In our earlier work, we have presented the development of a novel dual specificity kinase inhibitor, ON 123300, which exhibits potent activity against Mantle Cell Lymphomas (MCLs) both in vitro and in vivo. Mantle cell lymphoma is genetically characterized by the t(11;14)(q13;q32) chromosomal translocation which results in constitutive overexpression of cyclin D1. In addition, MCLs also activate other pathways, including aberrant B-Cell Receptor and PI3K/AKT/mTOR signaling. As a result, MCL has a poor clinical outcome with a median survival of 4-5 years. We have shown that ON123300, which inhibits both CDK4/6 and PI3K-a (the predominant PI3K catalytic subunit expressed in MCL cells), was a superior inducer of apoptosis of MCL cells when compared to PD0332991, a selective inhibitor of CDK4/6 kinases. In this study, we have made water-soluble analogs of ON 123300 (lactate, fumarate, citrate, sulfate, triflate and mesylate) and tested the effects of ON 123300-lactate in nude mouse xenograft assays using Z138 MCL cells. These studies revealed a strong inhibition of tumor growth when tumor-bearing mice were treated daily with 100 mg/kg of ON123300-lactate. In addition, there was little evidence of toxicity as measured by change in the body weight in ON123300-lactate treated mice.

Targeting of PI3K-a and CDK4/6 kinases in mantle cell lymphomas with dual kinase inhibitor ON 123300-lactate

248th National Meeting (2014)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.