Discovery of QCA570 as an Exceptionally Potent and Efficacious Proteolysis Targeting Chimera (PROTAC) Degrader of the Bromodomain and Extra-Terminal (BET) Proteins Capable of Inducing Complete and Durable Tumor Regression

Qin, Chong; Hu, Yang; Zhou, Bing; Fernandez-Salas, Ester; Yang, Chao-Yie; Liu, Liu; McEachern, Donna; Przybranowski, Sally; Wang, Mi; Stuckey, Jeanne; Meagher, Jennifer; Bai, Longchuan; Chen, Zhuo; Lin, Mei; Yang, Jiuling; Ziazadeh, Danya N.; Xu, Fuming; Hu, Jiantao; Xiang, Weiguo; Huang, Liyue; Li, Siwei; Wen, Bo; Sun, Duxin; Wang, Shaomeng

doi:10.1021/acs.jmedchem.8b00506

Title: Discovery of QCA570 as an Exceptionally Potent and Efficacious Proteolysis Targeting Chimera (PROTAC) Degrader of the Bromodomain and Extra-Terminal (BET) Proteins Capable of Inducing Complete and Durable Tumor Regression

Journal Article · Wed Jul 18 00:00:00 EDT 2018 · Journal of Medicinal Chemistry

DOI:https://doi.org/10.1021/acs.jmedchem.8b00506· OSTI ID:1544861

Qin, Chong ^[1]; Hu, Yang ^[1];

^[1]; Fernandez-Salas, Ester ^[1]; Yang, Chao-Yie ^[1]; Liu, Liu ^[1]; McEachern, Donna ^[1]; Przybranowski, Sally ^[1]; Wang, Mi ^[1]; Stuckey, Jeanne ^[2]; Meagher, Jennifer ^[2]; Bai, Longchuan ^[1]; Chen, Zhuo ^[1]; Lin, Mei ^[1]; Yang, Jiuling ^[1]; Ziazadeh, Danya N. ^[1]; Xu, Fuming ^[1]; Hu, Jiantao ^[1]; Xiang, Weiguo ^[1]; Huang, Liyue ^[1] more »

Univ. of Michigan Medical School, Ann Arbor, MI (United States)
Univ. of Michigan, Ann Arbor, MI (United States)

Proteins of the bromodomain and extra-terminal (BET) family are epigenetics “readers” and promising therapeutic targets for cancer and other human diseases. We describe herein a structure-guided design of [1,4]oxazepines as a new class of BET inhibitors and our subsequent design, synthesis, and evaluation of proteolysis-targeting chimeric (PROTAC) small-molecule BET degraders. Our efforts have led to the discovery of extremely potent BET degraders, exemplified by QCA570, which effectively induces degradation of BET proteins and inhibits cell growth in human acute leukemia cell lines even at low picomolar concentrations. We report QCA570 achieves complete and durable tumor regression in leukemia xenograft models in mice at well-tolerated dose-schedules. QCA570 is the most potent and efficacious BET degrader reported to date.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: Breast Cancer Research Foundation; Prostate Cancer Foundation; National Cancer Institute (NCI); National Institutes of Health (NIH)

Grant/Contract Number:: R01CA215758; P30 CA046592

OSTI ID:: 1544861

Journal Information:: Journal of Medicinal Chemistry, Vol. 61, Issue 15; ISSN 0022-2623

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 162 works

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Title: Discovery of QCA570 as an Exceptionally Potent and Efficacious Proteolysis Targeting Chimera (PROTAC) Degrader of the Bromodomain and Extra-Terminal (BET) Proteins Capable of Inducing Complete and Durable Tumor Regression

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