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 & 18 others 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, Paul E. Hughes

Research output: Contribution to journalArticleResearchpeer-review

Abstract

The prosurvival BCL2 family member MCL1 is frequently dysregulated in cancer. To overcome the significant challenges associated with inhibition of MCL1 protein–pro-tein 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.

Original languageEnglish
Pages (from-to)1582-1597
Number of pages16
JournalCancer Discovery
Volume8
Issue number12
DOIs
Publication statusPublished - 1 Dec 2018

Cite this

Caenepeel, S., Brown, S. P., Belmontes, B., Moody, G., Keegan, K. S., Chui, D., ... Hughes, P. E. (2018). AMG 176, a selective MCL1 inhibitor, is effective in hematologic cancer models alone and in combination with established therapies. Cancer Discovery, 8(12), 1582-1597. https://doi.org/10.1158/2159-8290.CD-18-0387
Caenepeel, Sean ; Brown, Sean P. ; Belmontes, Brian ; Moody, Gordon ; Keegan, Kathleen S. ; Chui, Danny ; Whittington, Douglas A. ; Huang, Xin ; Poppe, Leszek ; Cheng, Alan C. ; Cardozo, Mario ; Houze, Jonathan ; Li, Yunxiao ; Lucas, Brian ; Paras, Nick A. ; Wang, Xianghong ; Taygerly, Joshua P. ; Vimolratana, Marc ; Zancanella, Manuel ; Zhu, Liusheng ; Cajulis, Elaina ; Osgood, Tao ; Sun, Jan ; Damon, Leah ; Egan, Regina K. ; Greninger, Patricia ; McClanaghan, Joseph D. ; Gong, Jianan ; Moujalled, Donia ; Pomilio, Giovanna ; Beltran, Pedro ; Benes, Cyril H. ; Roberts, Andrew W. ; Huang, David C. ; Wei, Andrew ; Canon, Jude ; Coxon, Angela ; Hughes, Paul E. / AMG 176, a selective MCL1 inhibitor, is effective in hematologic cancer models alone and in combination with established therapies. In: Cancer Discovery. 2018 ; Vol. 8, No. 12. pp. 1582-1597.
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title = "AMG 176, a selective MCL1 inhibitor, is effective in hematologic cancer models alone and in combination with established therapies",
abstract = "The prosurvival BCL2 family member MCL1 is frequently dysregulated in cancer. To overcome the significant challenges associated with inhibition of MCL1 protein–pro-tein 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.",
author = "Sean Caenepeel and Brown, {Sean P.} and Brian Belmontes and Gordon Moody and Keegan, {Kathleen S.} and Danny Chui and Whittington, {Douglas A.} and Xin Huang and Leszek Poppe and Cheng, {Alan C.} and Mario Cardozo and Jonathan Houze and Yunxiao Li and Brian Lucas and Paras, {Nick A.} and Xianghong Wang and Taygerly, {Joshua P.} and Marc Vimolratana and Manuel Zancanella and Liusheng Zhu and Elaina Cajulis and Tao Osgood and Jan Sun and Leah Damon and Egan, {Regina K.} and Patricia Greninger and McClanaghan, {Joseph D.} and Jianan Gong and Donia Moujalled and Giovanna Pomilio and Pedro Beltran and Benes, {Cyril H.} and Roberts, {Andrew W.} and Huang, {David C.} and Andrew Wei and Jude Canon and Angela Coxon and Hughes, {Paul E.}",
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Caenepeel, S, Brown, SP, Belmontes, B, Moody, G, Keegan, KS, Chui, D, Whittington, DA, Huang, X, Poppe, L, Cheng, AC, Cardozo, M, Houze, J, Li, Y, Lucas, B, Paras, NA, Wang, X, Taygerly, JP, Vimolratana, M, Zancanella, M, Zhu, L, Cajulis, E, Osgood, T, Sun, J, Damon, L, Egan, RK, Greninger, P, McClanaghan, JD, Gong, J, Moujalled, D, Pomilio, G, Beltran, P, Benes, CH, Roberts, AW, Huang, DC, Wei, A, Canon, J, Coxon, A & Hughes, PE 2018, 'AMG 176, a selective MCL1 inhibitor, is effective in hematologic cancer models alone and in combination with established therapies' Cancer Discovery, vol. 8, no. 12, pp. 1582-1597. https://doi.org/10.1158/2159-8290.CD-18-0387

AMG 176, a selective MCL1 inhibitor, is effective in hematologic cancer models alone and in combination with established therapies. / Caenepeel, Sean; Brown, Sean P.; Belmontes, Brian; Moody, Gordon; Keegan, Kathleen S.; Chui, Danny; Whittington, Douglas A.; Huang, Xin; Poppe, Leszek; Cheng, Alan C.; Cardozo, Mario; Houze, Jonathan; Li, Yunxiao; Lucas, Brian; Paras, Nick A.; Wang, Xianghong; Taygerly, Joshua P.; Vimolratana, Marc; Zancanella, Manuel; Zhu, Liusheng; Cajulis, Elaina; Osgood, Tao; Sun, Jan; Damon, Leah; Egan, Regina K.; Greninger, Patricia; McClanaghan, Joseph D.; Gong, Jianan; Moujalled, Donia; Pomilio, Giovanna; Beltran, Pedro; Benes, Cyril H.; Roberts, Andrew W.; Huang, David C.; Wei, Andrew; Canon, Jude; Coxon, Angela; Hughes, Paul E.

In: Cancer Discovery, Vol. 8, No. 12, 01.12.2018, p. 1582-1597.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - AMG 176, a selective MCL1 inhibitor, is effective in hematologic cancer models alone and in combination with established therapies

AU - Caenepeel, Sean

AU - Brown, Sean P.

AU - Belmontes, Brian

AU - Moody, Gordon

AU - Keegan, Kathleen S.

AU - Chui, Danny

AU - Whittington, Douglas A.

AU - Huang, Xin

AU - Poppe, Leszek

AU - Cheng, Alan C.

AU - Cardozo, Mario

AU - Houze, Jonathan

AU - Li, Yunxiao

AU - Lucas, Brian

AU - Paras, Nick A.

AU - Wang, Xianghong

AU - Taygerly, Joshua P.

AU - Vimolratana, Marc

AU - Zancanella, Manuel

AU - Zhu, Liusheng

AU - Cajulis, Elaina

AU - Osgood, Tao

AU - Sun, Jan

AU - Damon, Leah

AU - Egan, Regina K.

AU - Greninger, Patricia

AU - McClanaghan, Joseph D.

AU - Gong, Jianan

AU - Moujalled, Donia

AU - Pomilio, Giovanna

AU - Beltran, Pedro

AU - Benes, Cyril H.

AU - Roberts, Andrew W.

AU - Huang, David C.

AU - Wei, Andrew

AU - Canon, Jude

AU - Coxon, Angela

AU - Hughes, Paul E.

PY - 2018/12/1

Y1 - 2018/12/1

N2 - The prosurvival BCL2 family member MCL1 is frequently dysregulated in cancer. To overcome the significant challenges associated with inhibition of MCL1 protein–pro-tein 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.

AB - The prosurvival BCL2 family member MCL1 is frequently dysregulated in cancer. To overcome the significant challenges associated with inhibition of MCL1 protein–pro-tein 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.

UR - http://www.scopus.com/inward/record.url?scp=85056860831&partnerID=8YFLogxK

U2 - 10.1158/2159-8290.CD-18-0387

DO - 10.1158/2159-8290.CD-18-0387

M3 - Article

VL - 8

SP - 1582

EP - 1597

JO - Cancer Discovery

JF - Cancer Discovery

SN - 2159-8274

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ER -