8U8X

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

Summary for 8U8X

• Entry DOI: 10.2210/pdb8u8x/pdb
• Descriptor: Receptor tyrosine-protein kinase erbB-2, 1-{(1R,3r,5S)-3-[(3M)-4-methyl-3-{3-methyl-4-[(1-methyl-1H-benzimidazol-5-yl)oxy]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-8-azabicyclo[3.2.1]octan-8-yl}propan-1-one, DI(HYDROXYETHYL)ETHER, ... (5 entities in total)
• Functional Keywords: proto-oncogene c-erbb-2, tyrosine kinase-type cell surface, signaling protein, transferase-inhibitor complex, transferase/inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 40200.76

Authors

Wang, J.,Mou, T.C. (deposition date: 2023-09-18, release date: 2024-06-12, Last modification date: 2024-10-30)

Primary citation

Hicken, E.J.,Brown, K.,Dwulet, N.C.,Gaudino, J.J.,Hansen, E.P.,Hartley, D.P.,Kowalski, J.P.,Laird, E.R.,Lazzara, N.C.,Li, B.,Mou, T.C.,Mutryn, M.F.,Oko, L.,Pajk, S.,Pipal, R.W.,Rosen, R.Z.,Shelp, R.,Singh, A.,Wang, J.,Wise, C.E.,Wong, C.,Wong, J.Y.
Discovery of Potent and Selective Covalent Inhibitors of HER2 WT and HER2 YVMA .
J.Med.Chem., 67:9759-9771, 2024

PubMed Abstract: 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 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 and HER2 mutants while sparing EGFR activity. Herein, we describe the development of a potent, covalent inhibitor of HER2 and the YVMA insertion mutant while providing oral bioavailability and avoiding the inhibition of EGFR.

PubMed: 38820338
DOI: 10.1021/acs.jmedchem.4c00978

Experimental method

X-RAY DIFFRACTION (1.69 Å)