Targeted Polypharmacology: Discovery of a Highly Potent Non-Hydroxamate Dual Matrix Metalloproteinase (MMP)-10/-13 Inhibitor

Matrix metalloproteinases (MMPs) play a key role in many diseases like cancer, atherosclerosis or arthritis. Interest in MMP inhibition has been revitalized very recently as the knowledge on the underlying network of biological pathways is steadily growing. On the basis of this new insight into the relevance of MMP-10 and MMP-13 within the MMP network and the ban of hydroxamate inhibitors from clinical development, the discovery of non-hydroxamate multitarget drugs against specific MMPs is of foremost interest. Here, we disclose the discovery of a very potent and selective non-hydroxamate MMP-10/-13 inhibitor. The high potency (IC50 of 31 nM [MMP-10] and 5 nM [MMP-13]) and selectivity over MMP-1, -2, -3, -7, -8, -9, -12, and -14 enable this compound to decipher disease causing MMP networks and to generate new treatment options through targeted polypharmacology.基质金属蛋白酶（Matrix metalloproteinases，MMPs）在癌症、动脉粥样硬化、关节炎等多种疾病中发挥关键作用。近年来，随着对其介导的生物学通路网络的认知不断深化，人们对MMP抑制疗法的研究兴趣再度升温。基于对MMP-10与MMP-13在MMP网络中作用相关性的新认知，以及羟肟酸类抑制剂（hydroxamate inhibitors）被禁止用于临床开发的现状，针对特定MMP的非羟肟酸类多靶点药物的研发已成为当前的核心研究热点。本文报道了一种强效且高选择性的非羟肟酸类MMP-10/-13抑制剂的发现过程。该化合物活性优异，对MMP-10的半最大效应浓度IC50为31 nM，对MMP-13为5 nM，且对MMP-1、-2、-3、-7、-8、-9、-12及-14均具有良好的选择性，可用于解析疾病相关的MMP网络，并通过靶向多药理学策略为疾病治疗开辟全新的潜在治疗途径。