Discovery\nof Novel Pyrimidine Derivatives as Human\nPin1 Covalent Inhibitors

Pin1 (peptidyl-prolyl cis–trans isomerase NIMA-interacting\n1) is a unique peptidyl-prolyl isomerase (PPIase), and inactivation\nof Pin1 with a covalent inhibitor is a potential strategy for developing\nanticancer agents. Herein, a series of sulfolane amino-substituted\n2-chloro-5-nitropyrimidine derivatives were disclosed as structurally\ndistinct covalent inhibitors toward Pin1, which were validated for\ntheir covalent binding to Cys113 of Pin1 by X-ray cocrystal structures\nof compounds <b>4a</b> (IC<sub>50</sub> = 11.55 μM) and <b>6a</b> (IC<sub>50</sub> = 3.15 μM). This work provided a\nnew approach for covalent inhibition of Pin1 by taking advantage of\nthe 2-chloro-5-nitropyrimidine as the electrophilic warhead, which\nmight benefit the discovery of potent and drug-like Pin1 inhibitors.