From a novel HTS hit to potent, selective, and orally bioavailable KDM5 inhibitors

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:27

Article

Liang, Jun¹  Labadie, Sharada¹  Zhang, Birong¹  Ortwine, Daniel F.¹  Patel, Snahel¹  Vinogradova, Maia¹  Kiefer, James R.¹  Mauer, Till¹  Gehling, Victor S.²  Harmange, Jean-Christophe²  Cummings, Richard²  Lai, Tommy³  Liao, Jiangpeng³  Zheng, Xiaoping³  Liu, Yichin¹  Gustafson, Amy¹  Van der Porten, Erica¹  Mao, Weifeng³  Liederer, Bianca M.¹  Deshmukh, Gauri¹  An, Le¹  Ran, Yingqing¹  Classon, Marie¹  Trojer, Patrick²  Dragovich, Peter S.¹  Murray, Lesley¹ 

[1] Genentech Inc, 1 DNA Way, San Francisco, CA 94080 USA

[2] Constellat Pharmaceut Inc, 215 First St,Suite 200, Cambridge, MA 02142 USA

[3] WuXi AppTec Co Ltd, 288 Fute Zhong Rd, Shanghai 200131, Peoples R China

关键词: KDM5;    KDM5 inhibitors;    Epigenetics;    Structure-based drug discovery;    Overcome cancer resistance;   

DOI  :  10.1016/j.bmcl.2017.05.016

来源: Elsevier

【 摘 要 】

A high-throughput screening (HTS) of the Genentech/Roche library identified a novel, uncharged scaffold as a KDM5A inhibitor. Lacking insight into the binding mode, initial attempts to improve inhibitor potency failed to improve potency, and synthesis of analogs was further hampered by the presence of a C-C bond between the pyrrolidine and pyridine. Replacing this with a C-N bond significantly simplified synthesis, yielding pyrazole analog 35, of which we obtained a co-crystal structure with KDM5A. Using structure-based design approach, we identified 50 with improved biochemical, cell potency and reduced MW and lower lipophilicity (LogD) compared with the original hit. Furthermore, 50 showed lower clearance than 9 in mice. In combination with its remarkably low plasma protein binding (PPB) in mice (40%), oral dosing of 50 at 5 mg/kg resulted in unbound C-max similar to 2-fold of its cell potency (PC9 H3K4Me3 0.96 mu M), meeting our criteria for an in vivo tool compound from a new scaffold. (C) 2017 Elsevier Ltd. All rights reserved.

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