Thieno[2,3-b]pyridine compounds potently inhibit prostate cancer growth and motility.

Abstract

Objective: Prostate cancer growth is dependent upon androgens and hence therapies often target this signalling axis. These therapies, for example the antiandrogen enzalutamide, are successful in the majority of men; however, resistance is inevitable and the tumour progresses to the castrate-resistant stage, a disease of unmet clinical need. Consequently, there is a great need for novel therapeutics for castrate-resistant prostate cancer. Thieno[2,3-b]pyridine compounds have shown promise as novel anti-cancer molecules, but little is known about their efficacy in prostate cancer. To address this, a panel of thieno[2,3-b]pyridine compounds was screened to identify those with cytostatic/cytotoxic activity in prostate cancer.

Methods: The effect of the compounds upon prostate cancer proliferation and motility was assessed in a panel of cell lines representing different stages of the disease and non-tumorigenic controls. The effect of the compounds upon cell morphology and cell death was assessed using imaging and flow cytometry, respectively. The efficacy of the lead compound was also assessed in a patient-derived explant model.

Results: The compounds were found to inhibit prostate cancer proliferation and motility, promote G2/M arrest, multinucleation and apoptosis. Importantly, treatment of patient-derived explants with the lead compound DJ160 demonstrated that the molecule inhibits prostate cancer proliferation, even in samples that appear to be resistant to enzalutamide.

Conclusions: Thieno[2,3-b]pyridines therefore represent a potential therapy for prostate cancer, even when current therapies have failed.