qHTS to Identify Inhibitors of NNMT1

National Center For Advancing Translational Sciences

Investigators

Abstract

Members of the project team have identified a central role of the metabolic enzyme NNMT in the stroma of ovarian cancer. The target enzyme is highly expressed in the stroma of ovarian cancer metastases and is also expressed in primary cancer-associated fibroblasts (CAFs). Knockdown of the enzyme leads to a reversion of many of the features of CAFs and attenuates their ability to promote cancer cell growth both in vitro and in vivo. Assays were developed to report on in vitro target engagement and cellular inhibition, and co-crystal structures of a number of hit compounds with recombinant human NNMT have been obtained and been used to guide the medicinal chemistry efforts. The project was accepted by the NCI Experimental Therapeutics (NExT) program under the management of Chemical Biology Consortium (CBC), and potent and selective analogs with attractive drug-like properties have been characterized in single-dose mouse pharmacokinetic-pharmacodynamic experiments and two compounds are being progressed towards proof-of-concept efficacy experiments in an ovarian cancer animal model.