4MKC

Crystal Structure of Anaplastic Lymphoma Kinase Complexed with LDK378

Summary for 4MKC

• Entry DOI: 10.2210/pdb4mkc/pdb
• Related: 3L9P 3LCS 3LCT
• Descriptor: ALK tyrosine kinase receptor, GLYCEROL, 5-chloro-N~2~-[5-methyl-4-(piperidin-4-yl)-2-(propan-2-yloxy)phenyl]-N~4~-[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine, ... (4 entities in total)
• Functional Keywords: kinase domain, phosphotransferase, atp binding, transferase, 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: 42357.82

Authors

Lee, C.C.,Spraggon, G. (deposition date: 2013-09-04, release date: 2014-04-09, Last modification date: 2023-09-20)

Primary citation

Friboulet, L.,Li, N.,Katayama, R.,Lee, C.C.,Gainor, J.F.,Crystal, A.S.,Michellys, P.Y.,Awad, M.M.,Yanagitani, N.,Kim, S.,Pferdekamper, A.C.,Li, J.,Kasibhatla, S.,Sun, F.,Sun, X.,Hua, S.,McNamara, P.,Mahmood, S.,Lockerman, E.L.,Fujita, N.,Nishio, M.,Harris, J.L.,Shaw, A.T.,Engelman, J.A.
The ALK Inhibitor Ceritinib Overcomes Crizotinib Resistance in Non-Small Cell Lung Cancer.
Cancer Discov, 4:662-673, 2014

PubMed Abstract: Non-small cell lung cancers (NSCLC) harboring anaplastic lymphoma kinase (ALK) gene rearrangements invariably develop resistance to the ALK tyrosine kinase inhibitor (TKI) crizotinib. Herein, we report the first preclinical evaluation of the next-generation ALK TKI, ceritinib (LDK378), in the setting of crizotinib resistance. An interrogation of in vitro and in vivo models of acquired resistance to crizotinib, including cell lines established from biopsies of patients with crizotinib-resistant NSCLC, revealed that ceritinib potently overcomes crizotinib-resistant mutations. In particular, ceritinib effectively inhibits ALK harboring L1196M, G1269A, I1171T, and S1206Y mutations, and a cocrystal structure of ceritinib bound to ALK provides structural bases for this increased potency. However, we observed that ceritinib did not overcome two crizotinib-resistant ALK mutations, G1202R and F1174C, and one of these mutations was identified in 5 of 11 biopsies from patients with acquired resistance to ceritinib. Altogether, our results demonstrate that ceritinib can overcome crizotinib resistance, consistent with clinical data showing marked efficacy of ceritinib in patients with crizotinib-resistant disease.

PubMed: 24675041
DOI: 10.1158/2159-8290.CD-13-0846

Experimental method

X-RAY DIFFRACTION (2.01 Å)