title: The Potent ALK Inhibitor Brigatinib (AP26113) Overcomes Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors in Preclinical Models.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors: ARIAD Pharmaceuticals, Inc, Cambridge, Massachusetts.
authors: Sen
authors: S
authors: Zhang
authors: ARIAD Pharmaceuticals, Inc, Cambridge, Massachusetts.
authors: Rana
authors: R
authors: Anjum
authors: ARIAD Pharmaceuticals, Inc, Cambridge, Massachusetts.
authors: Rachel
authors: R
authors: Squillace
authors: ARIAD Pharmaceuticals, Inc, Cambridge, Massachusetts.
authors: Sara
authors: S
authors: Nadworny
authors: ARIAD Pharmaceuticals, Inc, Cambridge, Massachusetts.
authors: Tianjun
authors: T
authors: Zhou
authors: ARIAD Pharmaceuticals, Inc, Cambridge, Massachusetts.
authors: Jeff
authors: J
authors: Keats
authors: ARIAD Pharmaceuticals, Inc, Cambridge, Massachusetts.
authors: Yaoyu
authors: Y
authors: Ning
authors: ARIAD Pharmaceuticals, Inc, Cambridge, Massachusetts.
authors: Scott D
authors: SD
authors: Wardwell
authors: ARIAD Pharmaceuticals, Inc, Cambridge, Massachusetts.
authors: David
authors: D
authors: Miller
authors: ARIAD Pharmaceuticals, Inc, Cambridge, Massachusetts.
authors: Youngchul
authors: Y
authors: Song
authors: ARIAD Pharmaceuticals, Inc, Cambridge, Massachusetts.
authors: Lindsey
authors: L
authors: Eichinger
authors: ARIAD Pharmaceuticals, Inc, Cambridge, Massachusetts.
authors: Lauren
authors: L
authors: Moran
authors: ARIAD Pharmaceuticals, Inc, Cambridge, Massachusetts.
authors: Wei-Sheng
authors: WS
authors: Huang
authors: ARIAD Pharmaceuticals, Inc, Cambridge, Massachusetts.
authors: Shuangying
authors: S
authors: Liu
authors: ARIAD Pharmaceuticals, Inc, Cambridge, Massachusetts.
authors: Dong
authors: D
authors: Zou
authors: ARIAD Pharmaceuticals, Inc, Cambridge, Massachusetts.
authors: Yihan
authors: Y
authors: Wang
authors: ARIAD Pharmaceuticals, Inc, Cambridge, Massachusetts.
authors: Qurish
authors: Q
authors: Mohemmad
authors: ARIAD Pharmaceuticals, Inc, Cambridge, Massachusetts.
authors: Hyun Gyung
authors: HG
authors: Jang
authors: ARIAD Pharmaceuticals, Inc, Cambridge, Massachusetts.
authors: Emily
authors: E
authors: Ye
authors: ARIAD Pharmaceuticals, Inc, Cambridge, Massachusetts.
authors: Narayana
authors: N
authors: Narasimhan
authors: ARIAD Pharmaceuticals, Inc, Cambridge, Massachusetts.
authors: Frank
authors: F
authors: Wang
authors: ARIAD Pharmaceuticals, Inc, Cambridge, Massachusetts.
authors: Juan
authors: J
authors: Miret
authors: ARIAD Pharmaceuticals, Inc, Cambridge, Massachusetts.
authors: Xiaotian
authors: X
authors: Zhu
authors: ARIAD Pharmaceuticals, Inc, Cambridge, Massachusetts.
authors: Tim
authors: T
authors: Clackson
authors: ARIAD Pharmaceuticals, Inc, Cambridge, Massachusetts.
authors: David
authors: D
authors: Dalgarno
authors: ARIAD Pharmaceuticals, Inc, Cambridge, Massachusetts.
authors: William C
authors: WC
authors: Shakespeare
authors: ARIAD Pharmaceuticals, Inc, Cambridge, Massachusetts. victor.rivera@ariad.com.
authors: Victor M
authors: VM
authors: Rivera
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D000077547:Crizotinib; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D056945:Hep G2 Cells; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D009154:Mutation / Q000187:drug effects; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D013450:Sulfones / Q000494:pharmacology; D020298:U937 Cells
chemical_list: D000970:Antineoplastic Agents; D009943:Organophosphorus Compounds; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D011743:Pyrimidines; D013450:Sulfones; D000077547:Crizotinib; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases; C000598580:brigatinib; C586847:ceritinib