Discovery of Novel Pyrimidine Derivatives as Human Pin1 Covalent Inhibitors

PIN1 (peptidyl-prolyl cis-trans isomerase NIMA-interacting 1) is a unique peptidyl-prolyl isomerase (PPIase), and inactivation of PIN1 with a covalent inhibitor is a potential strategy for developing Anticancer agents. Herein, a series of sulfolane amino-substituted 2-chloro-5-nitropyrimidine derivatives were disclosed as structurally distinct covalent inhibitors toward PIN1, which were validated for their covalent binding to Cys113 of PIN1 by X-ray cocrystal structures of compounds 4a (IC₅₀ = 11.55 μM) and 6a (IC₅₀ = 3.15 μM). This work provided a new approach for covalent inhibition of PIN1 by taking advantage of the 2-chloro-5-nitropyrimidine as the electrophilic warhead, which might benefit the discovery of potent and drug-like PIN1 inhibitors.