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

Bioorganic & Medicinal Chemistry Letters
Jun LiangLesley J Murray

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 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 5mg/kg resulted in unbound Cmax ∼2-fold of its cell potency (PC9 H3K4Me3 0.96μM), meeting our criteria for an in vivo tool compound from a new scaffold.

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Citations

Apr 14, 2018·Journal of Enzyme Inhibition and Medicinal Chemistry·Hongzhi LinHaopeng Sun
Nov 16, 2018·Angewandte Chemie·Saleta Vazquez-RodriguezPaul E Brennan
Oct 12, 2019·Nature Reviews. Drug Discovery·Soufiane Boumahdi, Frederic J de Sauvage
Jan 11, 2019·Nature Communications·James E LongbothamDanica Galonić Fujimori
Apr 25, 2018·Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences·A Ganesan
Feb 19, 2021·Journal of Hematology & Oncology·Guan-Jun YangJiong Chen
Feb 13, 2019·Bioorganic & Medicinal Chemistry·Yuka MiyakeTakayoshi Suzuki
Jun 24, 2020·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Sarder ArifuzzamanRabeya Khatun
May 13, 2019·Trends in Pharmacological Sciences·Timothy R BishopMichael A Erb
Jan 5, 2021·Journal of Medicinal Chemistry·Candice Soares de MeloSandeep R Ghorpade
Mar 15, 2018·Journal of Medicinal Chemistry·John R HortonXiaodong Cheng
Nov 6, 2018·Journal of Medicinal Chemistry·John R HortonXiaodong Cheng
Jan 28, 2020·Biochemistry·Nektaria PetronikolouDanica Galonić Fujimori

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