BRD4 PROTAC degrader ARV-825 inhibits T-cell acute lymphoblastic leukemia by targeting 'Undruggable' Myc-pathway genes

Abstract Background T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive disease with a high risk of induction failure and poor outcomes, relapse due to drug resistance. Recent studies show that bromodomains extra-terminal (BET) protein inhibitors are promising anti-cancer agents. ARV-825, comprising BET inhibitor conjugated cereblon ligand, was recently developed attenuate the growth multiple tumors in vitro vivo. However, functional molecular mechanisms ARV-825 T-ALL remain unclear. This study aimed investigate therapeutic efficacy potential mechanism T-ALL. Methods Expression BRD4 were determined pediatric samples differential gene expression after treatment explored by RNA-seq quantitative reverse transcription-polymerase chain reaction. cell viability measured CCK8 assay administration. Cell cycle analyzed propidium iodide (PI) staining apoptosis assessed Annexin V/PI staining. BRD4, BRD3 BRD2 proteins detected western blot cells treated ARV-825. The effect on pathways involved verified chromatin immunoprecipitation (ChIP). Results higher compared T-cells from healthy donors. High indicated outcome. suppressed proliferation arresting inducing apoptosis, elevated poly-ADP ribose polymerase cleaved caspase 3. BRD3, degraded line reduced cells. had lower IC50 JQ1, dBET1 OTX015. perturbed H3K27Ac-Myc pathway c-Myc levels according ChIP. In xenograft model, significantly tumor led dysregulation Ki67 Moreover, inhibited depleting Conclusions indicates prognosis degrader can effectively suppress promote via depletion inhibition, thus providing new strategy for