describes antiapoptotic proteins binding BH3-only proteins such as BIM, but the paper does not establish that BCL-xL’s capacity to neutralize BIM predicts sensitivity. (LLM, conf=0.85)
Experimental — accuracy not yet measuredDecreased B cells and monocytes were observed, with no additional effects in combination with sotorasib compared with AMG 176 alone.
“Consistent with the expected effects of on-target MCL-1 inhibition61, we observed decreased B cells and monocytes, however no additional effects were observed in combination with sotorasib compared with AMG 176 alone (Fig. S13E).”
From LKB1 regulates JNK-dependent stress signaling and apoptotic dependency of KRAS-mutant lung cancers (2025) · cites this paper as [61]
In humanized MCL-1 knock-in mice, the combination of sotorasib with AMG 176 was well tolerated with no overt signs of toxicity.
“In humanized MCL-1 knock-in mice61 the combination of sotorasib with AMG 176 was well tolerated with no overt signs of toxicity (Fig. S13D).”
From LKB1 regulates JNK-dependent stress signaling and apoptotic dependency of KRAS-mutant lung cancers (2025) · cites this paper as [61]
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Cites
Hallmarks of Cancer: The Next Generation
Hanahan, D., & Weinberg, R. A. (2011) · Cell · doi:10.1016/j.cell.2011.02.013 · Cited by 66,590 · see citing works
The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity
Barretina, J., Caponigro, G., Stransky, N., Venkatesan, K., Margolin, A. A., Kim, S., Wilson, C. J., Lehár, J., Kryukov, G. V., Sonkin, D., et al. (2012) · Nature · doi:10.1038/nature11003 · Cited by 7,950 · see citing works
Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy
Czabotar, P. E., Lessene, G., Strasser, A., & Adams, J. M. (2014) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3722 · Cited by 3,219 · see citing works
Systematic identification of genomic markers of drug sensitivity in cancer cells
Garnett, M. J., Edelman, E. J., Heidorn, S. J., Greenman, C. D., Dastur, A., Lau, K. W., Greninger, P., Thompson, I. R., Luo, X., Soares, J., et al. (2012) · Nature · doi:10.1038/nature11005 · Cited by 2,456 · see citing works
Self-citationThe Bcl-2 apoptotic switch in cancer development and therapy
Adams, J. M., & Cory, S. (2007) · Oncogene · doi:10.1038/sj.onc.1210220 · Cited by 2,178 · see citing works
Targeting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia
Roberts, A. W., Davids, M. S., Pagel, J. M., Kahl, B. S., Puvvada, S. D., Gerecitano, J. F., Kipps, T. J., Anderson, M. A., Brown, J. R., Gressick, L. A., et al. (2015) · New England Journal of Medicine · doi:10.1056/nejmoa1513257 · Cited by 1,901 · see citing works
Self-citation‘Acute myeloid leukemia: a comprehensive review and 2016 update’
de Kouchkovsky, I., & Abdul‐Hay, M. (2016) · Blood Cancer Journal · doi:10.1038/bcj.2016.50 · Cited by 1,326 · see citing works
van Delft, M. F., Wei, A. H., Mason, K. D., Vandenberg, C. J., Chen, L., Czabotar, P. E., Willis, S. N., Scott, C. L., Day, C. L., Cory, S., et al. (2006) · Cancer Cell · doi:10.1016/j.ccr.2006.08.027 · Cited by 1,237 · see citing works
Self-citationKonopleva, M. Y., Pollyea, D. A., Potluri, J., Chyla, B., Hogdal, L. J., Busman, T. A., McKeegan, E. M., Salem, A. H., Zhu, M., Ricker, J. L., et al. (2016) · Cancer Discovery · doi:10.1158/2159-8290.cd-16-0313 · Cited by 1,067 · see citing works
A Common Mechanism Underlying Promiscuous Inhibitors from Virtual and High-Throughput Screening
McGovern, S. L., Caselli, E., Grigorieff, N., & Shoichet, B. K. (2002) · Journal of Medicinal Chemistry · doi:10.1021/jm010533y · Cited by 1,048 · see citing works
The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models
Kotschy, A., Szlavik, Z., Murray, J., Davidson, J., Maragno, A. L., Le Toumelin-Braizat, G., Chanrion, M., Kelly, G. L., Gong, J.-N., Moujalled, D. M., et al. (2016) · Nature · doi:10.1038/nature19830 · Cited by 1,047 · see citing works
Self-citationTwenty years on: the impact of fragments on drug discovery
Erlanson, D. A., Fesik, S. W., Hubbard, R. E., Jahnke, W., & Jhoti, H. (2016) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2016.109 · Cited by 1,000 · cited 1× · see citing works
“019,24]pentacosa[8,16,18,24] tetraen]-15′-one-13′, 13′-dioxide) and other small-molecule inhibitors of MCL1 described were synthesized at Amgen Inc.”
BackgroundFrom basic apoptosis discoveries to advanced selective BCL-2 family inhibitors
Ashkenazi, A., Fairbrother, W. J., Leverson, J. D., & Souers, A. J. (2017) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2016.253 · Cited by 903 · see citing works
Multiple Myeloma: Diagnosis and Treatment
Rajkumar, S. V., & Kumar, S. (2016) · Mayo Clinic Proceedings · doi:10.1016/j.mayocp.2015.11.007 · Cited by 812 · see citing works
Sensitivity to antitubulin chemotherapeutics is regulated by MCL1 and FBW7
Wertz, I. E., Kusam, S., Lam, C., Okamoto, T., Sandoval, W. N., Anderson, D. J., Helgason, E., Ernst, J. A., Eby, M., Liu, J., et al. (2011) · Nature · doi:10.1038/nature09779 · Cited by 784 · see citing works
Self-citationTzelepis, K., Koike-Yusa, H., De Braekeleer, E., Li, Y., Metzakopian, E., Dovey, O. M., Mupo, A., Grinkevich, V., Li, M., Mazan, M., et al. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.09.079 · Cited by 761 · see citing works
Self-citationThirty years of BCL-2: translating cell death discoveries into novel cancer therapies
Delbridge, A. R. D., Grabow, S., Strasser, A., & Vaux, D. L. (2016) · Nature Reviews Cancer · doi:10.1038/nrc.2015.17 · Cited by 752 · see citing works
Efficacy of venetoclax as targeted therapy for relapsed/refractory t(11;14) multiple myeloma
Kumar, S. K., Kaufman, J. L., Gasparetto, C., Mikhael, J. R., Vij, R., Pegourié, B., Benboubker, L., Facon, T. T. F., Amiot, M., Moreau, P., et al. (2017) · Blood · doi:10.1182/blood-2017-06-788786 · Cited by 526 · see citing works
Leverson, J. D., Zhang, H., Chen, J., Tahir, S. K., Phillips, D. C., Xue, J., Nimmer, P., Jin, S., Smith, M., Xiao, Y., et al. (2015) · Cell Death & Disease · doi:10.1038/cddis.2014.561 · Cited by 440 · see citing works
Anti-apoptotic Mcl-1 is essential for the development and sustained growth of acute myeloid leukemiaPreprint
Glaser, S. P., Lee, E. F., Trounson, E., Bouillet, P., Wei, A. H., Fairlie, W. D., Izon, D. J., Zuber, J. A., Rappaport, A., Herold, M. J., et al. (2012) · Genes & Development · doi:10.1101/gad.182980.111 · Cited by 427 · see citing works
Self-citationMcl-1 deficiency results in peri-implantation embryonic lethality
Rinkenberger, J. L., Horning, S., Klocke, B., Roth, K., & Korsmeyer, S. J. (2000) · Genes & Development · doi:10.1101/gad.14.1.23 · Cited by 397 · see citing works
Brameld, K. A., Kuhn, B., Reuter, D. C., & Ståhl, M. (2008) · Journal of Chemical Information and Modeling · doi:10.1021/ci7002494 · Cited by 382 · see citing works
Rational Approaches to Improving Selectivity in Drug Design
Huggins, D. J., Sherman, W., & Tidor, B. (2012) · Journal of Medicinal Chemistry · doi:10.1021/jm2010332 · Cited by 378 · see citing works
Mcl-1 is essential for the survival of plasma cells
Peperzak, V., Vikstrom, I. B., Walker, J. A., Glaser, S. P., LePage, M., Coquery, C. M., Erickson, L. D., Fairfax, K. A., Mackay, F., Strasser, A., et al. (2013) · Nature Immunology · doi:10.1038/ni.2527 · Cited by 321 · see citing works
The antiapoptotic protein Mcl-1 is essential for the survival of neutrophils but not macrophages
Dzhagalov, I. L., John, A. L. S., & He, Y.-W. (2006) · Blood · doi:10.1182/blood-2006-03-013771 · Cited by 279 · see citing works
Loss of MCL-1 leads to impaired autophagy and rapid development of heart failurePreprint
Thomas, R. L., Roberts, D. J., Kubli, D. A., Lee, Y., Quinsay, M. N., Owens, J. B., Fischer, K. M., Sussman, M. A., Miyamoto, S., & Gustafsson, Å. B. (2013) · Genes & Development · doi:10.1101/gad.215871.113 · Cited by 268 · see citing works
Ozawa, T., Kaihara, A., Sato, M., Tachihara, K., & Umezawa, Y. (2001) · Analytical Chemistry · doi:10.1021/ac0013296 · Cited by 252 · see citing works
Delving deeper: MCL-1's contributions to normal and cancer biology
Perciavalle, R. M., & Opferman, J. T. (2012) · Trends in Cell Biology · doi:10.1016/j.tcb.2012.08.011 · Cited by 233 · see citing works
Mcl-1 Is Essential for Germinal Center Formation and B Cell Memory
Vikstrom, I. B., Carotta, S., Lüthje, K., Peperzak, V., Jost, P. J., Glaser, S. P., Busslinger, M., Bouillet, P., Strasser, A., Nutt, S. L., et al. (2010) · Science · doi:10.1126/science.1191793 · Cited by 215 · see citing works
Mérino, D., Whittle, J. R., Vaillant, F., Serrano, A., Gong, J.-N., Giner, G., Maragno, A. L., Chanrion, M., Schneider, E., Pal, B., et al. (2017) · Science Translational Medicine · doi:10.1126/scitranslmed.aam7049 · Cited by 186 · see citing works
Self-citationWei, G., Margolin, A. A., Haery, L., Brown, E., Cucolo, L., Julian, B., Shehata, S., Kung, A. L., Beroukhim, R., & Golub, T. R. (2012) · Cancer Cell · doi:10.1016/j.ccr.2012.02.028 · Cited by 185 · see citing works
Targeting of MCL-1 kills MYC-driven mouse and human lymphomas even when they bear mutations in p53Preprint
Kelly, G. L., Grabow, S., Glaser, S. P., Fitzsimmons, L., Aubrey, B. J., Okamoto, T., Valente, L. J., Robati, M., Tai, L., Fairlie, W. D., et al. (2014) · Genes & Development · doi:10.1101/gad.232009.113 · Cited by 166 · see citing works
Self-citationHierarchy for targeting prosurvival BCL2 family proteins in multiple myeloma: pivotal role of MCL1
Gong, J.-N., Khong, T. T., Segal, D., Yao, Y., Riffkin, C. D., Garnier, J.-M., Khaw, S. L., Lessène, G., Spencer, A. G., Herold, M. J., et al. (2016) · Blood · doi:10.1182/blood-2016-03-704908 · Cited by 150 · see citing works
Self-citationTiedemann, R. E., Zhu, Y. X., Schmidt, J. E., Chang, S., Sereduk, C., Yin, H. H., Mousses, S., & Stewart, A. K. (2011) · Cancer Research · doi:10.1158/0008-5472.can-11-2781 · Cited by 130 · see citing works
Xiao, Y., Nimmer, P. M., Sheppard, G. S., Bruncko, M., Hessler, P., Lu, X. L., Roberts-Rapp, L. A., Pappano, W. N., Elmore, S. W., Souers, A. J., et al. (2015) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-14-0928 · Cited by 120 · see citing works
Mcl‐1–Bim complexes accommodate surprising point mutations via minor structural changes
Fire, E., Gullà, S. V., Grant, R. A., et al. (2010) · Protein Science · doi:10.1002/pro.329 · Cited by 102 · see citing works
Ordering of the N-Terminus of Human MDM2 by Small Molecule Inhibitors
Michelsen, K., Jordan, J. B., Lewis, J. K., Long, A. M., Yang, E., Rew, Y., Zhou, J., Yakowec, P. S., Schnier, P. D., Huang, X. Y., et al. (2012) · Journal of the American Chemical Society · doi:10.1021/ja305839b · Cited by 71 · see citing works
Self-citationVikstrom, I. B., Slomp, A., Carrington, E. M., Moesbergen, L. M., Chang, C. W. T., Kelly, G. L., Glaser, S. P., Jansen, J. H. M., Leusen, J. H. W., Strasser, A., et al. (2016) · Cell Death and Disease · doi:10.1038/cddis.2016.237 · Cited by 59 · see citing works
Self-citationSaiki, A. Y., Caenepeel, S., Yu, D., Lofgren, J. A., Osgood, T., Robertson, R., Canon, J., Su, C., Jones, A., Zhao, X., et al. (2014) · Oncotarget · doi:10.18632/oncotarget.1918 · Cited by 55 · see citing works
Self-citationGrabow, S., Delbridge, A. R. D., Aubrey, B. J., Vandenberg, C. J., & Strasser, A. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.02.039 · Cited by 46 · see citing works
Liu, G., Poppe, L., Aoki, K., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0096521 · Cited by 34 · see citing works
Self-citation
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Nangia, V., Siddiqui, F. M., Caenepeel, S., Timonina, D., Bilton, S. J., Phan, N., Gomez-Caraballo, M., Archibald, H. L., Li, C., Fraser, C., et al. (2018) · Cancer Discovery · doi:10.1158/2159-8290.cd-18-0277 · Cited by 94 · see citing works
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Hamilton, C., Fox, J. P., Longley, D. B., & Higgins, C. A. (2021) · Cancers · doi:10.3390/cancers13112618 · Cited by 26 · see citing works
LKB1 regulates JNK-dependent stress signaling and apoptotic dependency of KRAS-mutant lung cancers
Li, C., Syed, M. U., Nimbalkar, A., Shen, Y., Vieira, M. D., Fraser, C., Inde, Z., Qin, X., Ouyang, J., Kreuzer, J., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-58753-y · Cited by 11 · see citing works
“Consistent with the expected effects of on-target MCL-1 inhibition 61 , we observed decreased B cells and monocytes, however no additional effects were observed in combination with sotorasib compared with AMG 176 alone (Fig.”
Self-citationHuang, S., Li, C., Zhang, X., Pan, J., Li, F., Lv, Y., Huang, J., Ling, Q., Ye, W., Mao, S., et al. (2020) · Molecular Oncology · doi:10.1002/1878-0261.12742 · Cited by 7 · see citing works
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- Authors
- Caenepeel, S., Brown, S. P., Belmontes, B., Moody, G., Keegan, K. S., Chui, D., Whittington, D. A., Huang, X., Poppe, L., Cheng, A. C., Cardozo, M., Houze, J., Li, Y., Lucas, B., Paras, N. A., Wang, X., Taygerly, J. P., Vimolratana, M., Zancanella, M., Zhu, L., Cajulis, E., Osgood, T., Sun, J., Damon, L., Egan, R. K., Greninger, P., McClanaghan, J. D., Gong, J., Moujalled, D., Pomilio, G., Beltran, P., Benes, C. H., Roberts, A. W., Huang, D. C., Wei, A., Canon, J., Coxon, A., & Hughes, P. E.
- Affiliations
- Amgen (United States) (US)
- Massachusetts General Hospital (US)
- The University of Melbourne (AU)
- The Alfred Hospital (AU)
- The Royal Melbourne Hospital (AU)
- Corresponding author
- Brown, Sean P.
- Hughes, Paul E.
- ORCID
- Caenepeel, Sean
- Brown, Sean P.
- Belmontes, Brian
- Moody, Gordon
- Whittington, Douglas A.
- Huang, Xin
- Poppe, Leszek
- Cheng, Alan C.
- Cardozo, Mario
- Li, Yunxiao
- Lucas, Brian
- Paras, Nick A.
- Wang, Xianghong
- Taygerly, Joshua P.
- Osgood, Tao
- Damon, Leah
- Egan, Regina K.
- Greninger, Patricia
- Gong, Jianan
- Moujalled, Donia
- Beltran, Pedro
- Benes, Cyril H.
- Roberts, Andrew W.
- Huang, David C.
- Wei, Andrew
- Canon, Jude
- Coxon, Angela
- Hughes, Paul E.
- Venue
- Cancer Discovery
- Published
- 2018-12-01
- Volume
- 8
- Issue
- 12
- Pages
- 1582-1597
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- OpenAlex
- W2892573863
- Cited by
- 432
- References
- 41
- Citations by year
- 2026: 23 · 2025: 49 · 2024: 46 · 2023: 54 · 2022: 62 · 2021: 66 · 2020: 82 · 2019: 45 · 2018: 4
- FWCI
- 18.05
- Type
- journal article
- Language
- en
- Update notices
- correction (2019-07-01)
- Open access
- bronze
- doi.org
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- Monash University Research Portal (Monash University) (submittedVersion, other-oa)
- Funders
- Amgen (Amgen Inc.)
- Australian Cancer Research Foundation (ACRF) (Victorian State Government Operational Infrastructure Support (OIS) Grant)
- Department of Health | National Health and Medical Research Council (NHMRC) (Research Fellowship 1079560,Program Grant 1016701,Program Grant 1113577, Research Fellowship 1079560,Project Grant 1057742)
- Independent Research Institutes (Infrastructure Support Scheme Grant 9000220)
- The Cancer Council Victoria (Grant-in-aid)
- Leukemia and Lymphoma Society (LLS) (SCOR Grant 7001-13)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- Mcl-1 inhibitors, Mcl-1, Bcl-2 family proteins, apoptosis, hematologic malignancies, acute myeloid leukemia, venetoclax, BH3 mimetics, combination therapy, conformational restriction, pharmacodynamics, oral bioavailability
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