The VEGFR juxtamembrane (JM) domain is a key determinant of VEGFR kinase inhibitor activity.

  • Major finding: The VEGFR juxtamembrane (JM) domain is a key determinant of VEGFR kinase inhibitor activity.

  • Concept: Type IV kinase inhibitors stabilize the JM domain in an autoinhibitory conformation.

  • Impact: Type IV inhibitors can inhibit VEGFR kinase with high levels of efficiency and selectivity.

The VEGF receptor (VEGFR) family of receptor tyrosine kinases (RTK) has emerged as a therapeutic target in renal cell carcinoma (RCC) and other cancers, but the clinical efficacy and safety of small-molecule VEGFR inhibitors that have been approved for RCC varies significantly. VEGFR constructs containing only the catalytic kinase domain largely guided the design of these small-molecule inhibitors, but increasing evidence points to a role of the juxtamembrane (JM) domain in VEGFR kinase regulation and inhibitor potency. McTigue and colleagues therefore evaluated how a VEGFR construct including both the catalytic and JM domains (plus-JM) interacts with approved VEGFR kinase inhibitors. Crystal structures of plus-JM in complex with axitinib, pazopanib, sorafenib, sunitinib, and tivozanib revealed that, although each inhibitor similarly forced the aspartate-phenylalanine-glycine (DFG) segment of the activation loop to adopt an inactive “out” conformation, the VEGFR inhibitors had different effects on the JM domain, with axitinib, pazopanib, and sunitinib inducing an autoinhibitory JM “in” conformation and sorafenib and tivozanib sterically displacing the JM into an “out” conformation. VEGFR inhibitors that stabilized a JM-in conformation (termed type IV kinase inhibitors to distinguish them from ATP-pocket, DFG-pocket, or allosteric inhibitors) had at least a 10-fold higher binding affinity for the plus-JM construct than a construct lacking the JM domain (minus-JM). Additionally, the potencies of cell-based VEGFR inhibition were generally matched more closely by binding affinities for the plus-JM rather than the minus-JM construct. Moreover, plus-JM binding efficiency was significantly correlated with increased selectivity for VEGFR family kinases in a kinase screen and with longer progression-free survival in RCC clinical trials. Collectively, these findings provide insight into the underlying causes of the variable efficacy of VEGFR inhibitors and underscore the importance of using physiologically relevant target constructs in early stages of drug development to decrease the chances of failure in clinical testing.

McTigue M, Murray BW, Chen JH, Deng YL, Solowiej J, Kania RS. Molecular conformations, interactions, and properties associated with drug efficiency and clinical performance among VEGFR TK inhibitors. Proc Natl Acad Sci U S A 2012 Sept 17 [Epub ahead of print].

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