Background: Androgen Receptor (AR) is one of the highly explored targets for the treatment of
prostate cancer. The emergence of point mutation in the Ligand Binding Domain (LBD) of AR has resulted in
the development of resistance against AR antagonist. The point mutation T877A, W741L and F876L confer
resistance to flutamide, bicalutamide and enzalutamide respectively. There is no AR antagonist in the present
clinical set up without resistance. Hence, our aim in this study is to design a novel molecule to overcome the
resistance caused by point mutation.
Methods: Here, we developed novel AR antagonist bearing (5-methyl-1H-pyrazol-3-yl)-1, 3,4-oxadiazole core
by rational drug design. The test molecules 8a-h were synthesized from the corresponding dihydrazide compounds
7a-h on treatment with phosphorous oxychloride on reflux conditions. The structure of the molecules
was confirmed from spectral data such as IR, 1H-NMR, HRMS and 13C-NMR. The synthesized compounds were
screened for cytotoxicity in prostate cancer cell lines LNCaP-FGC and PC3. The confirmation of AR mediated
activity of the test compounds was confirmed by gene expression study. The interaction of the best active
ligands with mutant AR was predicted and drug design was rationalized through docking studies.
Results: The test compounds 8a-h were synthesized and the structures were conformed using suitable techniques
like IR, 1H-NMR, HRMS and 13C-NMR. Among the tested compounds, 8b and 8d showed potent antiproliferative
activity against mutant AR cell lines. Further, these compounds significantly decreased the gene
expression of prostate cancer biomarkers.
Conclusion: In this study, we have identified a potential hit molecule for AR antagonism that could be further
developed to obtain a potent clinical candidate.