Targetirng The ?H2AX-MDC1 Axis For Cancer Therapeutics

DNA double-strand breaks(DSBs)are the most serious and toxic type of DNA damage in mammalian cells.Mis-repair or un-repair of DSBs will cause either cell death or genomic instability,which can contribute to the development of human diseases including cancer.Thus,the cells have evolved two major DSB repair pathways,namly homologous recombination(HR)and non-homologous end joining(NHEJ),to ensure proper and timely repair of DSBs and maintain the integrity of the genome.HR uses the homologous sequences as a template to repair broken DNA and retrieve sequences that are lost due to DNA damage.HR invovles many tumor susceptibility genes,mutations and deletions of which can cause HR defects,leading to genomic instability and cancer.However,HR deficiency is also used as a therapeutic target in cancer therapy.A novel and promising cancer therapy has emerged by attacking HR defects in cancer cells.For example,familial breast cancers or ovarian cancers carrying germline mutations of the HR genes BRCA1 and BRCA2 are HR deficient and hypersensitive to PARP inhibitors(PARPi)due to "synthetic lethal" effect with HR defects.Despite the success of PARPi in treatment of breast or ovarian cancer with BRCA1/BRCA2 germline mutations,many patients with HR defects are not sensitive to PARPi as expected.One reason is that these patients may maintain a sufficient level of HR activity,which renders cells resistant to PARPi.Our research shows that one of the remaining HR pathways is mediated by the interaction between phosphorylated histone H2AX(yH2AX)and MDC1.Therefore,in order to enhance the sensitivity of these cancer cells to PARPi,we taget the yHAX-MDC1 axis and design small molecule compounds to aggravate the HR deficiency of cancer cells.Based on the structure of phosphorylated SQEY motif of yH2AX,we used computer-aided drug design to perform virtual ligand screening of ChemDiv chemical library and search for candidate compounds that disrupt the ?H2AX-MDC1 interaction.Using our newly established HR reporter system,we further screened these candidates and identified a few of small molecule compounds that inhibit ?H2AX-mediated HR.In long term,we aim to develop lead compounds into a novel tumor-targeting drug as single agent or a combination drug that enhances the therapeutic effects of PARP inhibitors.