Phospho-BRD4 IDR-Targeting Compounds as Antiviral and Anticancer Agents

 

Phospho-BRD4 IDR-Targeting Compounds as Antiviral and Anticancer Agents

 

Date: 18^th November, 2024 (Monday)

Time: 4 - 5 pm (HKT)

Prof. Cheng-Ming Chiang

 

Simmons Comprehensive Cancer Center

University of Texas Southwestern Medical Center

Bromodomain-containing protein 4 (BRD4) is an epigenetic regulator and transcription cofactor whose phosphorylation by casein kinase II (CK2) and dephosphorylation by protein phosphatase 2A (PP2A) modulates its function in gene-specific targeting and recruitment of transcriptional regulators and chromatin modifiers.  BRD4 has emerged as an important cancer therapeutic target due to widely available small-molecule inhibitors, such as JQ1 and I-BET, targeting the bromodomain and extra-terminal (BET) family members.  Besides transcriptional control, BRD4 also plays a crucial role in genome dynamics regulating cell cycle progression, DNA damage response, chromatin structure maintenance, stem cell reprogramming, cell lineage differentiation, viral latency and reactivation, heart disease, osteoporosis, aging, and neuronal degeneration.  While BET inhibitors and degraders show promising anticancer effects, issues related to off-target effects and drug resistance remain a challenge in BET-targeted therapeutics development.  Recently, we identified a new class of small-molecule inhibitors targeting an intrinsically disordered region (IDR) of phospho-BRD4 that interacts with distinct transcription/replication and DNA damage response (DDR) factors, including p53, c-Myc, AP-1, cancer-associated human papillomavirus E2, 53BP1, and BARD1.  Some of these compounds effectively block HPV genome replication and cancer cell growth, migration, and in vivo mouse tumor formation and metastasis.  These first-in-class protein-protein interaction (PPI) inhibitors targeting a phosphorylated IDR of BRD4 highlight a molecular action that is distinct from the widely used BET bromodomain inhibitors and is more target-selective in minimalizing side effects and drug resistance for future antiviral and anticancer drug development.