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

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

in 13 / 13/2 / 631/67/1990/283/1897 / 639/638/309/2144 / 639/638/309/2420 / 692/4028/67/1990/804 / Acute myeloid leukemia / Animals / Anticancer properties / Antineoplastic Agents - therapeutic use / Antitumor activity / Antitumor agents / Apoptosis / Apoptosis - drug effects / Bcl-2 protein / Bortezomib / Bortezomib - pharmacology / Bridged Bicyclo Compounds, Heterocyclic - pharmacology / Cancer / Cell Line, Tumor / Crystallography, X-Ray / Humanities and Social Sciences / Humans / Leukemia / Leukemia, Myeloid, Acute - drug therapy / Leukemia, Myeloid, Acute - pathology / Mcl-1 protein / Mice / Mice, Inbred C57BL / Mice, SCID / Mitochondria / multidisciplinary / Multiple myeloma / Multiple Myeloma - drug therapy / Multiple Myeloma - pathology / Myeloid Cell Leukemia Sequence 1 Protein - antagonists & inhibitors / Myeloid Cell Leukemia Sequence 1 Protein - metabolism / Myeloid leukemia / Proteins / Rats / Rats, Nude / Regression analysis / Science / Science (multidisciplinary) / Selectivity / Sulfonamides - pharmacology / Tumorigenesis / Xenograft Model Antitumor Assays

2018

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

2018

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2018

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Journal Article

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

Su, Nancy,

Gibbons, Francis D.,

Aquila, Brian M.,

Matulis, Shannon M.,

Peng, Bo,

Adam, Ammar,

Ye, Qing,

Wilson, David M.,

Hargreaves, David,

Robbins, Daniel W.,

Yang, Wenzhan,

Boise, Lawrence H.,

Chiarparin, Elisabetta,

Hendricks, J. Adam,

Lamb, Michelle L.,

Clark, Edwin A.,

Packer, Martin J.,

Gregory, Gareth P.,

Schuller, Alwin G.,

Gangl, Eric,

Nooka, Ajay K.,

Cidado, Justin,

Zheng, Xiaolan,

Belmonte, Matthew A.,

Johnstone, Ricky W.,

Secrist, J. Paul,

Kazmirski, Steven L.,

Hird, Alexander W.,

Fawell, Stephen E.,

Kettle, Jason G.,

Johannes, Jeffrey W.,

Rawlins, Philip B.,

Tron, Adriana E.,

Embrey, Kevin J.

2018

Overview

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). High expression of Mcl-1 promotes tumorigenesis and resistance to anticancer therapies. Here they report a macrocyclic molecule with high selectivity and affinity for Mcl-1 that exhibits potent anti-tumor effects as single agent and in combination with bortezomib or venetoclax in preclinical models of multiple myeloma and acute myeloid leukemia.

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Publisher

Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio

Subject

/ 13/2

/ 631/67/1990/283/1897

/ 639/638/309/2144

/ 639/638/309/2420

/ 692/4028/67/1990/804

/ Acute myeloid leukemia

/ Animals