AI-assisted design and virtual profiling of targeted degraders for pancreatic cancer therapy via PROTAC technology.
Pancreatic cancer remains one of the most lethal malignancies because of late diagnosis, aggressive progression, therapy resistance, and limited effective treatment options. Bromodomain-containing protein 4 (BRD4) is an important epigenetic regulator implicated in pancreatic cancer progression through its role in transcriptional control, cell proliferation, and survival signaling. Targeted protein degradation using proteolysis-targeting chimeras (PROTACs) offers a potential strategy for eliminating disease-associated proteins through ubiquitin-proteasome-mediated degradation rather than transient pharmacological inhibition. In this study, an AI-assisted and structure-guided computational workflow was used to design and virtually prioritize BRD4-targeting PROTAC candidates recruiting DCAF15 as the E3 ligase component. The workflow integrated protein-structure evaluation, pharmacophore-based ligand screening, ADMET and Lipinski filtering, binary protein-ligand docking, molecular-interaction analysis, rational linker selection, BRD4-DCAF15 protein-protein docking, PROTAC-mediated ternary-complex docking, and molecular dynamics simulation. The results identified CLTTMPBA-linker-E7820 as a computationally prioritized PROTAC architecture with favorable predicted binding behavior, residue-level interaction patterns, and simulated ternary-complex stability. Importantly, this study is entirely computational and should be interpreted as an early-stage in silico prioritization framework rather than experimental evidence of BRD4 degradation or anticancer efficacy. The proposed BRD4-DCAF15 PROTAC candidates represent lead hypotheses that require biochemical, cellular, pharmacological, and in vivo validation, including confirmation of target engagement, ternary-complex formation, proteasome-dependent BRD4 degradation, downstream transcriptional modulation, pancreatic cancer cell inhibition, selectivity, pharmacokinetics, toxicity, and antitumor efficacy.