8fe5

Structure of J-PKAc chimera complexed with Aplithianine B

spinqualitylabelsall models 8fe5, resolution 2.51Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8fe5 is a 4 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 2.51Å Ligands: SEP, TPO, XTT Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed The DNAJB1-PRKACA oncogenic gene fusion results in an active kinase enzyme, J-PKAcalpha, that has been identified as an attractive antitumor target for fibrolamellar hepatocellular carcinoma (FLHCC). A high-throughput assay was used to identify inhibitors of J-PKAcalpha catalytic activity by screening the NCI Program for Natural Product Discovery (NPNPD) prefractionated natural product library. Purification of the active agent from a single fraction of an Aplidium sp. marine tunicate led to the discovery of two unprecedented alkaloids, aplithianines A (1) and B (2). Aplithianine A (1) showed potent inhibition against J-PKAcalpha with an IC(50) of approximately 1 muM in the primary screening assay. In kinome screening, 1 inhibited wild-type PKA with an IC(50) of 84 nM. Further mechanistic studies including cocrystallization and X-ray diffraction experiments revealed that 1 inhibited PKAcalpha catalytic activity by competitively binding to the ATP pocket. Human kinome profiling of 1 against a panel of 370 kinases revealed potent inhibition of select serine/threonine kinases in the CLK and PKG families with IC(50) values in the range approximately 11-90 nM. An efficient, four-step total synthesis of 1 has been accomplished, enabling further evaluation of aplithianines as biologically relevant kinase inhibitors. Discovery and Synthesis of a Naturally Derived Protein Kinase Inhibitor that Selectively Inhibits Distinct Classes of Serine/Threonine Kinases.,Du L, Wilson BAP, Li N, Shah R, Dalilian M, Wang D, Smith EA, Wamiru A, Goncharova EI, Zhang P, O'Keefe BR J Nat Prod. 2023 Oct 27;86(10):2283-2293. doi: 10.1021/acs.jnatprod.3c00394. Epub , 2023 Oct 16. PMID:37843072 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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