PRECLINICAL INVESTIGATION OF 3-DEAZANEPLANOCIN A (DZNEP) ANALOG 1-3 AS A NEW EPIGENETIC ANTICANCER AGENT IN HUMAN ACUTE MYELOID LEUKEMIA (AML) AND METASTATIC BREAST CANCER

Abstract

We have recently reported that 3-Deazaneplanocin A (DZNep) is a histone methylation inhibitor that can deplete oncogenic PRC2 complex and induce strong apoptosis in cancer cells but not in normal cells. To develop DZNep analogues toward druggability, we tested over 300 DZNep analogues for structure and activity relationship (SAR) analysis. This study led to one candidate compound named as I-3 that has shown promising result. The aim of my project is to characterize the anti-cancer effects of I-3 in acute myeloid leukemia (AML) and aggressive breast cancer. We found that I-3 targets not only bulk leukemic cells but also leukemia stem cells in AML. Moreover, I-3 in combination with HDAC inhibitor SAHA inhibits the metastasis property of MDA-MB-231 cells both in vitro and in vivo in part through E-cadherin induction. Our results demonstrated I-3 as a novel chromatin remodeling compound may constitute a novel potential for cancer therapy.