8u8x

crystal structure of the receptor tyrosine kinase Human HER2 (ERBB2) YVMA mutant kinase domain in complex with inhibitor compound 27

spinqualitylabelsall models 8u8x, resolution 1.69Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8u8x is a 1 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 1.69Å Ligands: CL, PEG, W9N Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed HER2 overexpression and amplification have been identified as oncogenic drivers, and the development of therapies to treat tumors harboring these markers has received considerable attention. Activation of HER2 signaling and subsequent cell growth can also be induced by HER2 mutations, including the common YVMA insertion in exon 20 within the kinase domain. Enhertu is currently the only approved treatment for HER2 mutant tumors in NSCLC. TKIs tested in this space have suffered from off-target activity, primarily due to EGFR(WT) inhibition or attenuated activity against HER2 mutants. The goal of this work was to identify a TKI that would provide robust inhibition of oncogenic HER2(WT) and HER2 mutants while sparing EGFR(WT) activity. Herein, we describe the development of a potent, covalent inhibitor of HER2(WT) and the YVMA insertion mutant while providing oral bioavailability and avoiding the inhibition of EGFR(WT). Discovery of Potent and Selective Covalent Inhibitors of HER2(WT) and HER2(YVMA).,Hicken EJ, Brown K, Dwulet NC, Gaudino JJ, Hansen EP, Hartley DP, Kowalski JP, Laird ER, Lazzara NC, Li B, Mou TC, Mutryn MF, Oko L, Pajk S, Pipal RW, Rosen RZ, Shelp R, Singh A, Wang J, Wise CE, Wong C, Wong JY J Med Chem. 2024 May 31. doi: 10.1021/acs.jmedchem.4c00978. PMID:38820338 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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