Activation of TGF Beta Receptor by Inhibition of DNA Methyltransferases to treat Advanced Prostate Cancer

Abstract

Prostate cancer is one of the major disease affects male. Currently androgen receptor (AR) antagonist like bicalutamide is used along with antigen specific antibodies administration to treat prostate cancer. Non androgenic pathway also plays an important role in the inducement of prostate cancer. Less importance or work has been carried out in elucidating its mechanism in prostate cancer development as well as targeted drugs. In the present study DNMT-TGFand#946; mediated mechanism has been studied to prevent the prostate cancer progression. The objective of the study is to develop DNMT and AR selective or having dual affinity new molecules for prostate cancer treatment. Different scaffolds were used to elucidate the new molecule efficacy in prostate cancer cell progression. The work was carried out in different phases, in the first phase through in silico studies the proposed new chemicals affinity was elucidated. Glide and DESMOND programs of Schrodinger software were used. The chemicals molecules had benzamide and oxadiazole nucleus. The target proteins selected for the study includes three isoforms of DNMT enzymes (DNMT1, DNMT 3A and DNMT3B). The AR protein includes two isoforms 20Z7 and 3V49. Similarly the PDB ids for DNMT enzymes were 3PTA, 3SWR and 2QRV and 3QKJ. The targets were validated using standard drug zebularine, 5 azacytidine, decitabine and RG108 compounds for DNMT enzymes. Similarly for AR, AR antagonist flutamide and bicalutamide were used to validate AR proteins. Similarly all the proposed compounds were docked and the G-score was ranked to know the best active compounds through virtual screening. The study can be concluded that, a novel oxadiazole molecule has been identified as HIT molecule to inhibit DNMT enzyme and resulting in arrest of AR mediated cell proliferation in prostate cancer cell line. The in vivo tumor model mediated efficacy assessment, druggability property of the new molecule and its toxicity evaluation might translate this molecule as a clinical candidate to treat advanced prostate cancer.