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Thieno[2,3-b]pyridine compounds potently inhibit prostate cancer growth and motility
M A Alkheilewi1, D A Leach2, A Mohr1
1School of Life Sciences, University of Essex, Colchester, UK.
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.
Insights
New thieno[2,3-b]pyridine compounds show promise in treating prostate cancer, including cases resistant to enzalutamide. These molecules inhibit cancer cell growth and motility, offering hope for castrate-resistant prostate cancer patients.
Area of Science:
- Oncology
- Medicinal Chemistry
Background:
- Prostate cancer growth relies on androgens, making androgen-targeting therapies like enzalutamide common.
- Therapy resistance inevitably develops, leading to castrate-resistant prostate cancer, a condition with significant unmet medical needs.
- Novel therapeutic strategies are crucial for effective castrate-resistant prostate cancer treatment.
Purpose of the Study:
- To screen thieno[2,3-b]pyridine compounds for anti-cancer activity in prostate cancer.
- To identify compounds with cytostatic and cytotoxic effects on prostate cancer cells.
- To evaluate the efficacy of lead compounds in preclinical models.
Main Methods:
- Screening of thieno[2,3-b]pyridine compounds against various prostate cancer cell lines and non-tumorigenic controls.
- Assessment of compound effects on cell proliferation, motility, morphology, and cell death (apoptosis) using imaging and flow cytometry.
- Evaluation of the lead compound's efficacy in patient-derived explant models.
Main Results:
- Thieno[2,3-b]pyridine compounds demonstrated inhibition of prostate cancer proliferation and motility.
- Compounds induced G2/M cell cycle arrest, multinucleation, and apoptosis.
- The lead compound, DJ160, effectively inhibited prostate cancer proliferation in patient-derived explants, including enzalutamide-resistant samples.
Conclusions:
- Thieno[2,3-b]pyridines exhibit significant anti-cancer properties against prostate cancer.
- These compounds represent a promising therapeutic avenue for prostate cancer, particularly in cases where current treatments have failed.
- DJ160 shows potential as a novel treatment for castrate-resistant prostate cancer.
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