4MKC

Crystal Structure of Anaplastic Lymphoma Kinase Complexed with LDK378

4MKC の概要

• エントリーDOI: 10.2210/pdb4mkc/pdb
• 関連するPDBエントリー: 3L9P 3LCS 3LCT
• 分子名称: 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)
• 機能のキーワード: kinase domain, phosphotransferase, atp binding, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cell membrane ; Single-pass type I membrane protein : Q9UM73
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 42357.82

構造登録者

Lee, C.C.,Spraggon, G. (登録日: 2013-09-04, 公開日: 2014-04-09, 最終更新日: 2023-09-20)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.01 Å)