S134 Kinase Selectivity Profiles Of Nintedanib And Imatinib

Abstract

<h3>Introduction</h3> Tyrosine kinase inhibition has shown inconsistent success in the treatment of idiopathic pulmonary fibrosis (IPF). While a study of imatinib showed no impact on survival or lung function in a placebo-controlled study, two recently announced placebo-controlled phase 3 trials of nintedanib demonstrated statistically significant impact on forced vital capacity. Comparing the kinase target profiles could inform future target selection for drugs in IPF. <h3>Methods</h3> <i>In vitro</i> kinase selectivity data of nintedanib and imatinib were collected using the kinomescan platform (DiscoveRx Inc). Binding data (% binding) for 451 human kinases (~80% of the human kinome) were initially collected at a single concentration (10 uM). For kinases that displayed significant binding, potencies (K_D) were measured in dose-response format. <h3>Results</h3> At a common concentration of 100 nM, imatinib and nintedanib bound to 12 and 50 kinases, respectively. Maximal drug concentrations (C_max) observed in patients were used to project therapeutically relevant kinase inhibition for both drugs. Using these criteria, nintedanib binds 44 kinases at drug levels seen in patients (K_D &lt; C_maxof 64 nM). Imatinib binds 34 kinases at drug levels seen in patients (K_D &lt; C_maxof 7500 nM). 14 kinases were bound by both compounds, including PDGFRA, PDGFRB and VEGFR2. <h3>Conclusions</h3> Our results suggest that nintedanib and imatinib have partially overlapping inhibition profiles; the kinases that are targeted by both agents are unlikely to be responsible for efficacy differences. Further work is required to identify which of the remaining kinase target (s) are responsible for efficacy in IPF and could therefore represent targets for follow-up compounds.