Abstract

Natural Product Drug Discovery for Cancer: From Primary HTS Directly to Phase I Clinical Trial

Mark Frattini, Associate Professor, Columbia University Medical Center

Cdc7 is a highly conserved serine/threonine protein kinase required for the initiation of DNA replication and G1 to S phase progression. It is a target of the S-phase checkpoint pathway and has an important role in promoting a faithful response to DNA damage in eukaryotic organisms. Down-regulation or inhibition of Cdc7 kinase activity results in slowing of S-phase progression and cell cycle arrest followed by accumulation of nuclear damage and eventual cell death via apoptosis. This kinase and its known substrate (the mini-chromosome maintenance or MCM replicative helicase) are over-expressed in many different tumors including the majority of solid tumors and hematologic malignancies. The Cdc7 signal transduction pathway has emerged over the last few years as a prime candidate for targeted cancer therapy, and in fact many pharmaceutical companies now have preclinical programs centered around this kinase pathway. Recently we have identified a novel natural-product small molecule inhibitor through an HTS screening approach, developed it pre-clinically, and shown it to be efficacious in standard cell based cytotoxicity assays and multiple different animal models of cancer. We will be taking this HTS hit directly to a Phase I clinical trial for patients with refractory cancer in mid-2014.