From a novel HTS hit to potent, selective, and orally bioavailable KDM5 inhibitors. Issue 13 (1st July 2017)

• Record Type: Journal Article
• Authors: Liang, Jun; Labadie, Sharada; Zhang, Birong; Ortwine, Daniel F.; Patel, Snahel; Vinogradova, Maia; Kiefer, James R.; Mauer, Till; Gehling, Victor S.; Harmange, Jean-Christophe; Cummings, Richard; Lai, Tommy; Liao, Jiangpeng; Zheng, Xiaoping; Liu, Yichin; Gustafson, Amy; Van der Porten, Erica; Mao, Weifeng; Liederer, Bianca M.; Deshmukh, Gauri; An, Le; Ran, Yingqing; Classon, Marie; Trojer, Patrick; Dragovich, Peter S.; Murray, Lesley
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 27:Issue 13(2017)
• Page Start: 2974
• Page End: 2981
• Publication Date: 2017-07-01
• Subjects: KDM5 -- KDM5 inhibitors -- Epigenetics -- Structure-based drug discovery -- Overcome cancer resistance; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2017.05.016
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: 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 analog35, of which we obtained a co-crystal structure with KDM5A. Using structure-based design approach, we identified50 with improved biochemical, cell potency and reduced MW and lower lipophilicity (Log D) compared with the original hit. Furthermore, 50 showed lower clearance than9 in mice. In combination with its remarkably low plasma protein binding (PPB) in mice (40%), oral dosing of50 at 5 mg/kg resulted in unbound Cmax ∼2-fold of its cell potency (PC9 H3K4Me3 0.96 μM), meeting our criteria for an in vivo tool compound from a new scaffold.