Synthetic Small Molecules in Prostate Cancer Therapeutics

Prostate cancer remains one of the world-leading malignancies presenting significant therapeutic challenges. Due to the emergence of castration-resistant prostate cancer (CRPC) and insensitivity to androgen-deprivation treatments, novel therapeutic strategies are required to improve overall outcomes and survival. There are several drivers that are associated with CRPC, including the ETS-related gene, ERG, and AR splice variants. ERG and ETV1 belong to the ETS family of transcription factors and are known oncogenes in prostate cancer proliferation and invasion. AR splice variants avoid androgen deprivation yet are capable of nuclear translocation. Conventionally, these targets are “undruggable” due to the lack of ligand-binding domains. However, recent breakthrough findings of small molecule inhibitors in prostate cancer have expanded the potential of targeting these cancer drivers. BRD32048, ERGi-USU, VPC-18005, and YK-4-279 are small molecule prostate cancer inhibitors that target ERG or ETV1, and KI-ARv-03 is a small molecule inhibitor that binds to CDK9 and downregulates AR spice variant complexes. The development of these promising small molecules could lead to the treatment of lethal prostate cancer.