9inp
From Proteopedia
Human Pin1 (Peptidyl-prolyl cis-trans isomerase) catalytic domain in complex with a covalent inhibitor
Structural highlights
FunctionPIN1_HUMAN Essential PPIase that regulates mitosis presumably by interacting with NIMA and attenuating its mitosis-promoting activity. Displays a preference for an acidic residue N-terminal to the isomerized proline bond. Catalyzes pSer/Thr-Pro cis/trans isomerizations. Down-regulates kinase activity of BTK. Can transactivate multiple oncogenes and induce centrosome amplification, chromosome instability and cell transformation. Required for the efficient dephosphorylation and recycling of RAF1 after mitogen activation.[1] [2] [3] Publication Abstract from PubMedPin1 (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 (IC(50) = 11.55 muM) and 6a (IC(50) = 3.15 muM). 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. Discovery of Novel Pyrimidine Derivatives as Human Pin1 Covalent Inhibitors.,Tian M, Wang X, Tang G, Cui G, Zhou J, Jin J, Xu B ACS Med Chem Lett. 2024 Dec 20;16(1):101-108. doi: , 10.1021/acsmedchemlett.4c00477. eCollection 2025 Jan 9. PMID:39811131[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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Categories: Homo sapiens | Large Structures | Tian MZ | Wang XY | Xu BL | Zhou J
