DEVELOPMENT OF TARGETED KINASE INHIBITORS THAT MODULATE THE CELL CYCLE

In mammalian cells, CDK4/6 associate with D-type cyclins and mediate progression through the G₁ phase when the cell prepares to initiate DNA synthesis. The detrimental effects of aberrant CYCLIN D1 activity is evident in mantle cell lymphoma (MCL), a well-defined and aggressive B-cell non-Hodgkin’s lymphoma (B-NHL) that is genetically characterized by the t(11;14)(q13;q32) chromosomal translocation which results in constitutive over-expression of CYCLIN D1. Although selective CDK4/6 inhibitors are cytostatic, these agents sensitize MCL cells to other cytotoxic drugs due to the fact that they frequently exhibit lesions in other signaling pathways, including those mediated by the B-cell receptor (BCR), PI3K, WNT and TGF-ß. Of these, dysregulated PI3K signaling is one of the most widely studied and represents an attractive therapeutic target.

Towards the goal of inhibiting both CYCLIN D/CDK4/Rb and PI3K-din MCL, we screened our collection of ATP-mimetics using in vitro tissue culture growth inhibitory (GI₅₀) assays. This screen revealed that one of these compounds, ON0123300, exhibited 10-100-fold higher cytotoxicities against MCL cell lines as compared to those of other tumors. ON123300 was effective in reducing the tumor burden in mouse xenograft models of MCL in the absence of adverse side effects. In addition, ON123300 effectively inhibited both the CDK4/Rb and PI3K/AKT/mTOR pathways in primary, patient-derived MCLs, including those that are resistant to ibrutinib.