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Clinical Cancer Research

Clinical Cancer Research

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The Potent ALK Inhibitor Brigatinib (AP26113) Overcomes Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors in Preclinical Models

Published:25 October 2016 DOI: 10.1158/1078-0432.CCR-16-0569
Sen Zhang,?R. Anjum,?R. Squillace,?S. Nadworny,?T. Zhou,?J. Keats,?Y. Ning,?Scott D. Wardwell,?David Miller,?Youngchul Song,?Lindsey W. Eichinger,?Lauren Moran,?Wei-sheng Huang,?Shuangying Liu,?D. Zou,?Yihan Wang,?Qurish K. Mohemmad,?H. G. Jang,?E. Ye,?N. Narasimhan,?Frank Y. Wang,?J. Miret,?Xiaotian Zhu,?T. Clackson,?D. Dalgarno,?W. Shakespeare,?V. Rivera

Abstract

Purpose: Non–small cell lung cancers (NSCLCs) harboring ALK gene rearrangements (ALK+) typically become resistant to the first-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) crizotinib through development of secondary resistance mutations in ALK or disease progression in the brain. Mutations that confer resistance to second-generation ALK TKIs ceritinib and alectinib have also been identified. Here, we report the structure and first comprehensive preclinical evaluation of the next-generation ALK TKI brigatinib. Experimental Design: A kinase screen was performed to evaluate the selectivity profile of brigatinib. The cellular and in vivo activities of ALK TKIs were compared using engineered and cancer-derived cell lines. The brigatinib–ALK co-structure was determined. Results: Brigatinib potently inhibits ALK and ROS1, with a high degree of selectivity over more than 250 kinases. Across a panel of ALK+ cell lines, brigatinib inhibited native ALK (IC50, 10 nmol/L) with 12-fold greater potency than crizotinib. Superior efficacy of brigatinib was also observed in mice with ALK+ tumors implanted subcutaneously or intracranially. Brigatinib maintained substantial activity against all 17 secondary ALK mutants tested in cellular assays and exhibited a superior inhibitory profile compared with crizotinib, ceritinib, and alectinib at clinically achievable concentrations. Brigatinib was the only TKI to maintain substantial activity against the most recalcitrant ALK resistance mutation, G1202R. The unique, potent, and pan-ALK mutant activity of brigatinib could be rationalized by structural analyses. Conclusions: Brigatinib is a highly potent and selective ALK inhibitor. These findings provide the molecular basis for the promising activity being observed in ALK+, crizotinib-resistant patients with NSCLC being treated with brigatinib in clinical trials. Clin Cancer Res; 22(22); 5527–38. ?2016 AACR.

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Related products
Procduct Name CAS Molecular Formula Supplier Price
Crizotinib 877399-52-5 C21H22Cl2FN5O 551 suppliers $5.00-$1963.50
Ceritinib (LDK378) 1032900-25-6 C28H36ClN5O3S 417 suppliers $25.00-$3600.00
Alectinib 1256580-46-7 C30H34N4O2 316 suppliers $35.00-$1504.50
Brigatinib 1197953-54-0 C29H39ClN7O2P 307 suppliers $5.00-$1504.50
AP26113 1197958-12-5 C26H34ClN6O2P 252 suppliers $28.00-$1169.00
ALK 18 suppliers Inquiry
ROS 18 suppliers Inquiry
AP26113 1197958-53-4 C24H30ClN6O2P 2 suppliers Inquiry

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