Abstract Rationale Aberrant signaling through platelet-derived growth factor receptor (PDGFR)α, PDGFRβ, and c-KIT tyrosine kinases drives cellular proliferation/migration and plays a key role in pulmonary arterial hypertension (PAH) pathophysiology. Imatinib mesylate, a tyrosine kinase inhibitor, has shown efficacy in PAH patients. However, tolerability issues including gastrointestinal side effects resulted in significant drug discontinuation in PAH trials, impeding further development. c-KIT activity in gut sub-mucosa is known to regulate gut contractility and motility. We propose that inhibitory effects of imatinib on c-KIT result in reduced gastrointestinal contractility contributing to gastrointestinal side effects. IKT-001, a novel, investigational prodrug of imatinib, was designed to minimize gastrointestinal exposure to imatinib and reduce gastrointestinal-related side effects. IKT-001 is stable in the gut and cleaved rapidly once entering the blood to generate free circulating imatinib. In vitro studies compared pharmacologic activity of IKT-001 and imatinib at key tyrosine kinases related to efficacy and tolerability. We also evaluated in vivo efficacy of IKT-001 in a rodent model of PAH. Methods In vitro pharmacology was assessed using biochemical and cell-based assays. Promega ADP-Glo assay technology was used to measure IKT-001 and imatinib activities at purified PDGFRα, PDGFRβ, and c-KIT enzymes. Primary cells and cell lines required to measure compound activities were obtained commercially and utilized for enzyme-linked immunosorbent- or homogeneous, time-resolved fluorescence-based assays measuring phosphorylation of receptor-tyrosine kinases and/or their substrates Erk1/2 phosphorylation. In vivo efficacy was assessed using single-dose SU5416 + low oxygen for 22 days to induce PAH in rats. Rats were treated with imatinib or IKT-001 starting on Day 22 under normoxic conditions until Day 43 terminal procedures. Echocardiography, hemodynamics, heart/lung measurements, and pulmonary vascular histology were performed on Day 21 (disease onset baseline) and Day 42 (end of treatment). Results In vitro findings indicate that IKT-001 has less inhibitory activity at PDGFRα/β and c-KIT compared with imatinib (Table). In the rat PAH model, treatment with IKT-001 after disease onset resulted in reduced impairment of pulmonary hemodynamics and improved right ventricular and pulmonary vascular remodeling. Efficacy of IKT-001 was similar to that observed for imatinib mesylate. Conclusions In vivo results confirm imatinib-like efficacy of IKT-001 in a PAH rat model, resulting from its conversion to imatinib in blood. Compared with imatinib, IKT-001 has less inhibitory activity at tyrosine kinases including PDGFRα/β and c-KIT supporting its potential to reduce on-target gastrointestinal side effects. Additional studies evaluating IKT-001 vs imatinib in models of gut motility are ongoing. This abstract is funded by: Inhibikase Therapeutics, Inc.
Adams et al. (Fri,) studied this question.