Abstract B11: Preclinical and preliminary phase 1 trial results of JI‐101: A novel, oral tyrosine kinase inhibitor that selectively targets VEGFR2, EphB4, and PDGFR

Introduction: JI‐101 is a highly selective and potent angiogenesis inhibitor with unique EphB4 activity that distinguishes it from other agents in clinical development. We report the preclinical pharmacology and early clinical experience with this compound. Procedures: Lead optimization was used to identify cgi1842 (now JI‐101) with a targeted activity profile that is selective and unique. JI‐101 was tested in binding, enzymatic, and cell‐based assays for activity against kinase and non‐kinase targets. Preclinical in vivo testing for PK, PD, efficacy, and safety pharmacology was performed in mouse, rat, guinea pig, and dog. A Phase I clinical trial is underway: 9 patients, 3/cohort, are being treated with 28‐day oral daily dosing at 100 mg, 200 mg, and 400 mg. PK, PD, and imaging analyses are being performed. Data: JI‐101 has a MW of 466D and high ( Conclusions: JI‐101 potently inhibits 3 critical angiogenic kinases (VEGFR2, EphB4, and PDGFR) and is the only such “triple” angiogenesis inhibitor currently in development. JI‐101 shows robust preclinical and clinical pharmacology and is well‐tolerated to date in human trials. In tumors where EphB4 may play an oncogenic role, such as head and neck cancer, JI‐101 may have anti‐proliferative effects in addition to anti‐angiogenic effects and should be amenable to combination therapy. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B11.