Discovery of a small-molecule inhibitor of specific serine residue BAD phosphorylation

• DOI: 10.1073/pnas.1804897115
• Publication Date: 2018-10-11T18:45:18Z
• Authors: Vijay Pandey; Baocheng Wang; Chakrabhavi Dhana...; Ainiah Rushdiana ...; Shobith Rangappa; Venkatachalaiah S...; Julian E. Fuchs; Kesturu S. Girish; Tao Zhu; Andreas Bender; Lan Ma; Zhinan Yin; Basappa; Kanchugarakoppal ...; Peter E. Lobie
• Keywords: 570; 0303 health sciences; Databases, Factual; Cell Survival; 610; Antineoplastic Agents; Apoptosis; Surface Plasmon Resonance; Piperazines; 3. Good health; Small Molecule Libraries; Chemistry; 03 medical and health sciences; Drug Delivery Systems; Benzamides; Drug Discovery; MCF-7 Cells; Serine; Humans; RNA Interference; bcl-Associated Death Protein; Phosphorylation; Cell Proliferation

Human BCL-2-associated death promoter (hBAD) is an apoptosis-regulatory protein mediating survival signals to carcinoma cells upon phosphorylation of Ser99, among other residues. Herein, we screened multiple small-molecule databases queried in a Laplacian-modified naive Bayesian-based cheminformatics platform and identified Petasis reaction product as site-specific inhibitor for hBAD phosphorylation. Based on apoptotic efficacy against mammary cells, N-cyclopentyl-3-((4-(2,3-dichlorophenyl) piperazin-1-yl) (2-hydroxyphenyl) methyl) benzamide (NPB) was potential lead compound. In vitro biochemical analyses demonstrated that NPB inhibited the specifically Ser99. observed exert this effect independently AKT kinase activities despite demonstration AKT-mediated BAD-Ser99 Using structure-based bioinformatics platform, exhibited predicted interactions with silico verified same by direct binding kinetics. reduced enhanced caspase 3/7 activity associated loss cell viability various human cancer lines derived from mammary, endometrial, ovarian, hepatocellular, colon, prostatic, pancreatic carcinoma. Furthermore, use xenograft model, it NPB, single agent, markedly diminished BAD tumor tissue significantly growth. Similar doses utilized acute toxicity studies mice did not exhibit significant effects. Hence, report models.