3AOX

X-ray crystal structure of human anaplastic lymphoma kinase in complex with CH5424802

Summary for 3AOX

• Entry DOI: 10.2210/pdb3aox/pdb
• Descriptor: ALK tyrosine kinase receptor, 9-ethyl-6,6-dimethyl-8-[4-(morpholin-4-yl)piperidin-1-yl]-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: alk kinase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cell membrane; Single-pass type I membrane protein: Q9UM73
• Total number of polymer chains: 1
• Total formula weight: 39545.49

Authors

Nagel, S.,Moertl, M.,Jestel, A.,Fukami, T.A. (deposition date: 2010-10-08, release date: 2011-05-25, Last modification date: 2023-11-01)

Primary citation

Sakamoto, H.,Tsukaguchi, T.,Hiroshima, S.,Kodama, T.,Kobayashi, T.,Fukami, T.A.,Oikawa, N.,Tsukuda, T.,Ishii, N.,Aoki, Y.
CH5424802, a selective ALK inhibitor capable of blocking the resistant gatekeeper mutant
Cancer Cell, 19:679-690, 2011

PubMed Abstract: Anaplastic lymphoma kinase (ALK) is a tyrosine kinase that is constitutively activated in certain cancers, following gene alterations such as chromosomal translocation, amplification, or point mutation. Here, we identified CH5424802, a potent, selective, and orally available ALK inhibitor with a unique chemical scaffold, showing preferential antitumor activity against cancers with gene alterations of ALK, such as nonsmall cell lung cancer (NSCLC) cells expressing EML4-ALK fusion and anaplastic large-cell lymphoma (ALCL) cells expressing NPM-ALK fusion in vitro and in vivo. CH5424802 inhibited ALK L1196M, which corresponds to the gatekeeper mutation conferring common resistance to kinase inhibitors, and blocked EML4-ALK L1196M-driven cell growth. Our results support the potential for clinical evaluation of CH5424802 for the treatment of patients with ALK-driven tumors.

PubMed: 21575866
DOI: 10.1016/j.ccr.2011.04.004

Experimental method

X-RAY DIFFRACTION (1.75 Å)