Highly Selective Sub-Nanomolar Cathepsin S Inhibitors by Merging Fragment Binders with Nitrile Inhibitors.,Journal of Medicinal Chemistry

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Highly Selective Sub-Nanomolar Cathepsin S Inhibitors by Merging Fragment Binders with Nitrile Inhibitors.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-09-03 , DOI: 10.1021/acs.jmedchem.0c00949
Markus Schade ₁ , Beatrix Merla ₁ , Bernhard Lesch ₁ , Markus Wagener ₁ , Simone Timmermanns ₁ , Katrien Pletinckx ₁ , Torsten Hertrampf ₁

Affiliation

Pharmacological inhibition of cathepsin S (CatS) allows for a specific modulation of the adaptive immune system and many major diseases. Here, we used NMR fragment screening and crystal structure-aided merging to synthesize novel, highly selective CatS inhibitors with picomolar enzymatic Ki values and nanomolar functional activity in human Raji cells. Noncovalent fragment hits revealed binding hotspots, while the covalent inhibitor structure–activity relationship enabled efficient potency optimization.

中文翻译：

通过将片段结合剂与腈抑制剂合并，实现高度选择性的亚纳米级组织蛋白酶S抑制剂。

组织蛋白酶S（CatS）的药理抑制作用可以对适应性免疫系统和许多主要疾病进行特异性调节。在这里，我们使用NMR片段筛查和晶体结构辅助合并来合成新型，高选择性CatS抑制剂，其在人Raji细胞中具有皮摩尔酶Ki和纳米摩尔功能活性。非共价片段命中揭示了结合热点，而共价抑制剂的结构与活性之间的关系实现了有效的效能优化。

更新日期：2020-10-22

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