Targeting Semaphorin 3C in Prostate Cancer With Small Molecules

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Advanced prostate cancer, including metastatic and castration-resistant forms, presents significant clinical challenges.
• Androgen receptor (AR) mutations, aberrant signaling, and AR-independent pathways drive resistance to standard therapies like chemical castration.
• Semaphorin 3C (SEMA3C), a secreted protein regulated by AR, promotes prostate cancer progression by driving epithelial-to-mesenchymal transition, stemness, and receptor tyrosine kinase activation.

Purpose of the Study:

• To investigate the therapeutic potential of inhibiting Semaphorin 3C (SEMA3C) using small molecules for prostate cancer treatment.
• To develop and validate small molecule inhibitors targeting the interaction between SEMA3C and its receptor, Neuropilin-1 (NRP1).

Main Methods:

• Homology modeling was used to create a SEMA3C protein structure and model its interaction with NRP1.
• In silico screening of 146 molecules from the National Cancer Institute library was performed.
• Experimental validation of identified compounds for their ability to bind SEMA3C, inhibit SEMA3C-NRP1 interaction, and reduce prostate cancer cell growth.

Main Results:

• Four promising small molecule candidates were identified that effectively bind to SEMA3C.
• These candidates demonstrated inhibition of the SEMA3C-NRP1 association.
• The identified compounds showed efficacy in attenuating prostate cancer growth in experimental models.

Conclusions:

• Small molecule inhibition of SEMA3C represents a feasible therapeutic strategy for prostate cancer.
• Targeting the SEMA3C pathway offers a novel approach to overcome resistance mechanisms in advanced prostate cancer.
• Further development of SEMA3C inhibitors could lead to new treatment options for patients with problematic prostate cancer.