Proximity-Driven Polyvalent RIPTAC Innovation for Molecular Eradication of Prostate Cancer

Objective

Prostate cancer (PCa) is the second most common malignancy in men and a major cause of cancer mortality. In metastatic castration-resistant PCa (mCRPC), therapeutic resistance almost invariably arises, highlighting the urgent need for transformative interventions. This project addresses this challenge by advancing chemically induced proximity (CIP) through Regulated Induced Proximity Targeting Chimeras (RIPTACs), a disruptive novel drug modality that harnesses the enforced proximity of disease-relevant proteins with pan-essential proteins (EPs) to trigger selective cell death, independently of E3 ligases or proteasomal degradation. The project will pioneer polyvalent RIPTACs, introducing first-in-class trivalent and tetravalent designs to maximize avidity, multifunctionality, and precision. Grounded in principles of polypharmacology, these constructs will integrate complementary mechanisms within single molecular entities, combining tumor targeting with immune checkpoint modulation, metabolic interference, and pathway-selective inhibition. By creating novel proximities between proteins not normally associated, RIPTACs can reprogram cellular networks and unlock entirely new therapeutic routes, expanding the possibilities of intervention in complex biological systems. Novel RIPTACs will be designed, assembled through modular synthetic platforms and validated using advanced biophysical, biochemical, and phenotypic assays in cutting-edge PCa models, both extracellular and intracellular. This strategy expands the pharmacological space of CIP-based therapeutics, offering unprecedented structural and functional versatility. The expected outcomes include lead compounds with superior potency, selectivity, and pharmacokinetic properties, able to overcome resistance while minimizing systemic toxicity. This project pioneers polyvalent RIPTACs to unlock new therapies, advance translation, and propel my path to independence.