Discovery of Mcl-1-specific inhibitor AZD5991 and preclinical activity in multiple myeloma and acute myeloid leukemia

Adriana E. Tron, Matthew A. Belmonte, Ammar Adam, Brian M. Aquila, Lawrence H. Boise, Elisabetta Chiarparin, Justin Cidado, Kevin J. Embrey, Eric Gangl, Francis D. Gibbons, Gareth P. Gregory, David Hargreaves, J. Adam Hendricks, Jeffrey W. Johannes, Ricky W. Johnstone, Steven L. Kazmirski, Jason G. Kettle, Michelle L. Lamb, Shannon M. Matulis, Ajay K. Nooka & 14 others Martin J. Packer, Bo Peng, Philip B. Rawlins, Daniel W. Robbins, Alwin G. Schuller, Nancy Su, Wenzhan Yang, Qing Ye, Xiaolan Zheng, J. Paul Secrist, Edwin A. Clark, David M. Wilson, Stephen E. Fawell, Alexander W. Hird

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Abstract

Mcl-1 is a member of the Bcl-2 family of proteins that promotes cell survival by preventing induction of apoptosis in many cancers. High expression of Mcl-1 causes tumorigenesis and resistance to anticancer therapies highlighting the potential of Mcl-1 inhibitors as anticancer drugs. Here, we describe AZD5991, a rationally designed macrocyclic molecule with high selectivity and affinity for Mcl-1 currently in clinical development. Our studies demonstrate that AZD5991 binds directly to Mcl-1 and induces rapid apoptosis in cancer cells, most notably myeloma and acute myeloid leukemia, by activating the Bak-dependent mitochondrial apoptotic pathway. AZD5991 shows potent antitumor activity in vivo with complete tumor regression in several models of multiple myeloma and acute myeloid leukemia after a single tolerated dose as monotherapy or in combination with bortezomib or venetoclax. Based on these promising data, a Phase I clinical trial has been launched for evaluation of AZD5991 in patients with hematological malignancies (NCT03218683).

Original languageEnglish
Article number5341
Number of pages14
JournalNature Communications
Volume9
Issue number1
DOIs
Publication statusPublished - 1 Dec 2018

Cite this

Tron, A. E., Belmonte, M. A., Adam, A., Aquila, B. M., Boise, L. H., Chiarparin, E., ... Hird, A. W. (2018). Discovery of Mcl-1-specific inhibitor AZD5991 and preclinical activity in multiple myeloma and acute myeloid leukemia. Nature Communications, 9(1), [5341]. https://doi.org/10.1038/s41467-018-07551-w
Tron, Adriana E. ; Belmonte, Matthew A. ; Adam, Ammar ; Aquila, Brian M. ; Boise, Lawrence H. ; Chiarparin, Elisabetta ; Cidado, Justin ; Embrey, Kevin J. ; Gangl, Eric ; Gibbons, Francis D. ; Gregory, Gareth P. ; Hargreaves, David ; Hendricks, J. Adam ; Johannes, Jeffrey W. ; Johnstone, Ricky W. ; Kazmirski, Steven L. ; Kettle, Jason G. ; Lamb, Michelle L. ; Matulis, Shannon M. ; Nooka, Ajay K. ; Packer, Martin J. ; Peng, Bo ; Rawlins, Philip B. ; Robbins, Daniel W. ; Schuller, Alwin G. ; Su, Nancy ; Yang, Wenzhan ; Ye, Qing ; Zheng, Xiaolan ; Secrist, J. Paul ; Clark, Edwin A. ; Wilson, David M. ; Fawell, Stephen E. ; Hird, Alexander W. / Discovery of Mcl-1-specific inhibitor AZD5991 and preclinical activity in multiple myeloma and acute myeloid leukemia. In: Nature Communications. 2018 ; Vol. 9, No. 1.
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abstract = "Mcl-1 is a member of the Bcl-2 family of proteins that promotes cell survival by preventing induction of apoptosis in many cancers. High expression of Mcl-1 causes tumorigenesis and resistance to anticancer therapies highlighting the potential of Mcl-1 inhibitors as anticancer drugs. Here, we describe AZD5991, a rationally designed macrocyclic molecule with high selectivity and affinity for Mcl-1 currently in clinical development. Our studies demonstrate that AZD5991 binds directly to Mcl-1 and induces rapid apoptosis in cancer cells, most notably myeloma and acute myeloid leukemia, by activating the Bak-dependent mitochondrial apoptotic pathway. AZD5991 shows potent antitumor activity in vivo with complete tumor regression in several models of multiple myeloma and acute myeloid leukemia after a single tolerated dose as monotherapy or in combination with bortezomib or venetoclax. Based on these promising data, a Phase I clinical trial has been launched for evaluation of AZD5991 in patients with hematological malignancies (NCT03218683).",
author = "Tron, {Adriana E.} and Belmonte, {Matthew A.} and Ammar Adam and Aquila, {Brian M.} and Boise, {Lawrence H.} and Elisabetta Chiarparin and Justin Cidado and Embrey, {Kevin J.} and Eric Gangl and Gibbons, {Francis D.} and Gregory, {Gareth P.} and David Hargreaves and Hendricks, {J. Adam} and Johannes, {Jeffrey W.} and Johnstone, {Ricky W.} and Kazmirski, {Steven L.} and Kettle, {Jason G.} and Lamb, {Michelle L.} and Matulis, {Shannon M.} and Nooka, {Ajay K.} and Packer, {Martin J.} and Bo Peng and Rawlins, {Philip B.} and Robbins, {Daniel W.} and Schuller, {Alwin G.} and Nancy Su and Wenzhan Yang and Qing Ye and Xiaolan Zheng and Secrist, {J. Paul} and Clark, {Edwin A.} and Wilson, {David M.} and Fawell, {Stephen E.} and Hird, {Alexander W.}",
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Tron, AE, Belmonte, MA, Adam, A, Aquila, BM, Boise, LH, Chiarparin, E, Cidado, J, Embrey, KJ, Gangl, E, Gibbons, FD, Gregory, GP, Hargreaves, D, Hendricks, JA, Johannes, JW, Johnstone, RW, Kazmirski, SL, Kettle, JG, Lamb, ML, Matulis, SM, Nooka, AK, Packer, MJ, Peng, B, Rawlins, PB, Robbins, DW, Schuller, AG, Su, N, Yang, W, Ye, Q, Zheng, X, Secrist, JP, Clark, EA, Wilson, DM, Fawell, SE & Hird, AW 2018, 'Discovery of Mcl-1-specific inhibitor AZD5991 and preclinical activity in multiple myeloma and acute myeloid leukemia', Nature Communications, vol. 9, no. 1, 5341. https://doi.org/10.1038/s41467-018-07551-w

Discovery of Mcl-1-specific inhibitor AZD5991 and preclinical activity in multiple myeloma and acute myeloid leukemia. / Tron, Adriana E.; Belmonte, Matthew A.; Adam, Ammar; Aquila, Brian M.; Boise, Lawrence H.; Chiarparin, Elisabetta; Cidado, Justin; Embrey, Kevin J.; Gangl, Eric; Gibbons, Francis D.; Gregory, Gareth P.; Hargreaves, David; Hendricks, J. Adam; Johannes, Jeffrey W.; Johnstone, Ricky W.; Kazmirski, Steven L.; Kettle, Jason G.; Lamb, Michelle L.; Matulis, Shannon M.; Nooka, Ajay K.; Packer, Martin J.; Peng, Bo; Rawlins, Philip B.; Robbins, Daniel W.; Schuller, Alwin G.; Su, Nancy; Yang, Wenzhan; Ye, Qing; Zheng, Xiaolan; Secrist, J. Paul; Clark, Edwin A.; Wilson, David M.; Fawell, Stephen E.; Hird, Alexander W.

In: Nature Communications, Vol. 9, No. 1, 5341, 01.12.2018.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Discovery of Mcl-1-specific inhibitor AZD5991 and preclinical activity in multiple myeloma and acute myeloid leukemia

AU - Tron, Adriana E.

AU - Belmonte, Matthew A.

AU - Adam, Ammar

AU - Aquila, Brian M.

AU - Boise, Lawrence H.

AU - Chiarparin, Elisabetta

AU - Cidado, Justin

AU - Embrey, Kevin J.

AU - Gangl, Eric

AU - Gibbons, Francis D.

AU - Gregory, Gareth P.

AU - Hargreaves, David

AU - Hendricks, J. Adam

AU - Johannes, Jeffrey W.

AU - Johnstone, Ricky W.

AU - Kazmirski, Steven L.

AU - Kettle, Jason G.

AU - Lamb, Michelle L.

AU - Matulis, Shannon M.

AU - Nooka, Ajay K.

AU - Packer, Martin J.

AU - Peng, Bo

AU - Rawlins, Philip B.

AU - Robbins, Daniel W.

AU - Schuller, Alwin G.

AU - Su, Nancy

AU - Yang, Wenzhan

AU - Ye, Qing

AU - Zheng, Xiaolan

AU - Secrist, J. Paul

AU - Clark, Edwin A.

AU - Wilson, David M.

AU - Fawell, Stephen E.

AU - Hird, Alexander W.

PY - 2018/12/1

Y1 - 2018/12/1

N2 - Mcl-1 is a member of the Bcl-2 family of proteins that promotes cell survival by preventing induction of apoptosis in many cancers. High expression of Mcl-1 causes tumorigenesis and resistance to anticancer therapies highlighting the potential of Mcl-1 inhibitors as anticancer drugs. Here, we describe AZD5991, a rationally designed macrocyclic molecule with high selectivity and affinity for Mcl-1 currently in clinical development. Our studies demonstrate that AZD5991 binds directly to Mcl-1 and induces rapid apoptosis in cancer cells, most notably myeloma and acute myeloid leukemia, by activating the Bak-dependent mitochondrial apoptotic pathway. AZD5991 shows potent antitumor activity in vivo with complete tumor regression in several models of multiple myeloma and acute myeloid leukemia after a single tolerated dose as monotherapy or in combination with bortezomib or venetoclax. Based on these promising data, a Phase I clinical trial has been launched for evaluation of AZD5991 in patients with hematological malignancies (NCT03218683).

AB - Mcl-1 is a member of the Bcl-2 family of proteins that promotes cell survival by preventing induction of apoptosis in many cancers. High expression of Mcl-1 causes tumorigenesis and resistance to anticancer therapies highlighting the potential of Mcl-1 inhibitors as anticancer drugs. Here, we describe AZD5991, a rationally designed macrocyclic molecule with high selectivity and affinity for Mcl-1 currently in clinical development. Our studies demonstrate that AZD5991 binds directly to Mcl-1 and induces rapid apoptosis in cancer cells, most notably myeloma and acute myeloid leukemia, by activating the Bak-dependent mitochondrial apoptotic pathway. AZD5991 shows potent antitumor activity in vivo with complete tumor regression in several models of multiple myeloma and acute myeloid leukemia after a single tolerated dose as monotherapy or in combination with bortezomib or venetoclax. Based on these promising data, a Phase I clinical trial has been launched for evaluation of AZD5991 in patients with hematological malignancies (NCT03218683).

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U2 - 10.1038/s41467-018-07551-w

DO - 10.1038/s41467-018-07551-w

M3 - Article

VL - 9

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

IS - 1

M1 - 5341

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