7R7K

Structure of Human Anaplastic Lymphoma Kinase Domain in complex with (4-[6-amino-5-[(1~{R})-1-[5-fluoro-2-(triazol-2-yl)phenyl]ethoxy]-3-pyridyl]isoindolin-1-one)

Summary for 7R7K

• Entry DOI: 10.2210/pdb7r7k/pdb
• Descriptor: ALK tyrosine kinase receptor, 4-(6-amino-5-{(1R)-1-[5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl]ethoxy}pyridin-3-yl)-2,3-dihydro-1H-isoindol-1-one (3 entities in total)
• Functional Keywords: kinase, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 37339.79

Authors

McTigue, M. (deposition date: 2021-06-24, release date: 2022-06-29, Last modification date: 2023-10-18)

Primary citation

Shiba-Ishii, A.,Johnson, T.W.,Dagogo-Jack, I.,Mino-Kenudson, M.,Johnson, T.R.,Wei, P.,Weinrich, S.L.,McTigue, M.A.,Walcott, M.A.,Nguyen-Phuong, L.,Dionne, K.,Acker, A.,Kiedrowski, L.A.,Do, A.,Peterson, J.L.,Barth, J.L.,Yeap, B.Y.,Gainor, J.F.,Lin, J.J.,Yoda, S.,Hata, A.N.
Analysis of lorlatinib analogs reveals a roadmap for targeting diverse compound resistance mutations in ALK-positive lung cancer.
Nat Cancer, 3:710-722, 2022

PubMed Abstract: Lorlatinib is currently the most advanced, potent and selective anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor for the treatment of ALK-positive non-small cell lung cancer in the clinic; however, diverse compound ALK mutations driving therapy resistance emerge. Here, we determine the spectrum of lorlatinib-resistant compound ALK mutations in patients, following treatment with lorlatinib, the majority of which involve ALK G1202R or I1171N/S/T. We further identify structurally diverse lorlatinib analogs that harbor differential selective profiles against G1202R versus I1171N/S/T compound ALK mutations. Structural analysis revealed increased potency against compound mutations through improved inhibition of either G1202R or I1171N/S/T mutant kinases. Overall, we propose a classification of heterogenous ALK compound mutations enabling the development of distinct therapeutic strategies for precision targeting following sequential tyrosine kinase inhibitors.

PubMed: 35726063
DOI: 10.1038/s43018-022-00399-6

Experimental method

X-RAY DIFFRACTION (1.831 Å)