Department of Microbiology and Immunology, Weill Cornell Medicine, 1300 York Avenue, Box 62, New York, New York 10065, United States.
Coferon, Inc., 25 Health Sciences Drive, Mailbox 123, Stony Brook, New York 11790, United States.
J Med Chem. 2020 Mar 26;63(6):3004-3027. doi: 10.1021/acs.jmedchem.9b01689. Epub 2020 Feb 27.
β-Tryptase, a homotetrameric serine protease, has four identical active sites facing a central pore, presenting an optimized setting for the rational design of bivalent inhibitors that bridge two adjacent sites. Using diol, hydroxymethyl phenols or benzoyl methyl hydroxamates, and boronic acid chemistries to reversibly join two [3-(1-acylpiperidin-4-yl)phenyl]methanamine core ligands, we have successfully produced a series of self-assembling heterodimeric inhibitors. These heterodimeric tryptase inhibitors demonstrate superior activity compared to monomeric modes of inhibition. X-ray crystallography validated the dimeric mechanism of inhibition, and compounds demonstrated high selectivity against related proteases, good target engagement, and tryptase inhibition in HMC1 xenograft models. Screening 3872 possible combinations from 44 boronic acid and 88 diol derivatives revealed several combinations that produced nanomolar inhibition, and seven unique pairs produced greater than 100-fold improvement in potency over monomeric inhibition. These heterodimeric tryptase inhibitors demonstrate the power of target-driven combinatorial chemistry to deliver bivalent drugs in a small molecule form.
β-胰凝乳蛋白酶，一种四聚体丝氨酸蛋白酶，具有四个相同的活性位点朝向中央孔，为合理设计桥接两个相邻位点的二价抑制剂提供了优化的设置。我们使用二醇、羟甲基苯酚或苯甲酰甲基羟胺酸和硼酸化学，可逆地连接两个[3-(1-酰基哌啶-4-基)苯基]甲胺核心配体，成功地生产了一系列自组装的杂二聚体抑制剂。与单体抑制模式相比，这些杂二聚体胰凝乳蛋白酶抑制剂表现出更高的活性。X 射线晶体学验证了抑制的二聚体机制，并且化合物表现出对相关蛋白酶的高选择性、良好的靶标结合以及在 HMC1 异种移植模型中的胰凝乳蛋白酶抑制作用。从 44 个硼酸和 88 个二醇衍生物中筛选 3872 种可能的组合，揭示了几种产生纳摩尔抑制的组合，并且有 7 对独特的组合在单体抑制的基础上提高了超过 100 倍的效力。这些杂二聚体胰凝乳蛋白酶抑制剂证明了基于靶标的组合化学在小分子形式下提供二价药物的强大功能。
