Elevated protein and activation levels of Src, a non-receptor tyrosine kinase, are thought to play important roles in primary tumor growth and metastatic progression. Several multikinase Src inhibitors have entered clinical trials (AZD0530, SKI-606) and one has recently reached the market (dasatinib). These multikinase inhibitors target the ubiquitous ATP substrate binding site, as do the vast majority of kinase inhibitors currently under investigation. Kinex Pharmaceuticals has developed a novel platform technology, MimeticaTM, that facilitates the development of peptide substrate site targeted inhibitors of kinases or phosphatases. The peptide substrate site is envisioned to be a more unique binding cavity, leading to more selective inhibitors, due to differing peptide substrate selectivity’s among the kinases. Utilizing this technology, Kinex developed KXO1, a novel small molecule, non-ATP competitive Src kinase inhibitor. Targeting the Src peptide substrate binding site provided much higher selectivity than is obtained with the ATP competitive Src inhibitors, as demonstrated by phosphotyrosine protein level analyses of cell lysates. KXO1 inhibits Src kinase activity in whole cells with low nM potency, Lyn and BCR-Abl at sub-micromolar potencies, yet is >1,000-fold less active against other tyrosine kinases such as EGFR, PDGFR, JAK1, JAK2, ZAP70 and Lck. KXO1 also has low nM potency as an in vitro inhibitor of tumor cell proliferation for a broad range of human cancer types. KXO1 substantially reduces the growth of human HT29 colon tumors in SCID mouse xenografts (T/C=30%) when dosed orally at 5 mg/kg/dose bid, and with no observed toxicity. KXO1 is currently completing late preclinical development and, in 2007, will be the first non-ATP competitive Src inhibitor to enter Phase I clinical trials.
98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA