9inr | pdb_00009inr

Crystal structure of PIN1 in complex with inhibitor C3

spinqualitylabelsall models 9inr, resolution 1.93Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9inr is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.93Å Ligands: A1D9K, PE3, SO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function PIN1_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. Publication Abstract from PubMed Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1) has emerged as a promising therapeutic target for cancer treatment. However, the current PIN1 inhibitors have shown limited efficacy in animal models, leaving the question of whether PIN1 is a proper oncologic target still unanswered. By screening a 1 trillion DNA-encoded library (DEL), we identified novel nonacidic compounds. Among resynthesized DEL compounds, DEL1067-56-469 (A0) is the most potent one (KD = 430 nM, IC(50) = 420 nM). Further optimization of A0 resulted in compound C10 with much improved potency (KD = 25 nM, IC(50) = 150 nM). As an alternative approach, C10 was then converted into proteolysis targeting chimeras (PROTACs) in order to achieve deeper downregulation of the PIN1 protein in cancer cell lines. Unfortunately, neither PIN1 inhibitors nor PIN1 PROTACs demonstrated meaningful antiproliferation activity. In addition, siRNA knock-down experiments provided unfavorable evidence of PIN1 as an oncologic target. Our findings highlight the complexity of targeting PIN1 for cancer therapy. Re-Evaluating PIN1 as a Therapeutic Target in Oncology Using Neutral Inhibitors and PROTACs.,Liu C, Chen Z, Chen T, Song H, Shen J, Yuan X, Xia S, Liu Q, Chen Q, Tian Q, Meng X, Han Z, Dong X, Yang Y, Cai L, Cheng X, Jia Y, Liu G, Li J, Ge J, Dou D J Med Chem. 2024 Sep 12;67(17):15780-15795. doi: 10.1021/acs.jmedchem.4c01412. , Epub 2024 Sep 4. PMID:39229909 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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