Optimization of Potent and Selective Tricyclic Indole Diazepinone Myeloid Cell Leukemia-1 Inhibitors Using Structure-Based Design [electronic resource]

• Ngôn ngữ: eng
• Ký hiệu phân loại: 574.8 [Unassigned]
• Thông tin xuất bản: Washington, D.C. : Oak Ridge, Tenn. : United States. Dept. of Energy. Office of Science ; Distributed by the Office of Scientific and Technical Information, U.S. Dept. of Energy, 2018
• Mô tả vật lý: Size: p. 2410-2421 : , digital, PDF file.
• Bộ sưu tập: Metadata
• ID: 260302
• Chủ đề: 1. 60 applied life sciences; 2. Amides; 3. Apoptosis; 4. Assays; 5. Cancer; 6. Et al; 7. Indoles; 8. Inhibitors; 9. Mcl-1 inhibitor; 10. Screening assays; 11. Structure-based design

Tóm tắt

Myeloid cell leukemia 1 (Mcl-1), an antiapoptotic member of the Bcl-2 family of proteins, has emerged as an attractive target for cancer therapy. Mcl-1 upregulation is often found in many human cancers and is associated with high tumor grade, poor survival, and resistance to chemotherapy. Here, we describe a series of potent and selective tricyclic indole diazepinone Mcl-1 inhibitors that were discovered and further optimized using structure-based design. These compounds exhibit picomolar binding affinity and mechanism-based cellular efficacy, including growth inhibition and caspase induction in Mcl-1-sensitive cells. Furthermore, they represent useful compounds to study the implication of Mcl-1 inhibition in cancer and serve as potentially useful starting points toward the discovery of anti-Mcl-1 therapeutics.