The disruption of protein-protein interactions as a therapeutic strategy for prostate cancer.

Prostate cancer (PCa) is one of the most common male-specific cancers worldwide, with high morbidity and mortality rates associated with advanced disease stages. The current treatment options of PCa are prostatectomy, hormonal therapy, chemotherapy or radiotherapy, the selection of which is usually dependent upon the stage of the disease. The development of PCa to a castration-resistant phenotype (CRPC) is associated with a more severe prognosis requiring the development of a new and effective therapy. Protein-protein interactions (PPIs) have been recognised as an emerging drug modality and targeting PPIs is a promising therapeutic approach for several diseases, including cancer. The efficacy of several compounds in which target PPIs and consequently impair disease progression were validated in phase I/II clinical trials for different types of cancer. In PCa, various small molecules and peptides proved successful in inhibiting important PPIs, mainly associated with the androgen receptor (AR), Bcl-2 family proteins, and kinases/phosphatases, thus impairing the growth of PCa cells in vitro. Moreover, a majority of these compounds require further validation in vivo and, preferably, in clinical trials. In addition, several other PPIs associated with PCa progression have been identified and now require experimental validation as potential therapeutic loci. In conclusion, we consider the disruption of PPIs to be a promising though challenging therapeutic strategy for Pca. Agents which modulate PPIs might be employed as a monotherapy or as an adjunct to classical chemotherapeutics to overcome drug resistance and improve efficacy. The discovery of new PPIs with important roles in disease progression, and of novel optimized strategies to target them, are major challenges for the scientific and pharmacological communities.

Pharmacological research. 2020 Aug 16 [Epub ahead of print]

Bárbara Matos, John Howl, Carmen Jerónimo, Margarida Fardilha

Laboratory of Signal Transduction, Department of Medical Sciences, Institute of Biomedicine - iBiMED, University of Aveiro, 3810-193, Aveiro, Portugal., Molecular Pharmacology Group, Research Institute in Healthcare Science, University of Wolverhampton, Wolverhampton WV1 1LY, UK., Cancer Biology and Epigenetics Group, IPO Porto Research Center (CI-IPOP), Portuguese Institute of Oncology of Porto (IPO Porto), Research Center-LAB 3, F Bdg., 1st Floor, Rua Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal; Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar- University of Porto (ICBAS-UP), Porto, Portugal., Laboratory of Signal Transduction, Department of Medical Sciences, Institute of Biomedicine - iBiMED, University of Aveiro, 3810-193, Aveiro, Portugal. Electronic address: .