2. Academic Validation
  3. Discovery of a small-molecule inhibitor of specific serine residue BAD phosphorylation

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

  • Proc Natl Acad Sci U S A. 2018 Oct 30;115(44):E10505-E10514. doi: 10.1073/pnas.1804897115.
Vijay Pandey 1,  Baocheng Wang 1 2 3,  Chakrabhavi Dhananjaya Mohan 4,  Ainiah Rushdiana Raquib 5,  Shobith Rangappa 6,  Venkatachalaiah Srinivasa 7,  Julian E Fuchs 8,  Kesturu S Girish 9,  Tao Zhu 10 11,  Andreas Bender 8,  Lan Ma 1,  Zhinan Yin 2 3 12 13 14,  Basappa 15 16,  Kanchugarakoppal S Rangappa 17,  Peter E Lobie 18 5
Affiliations

Affiliations

  • 1 Tsinghua-Berkeley Shenzhen Institute, Tsinghua University, 518055 Shenzhen, Peoples' Republic of China.
  • 2 The First Affiliated Hospital, Jinan University, 510632 Guangzhou, Peoples' Republic of China.
  • 3 Biomedical Translational Research Institute, Jinan University, 510632 Guangzhou, Peoples' Republic of China.
  • 4 Department of Studies in Molecular Biology, University of Mysore, Manasagangotri, 570006 Mysore, India.
  • 5 Cancer Science Institute of Singapore, National University of Singapore, 117599 Singapore.
  • 6 Adichunchanagiri Institute for Molecular Medicine, BG Nagara, 571448 Karnataka, India.
  • 7 Laboratory of Chemical Biology, Department of Chemistry, Bangalore University, 560001 Bangalore, India.
  • 8 Centre for Molecular Informatics, Department of Chemistry, University of Cambridge, Cambridge CB2 1TN, United Kingdom.
  • 9 Department of Studies and Research in Biochemistry, Tumkur University, 572103 Tumkur, India.
  • 10 Hefei National Laboratory for Physical Sciences at Microscale, University of Science and Technology of China, 230026 Anhui, Peoples' Republic of China.
  • 11 School of Life Sciences, University of Science and Technology of China, 230027 Anhui, Peoples' Republic of China.
  • 12 National Center for International Research of Biological Targeting Diagnosis and Therapy, Guangxi Medical University, 530021 Nanning, Peoples' Republic of China.
  • 13 Guangxi Key Laboratory of Biological Targeting Diagnosis and Therapy Research, Guangxi Medical University, 530021 Nanning, Peoples' Republic of China.
  • 14 Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Medical University, 530021 Nanning, Peoples' Republic of China.
  • 15 Laboratory of Chemical Biology, Department of Chemistry, Bangalore University, 560001 Bangalore, India; salundibasappa@gmail.com rangappaks@yahoo.com pelobie@sz.tsinghua.edu.cn.
  • 16 Department of Studies in Organic Chemistry, University of Mysore, Manasagangotri, 570006 Mysore, India.
  • 17 Institution of Excellence, University of Mysore, Manasagangotri, 570006 Mysore, India salundibasappa@gmail.com rangappaks@yahoo.com pelobie@sz.tsinghua.edu.cn.
  • 18 Tsinghua-Berkeley Shenzhen Institute, Tsinghua University, 518055 Shenzhen, Peoples' Republic of China; salundibasappa@gmail.com rangappaks@yahoo.com pelobie@sz.tsinghua.edu.cn.
PMID: 30309962 DOI: 10.1073/pnas.1804897115
Abstract

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

Keywords

AKT-PKB; BAD phosphorylation; Laplacian-modified naive Bayesian classifier; NPB; carcinoma.

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    ≥98.0%, Bcl-2 Family抑制剂
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