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. Using assays that were developed to report on in vitro target engagement and cellular inhibition, medicinal chemistry efforts have developed potent orally bioavailable selective inhibitors of NNMT. Lead compounds have shown positive PK/PD relationships in mice. Our collaborators at Univ of Chicago have shown that the lead inhibitor shows tumor and metastasis reduction in rodent cancer models, especially in combination with PD-L1 inhibitors. A novel mechanism has been proposed by which NNMT upregulation in CAFs causes global epigenetic changes that leads to secretion of complement factors which attract MDSCs and induce PD-L1 expression in them; this suppresses immunity mediated by PD-1 expressing CD8+ T cells.