The vacuolar (H+)-ATPases (V-ATPases) are a family of ATP driven proton pumps that couple ATP hydrolysis with translocation of protons across membranes. The V-ATPase plays a major role in the regulation of cellular pH conditions, and its role has been associated with cancer invasion, metastasis and drug resistance. Despite the clear involvement of V-ATPases in cancer, to date therapeutic use of V-ATPase targeting small molecules have not reached the clinic. Thus, V-ATPases are emerging as important targets for the identification of potential novel therapeutic agents. To discover new small molecules as Vacuolar (H+)-ATPase modulators, we screened a library of 362,000 compounds from the University of Cincinnati by virtual screening and identified a bisbenzimide derivative as initial hit. Initially our hit molecule was screened for selected breast and ovarian cancer cell lines and it exhibited high potency towards breast cancer cell lines (MDA-MB-468: IC50 0.72±0.08 µM and MDA-MB-231: IC50 1.02±0.08 µM) and moderate activity against three ovarian cancer cell lines (A2780: IC50 3.87±0.09 µM, CisA2780: IC50 3.95±0.33 µM, and PA-1: IC50 1.70±0.21 µM). We are synthesizing novel bisbenzimide analogs and evaluating them against breast and ovarian cancer cell lines. Additionally, these new small molecules will be screened for ATPase activity along with proton pumping assay.

Identification of vacuolar (H+)-ATPase modulators by virtual screening process

253rd National Meeting (2017)

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