Dual Cyclin-Dependent Kinase Inhibitor Effective Against Multiple Myeloma in Preclinical Studies

Results obtained during preclinical studies support the continued development of a dual cyclin-dependent kinase inhibitor for the treatment of multiple myeloma (MM).

The experimental drug ON123300 was developed by Onconova Therapeutics Inc. (Newtown, PA, USA). It is a novel small molecule, dual inhibitor of the c-MYC activated kinases ARK5 (AMPK-related protein kinase 5) and CDK4 (cyclin-dependent kinase 4).

c-MYC (v-myc myelocytomatosis viral oncogene homolog protein) is a master transcription factor that disrupts normal control of cellular metabolism through proteins such as ARK5, while also activating the cell cycle through proteins such as CDK4. Inhibition of ARK5 by ON123300 results in the collapse of oncogene-altered energy metabolism, leading to cell death. Targeting CDK4 leads to G1 arrest, inhibiting MYC-driven cell cycle activation and DNA synthesis.

Despite new therapies, multiple myeloma remains incurable, and patients ultimately develop drug resistance and succumb to the disease. Investigators at Mount Sinai School of Medicine (New York, NY, USA) examined whether dual inhibition of CDK4 and ARK5 kinases using ON123300 would result in a better therapeutic outcome.

To this end they worked with cancer cell cultures and a mouse xenograft MM model. Results published in the March 1, 2016, issue of the journal Cancer Research revealed that treatment of multiple myeloma cell lines and primary samples with ON123300 in vitro resulted in rapid induction of cell-cycle arrest followed by apoptosis. MM cells sensitive to ON123300 were found to have a unique genomic signature.

ON123300-mediated ARK5 inhibition or treatment with ARK5-specific siRNAs (short inhibiting RNAs) resulted in the inhibition of the mTOR/S6K pathway and upregulation of the AMPK kinase cascade. AMPK upregulation caused increased SIRT1 (sirtuin 1, a histone deacetylase involved in numerous critical cell processes including DNA repair and apoptosis) levels and destabilization of steady-state MYC protein. Furthermore, ON123300 was very effective in inhibiting tumor growth in mouse xenograft assays.

"Our study results show that ON123300 induces cell death and negatively regulates key oncogenic pathways in multiple myeloma cells," said senior author Dr. Samir Parekh, associate professor of medicine, hematology, medical oncology, and oncological sciences at Mount Sinai School of Medicine. "This is the first report showing potent cytotoxicity of CDK4/ARK5 inhibition in MM and provides the foundation for further clinical trials using CDK4/ARK5 inhibitors to improve outcomes for MM patients. Even in the era of great drug development, there is an urgent need an urgent need to develop drugs that are less toxic and achieve longer remissions for all patients."

Related Links:
Onconova Therapeutics Inc.
Mount Sinai School of Medicine