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 [electronic resource]

• Ngôn ngữ: eng
• Ký hiệu phân loại: 616.079 Immunity
• Thông tin xuất bản: Argonne, Ill. : Oak Ridge, Tenn. : Argonne National Laboratory ; Distributed by the Office of Scientific and Technical Information, U.S. Dept. of Energy, 2018
• Mô tả vật lý: Size: p. 6685-6704 : , digital, PDF file.
• Bộ sưu tập: Metadata
• ID: 260192
• Chủ đề: 1. 60 applied life sciences; 2. Inhibitors; 3. Mixtures; 4. Rodent models; 5. Tumors; 6. Ultraperformance liquid chromatography

Tóm tắt

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.