qHTS to Identify Inhibitors of NNMT1

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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. During this period, the project team successfully optimized a biochemical assay that was used to screen over 100,000 compounds for inhibitory activity against NNMT. Counter-screens against two components of the assay, and three related methyltransferase enzymes, were performed to filter out the false positives. Several chemotypes were identified with favorable activity profiles, and in vitro target engagement and cellular inhibition were assessed. 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. After the project was accepted by the NCI Experimental Therapeutics (NExT) program under the management of Chemical Biology Consortium (CBC), four potent and selective triazolone 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. Ongoing and future activities will focus on the further characterization in multiple efficacy and survival models of both these compounds and future analogs in combination with the standard of care treatment for ovarian cancer.