Senn Nicole, Ott Michael, Lanz Jan, Riedl Rainer
Institute of Chemistry and Biotechnology, Center for Organic and Medicinal Chemistry, ZHAW Zurich University of Applied Sciences , Einsiedlerstrasse 31, 8820 Wädenswil, Switzerland.
J Med Chem. 2017 Dec 14;60(23):9585-9598. doi: 10.1021/acs.jmedchem.7b01001. Epub 2017 Oct 13.
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 (IC 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（MMPs）在许多疾病如癌症、动脉粥样硬化或关节炎中起关键作用。随着对生物途径潜在网络的认识不断增加，对MMP抑制的兴趣最近得以重振。基于对MMP网络中MMP - 10和MMP - 13相关性的这一新见解以及临床开发中异羟肟酸酯抑制剂的禁用，发现针对特定MMPs的非异羟肟酸酯多靶点药物备受关注。在此，我们披露了一种非常强效且选择性的非异羟肟酸酯MMP - 10/-13抑制剂的发现。其高效性（MMP - 10的IC为31 nM，MMP - 13的IC为5 nM）以及对MMP - 1、-2、-3、-7、-8、-9、-12和-14的选择性，使该化合物能够解析导致疾病的MMP网络，并通过靶向多药理学产生新的治疗选择。
