Given the pivotal role of anti-apoptotic Bcl-2 family of proteins in cancer cell survival and resistance to chemotherapy, the development of novel anti-cancer therapeutics targeting the BH3 binding groove of anti- apoptotic Bcl-2 proteins have emerged as a promising, yet challenging therapeutic goal. The recent approval of Venetoclax (ABT199), a selective Bcl-2 antagonist whose design and development spanned well over fifteen years of iterative optimizations using extensive structure-based refinements, suggested that it is indeed possible, albeit extremely challenging, to attain inhibitors of protein-protein interactions (PPIs) that are clinically relevant. However, we and others found that overexpression of both Mcl-1 and, perhaps more relevant, Bfl-1 (two other members of the Bcl-2 family protein that are not targeted by Venetoclax), confer resistance to chemotherapy and to Bcl-2 antagonists. Recent efforts from our laboratory identified possible novel routes to design potent and selective inhibitors of PPIs targeting these oncogenes that encompass structure-based design of covalent inhibitors. Hence, we propose to further investigate these innovative structure-guided drug discovery strategies and to apply them to the design of potent dual Mcl-1/Bfl-1 antagonists. If successful, our studies could result in general methods to target PPIs and could also identify innovative lead compounds for the treatment of cancer.

Public Health Relevance

Our studies are aimed at the identification of innovative agents capable of antagonizing anti-apoptotic proteins Bfl-1 and Mcl-1, responsible for cancer cell resistance. We will optimize the novel, irreversible Bfl-1 and Mcl-1 agents that we have recently discovered, and subsequently we will use pharmacological studies to assess their potential anti-cancer activity against melanoma and leukemia.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA168517-06A1
Application #
9885307
Study Section
Macromolecular Structure and Function C Study Section (MSFC)
Program Officer
Forry, Suzanne L
Project Start
2012-07-09
Project End
2024-11-30
Budget Start
2019-12-12
Budget End
2020-11-30
Support Year
6
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of California Riverside
Department
Type
Schools of Medicine
DUNS #
627797426
City
Riverside
State
CA
Country
United States
Zip Code
92521
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Bottini, Angel; Wu, Bainan; Barile, Elisa et al. (2016) High-Throughput Screening (HTS) by NMR Guided Identification of Novel Agents Targeting the Protein Docking Domain of YopH. ChemMedChem 11:919-27
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Baggio, Carlo; Barile, Elisa; Di Sorbo, Gianluigi et al. (2016) The Cell Surface Receptor CD44: NMR-Based Characterization of Putative Ligands. ChemMedChem 11:1097-106
Menezes, Mitchell E; Shen, Xue-Ning; Das, Swadesh K et al. (2015) MDA-7/IL-24 functions as a tumor suppressor gene in vivo in transgenic mouse models of breast cancer. Oncotarget 6:36928-42
Kegelman, Timothy P; Das, Swadesh K; Emdad, Luni et al. (2015) Targeting tumor invasion: the roles of MDA-9/Syntenin. Expert Opin Ther Targets 19:97-112

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