DDRE-11. DEVELOPMENT OF THE FIRST-IN-CLASS INHIBITOR OF CHD4 - SENSITIZING RESISTANT GLIOMAS

Abstract

Abstract Glioblastoma is a lethal brain tumor with high recurrence rate. CHD4 overexpression, which drives resistance to DNA damage, is one of the major sources of recurrence. Since standard GBM treatments like radiation and temozolomide chemotherapy create DNA damage, inhibition of CHD4 offers a new therapeutic option for resensitizing GBM. CHD4 is a ubiquitously expressed ATP-dependent chromatin remodeler, which plays a crucial role in epigenetic regulation of gene expression and in DNA damage repair. Structurally, CHD4 contains an HMG-like domain, PHD domains, two chromodomains, a catalytic ATPase module, two domains of unknown function (DUF) and a C-terminal domain CHDCT2. Currently, no specific inhibitors targeting this chromatin remodeler have been reported yet. We aim to develop the first-in-class inhibitor targeting chromo-domain of CHD4. We have performed in silico screens to identify small molecules binding to the chromo-domains of CHD4. We present our growing in vitro data demonstrating biophysical properties and mechanism-of-action of these novel inhibitors. We expect that the experiments proposed here will result in the development of the first-in-class CHD4 inhibitor which can be used in the future not only to better study the physiological role of CHD4 but also to determine its potential as a novel targeted therapy for GBM.