Discovery of a Potent and Selective in Vivo Probe (GNE-272) for the Bromodomains of CBP/EP300

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• 作者：Terry D. Crawford ; F. Anthony Romero ; Kwong Wah Lai ; Vickie Tsui ; Alexander M. Taylor ; Gladys de Leon Boenig ; Cameron L. Noland ; Jeremy Murray ; Justin Ly ; Edna F. Choo ; Thomas L. Hunsaker ; Emily W. Chan ; Mark Merchant ; Samir Kharbanda ; Karen E. Gascoigne ; Susan Kaufman ; Maureen H. Beresini ; Jiangpeng Liao ; Wenfeng Liu ; Kevin X. Chen ; Zhongguo Chen ; Andrew R. Conery ; Alexandre Côté ; Hariharan Jayaram ; Ying Jiang ; James R. Kiefer ; Tracy Kleinheinz ; Yingjie Li ; Jonathan Maher ; Eneida Pardo ; Florence Poy ; Kerry L. Spillane ; Fei Wang ; Jian Wang ; Xiaocang Wei ; Zhaowu Xu ; Zhongya Xu ; Ivana Yen ; Laura Zawadzke ; Xiaoyu Zhu ; Steven Bellon ; Richard Cummings ; Andrea G. Cochran ; Brian K. Albrecht ; Steven Magnuson
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：December 8, 2016
• 年：2016
• 卷：59
• 期：23
• 页码：10549-10563
• 全文大小：827K
• ISSN：1520-4804

文摘

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.