| Autor: |
Jonathan Maher, F. Anthony Romero, Samir Kharbanda, Mark Merchant, Ivana Yen, Yingjie Li, Edna F. Choo, Jiangpeng Liao, Xiaocang Wei, Kwong Wah Lai, Karen E. Gascoigne, Richard D. Cummings, Hariharan Jayaram, Thomas Hunsaker, Steven F. Bellon, Jian Wang, Cameron L. Noland, Brian K. Albrecht, Ying Jiang, Jeremy Murray, Susan Kaufman, Kerry L. Spillane, Florence Poy, Zhaowu Xu, Fei Wang, James R. Kiefer, Laura Zawadzke, Zhongguo Chen, Alexander M. Taylor, Andrew R. Conery, Xiaoyu Zhu, Wenfeng Liu, Eneida Pardo, Alexandre Côté, Andrea G. Cochran, Vickie Tsui, Steven Magnuson, Terry Crawford, Maureen Beresini, Emily Chan, Kevin X. Chen, Gladys de Leon Boenig, Justin Ly, Tracy Kleinheinz, Zhongya Xu |
| Rok vydání: |
2016 |
| Předmět: |
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| Zdroj: |
Journal of medicinal chemistry. 59(23) |
| ISSN: |
1520-4804 |
| Popis: |
The single bromodomain of the closely related transcriptional regulators CBP/EP300 is a target of much recent interest in cancer and immune system regulation. A co-crystal structure of a ligand-efficient screening hit and the CBP bromodomain guided initial design targeting the LPF shelf, ZA loop, and acetylated lysine binding regions. Structure–activity relationship studies allowed us to identify a more potent analogue. Optimization of permeability and microsomal stability and subsequent improvement of mouse hepatocyte stability afforded 59 (GNE-272, TR-FRET IC50 = 0.02 μM, BRET IC50 = 0.41 μM, BRD4(1) IC50 = 13 μM) that retained the best balance of cell potency, selectivity, and in vivo PK. Compound 59 showed a marked antiproliferative effect in hematologic cancer cell lines and modulates MYC expression in vivo that corresponds with antitumor activity in an AML tumor model. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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