Cancer preventive bioactive food compounds are well documented. A clear understanding of the molecular targets for these food components is fundamental to the development of effective diet strategies against cancer. Despite the development of many methods, target identification for bioactive compounds is an unmet challenge due to the huge diversity in small-molecule structure, activity, and mechanisms of action. Current affinity-based target identification techniques are limited by the necessity to modify each drug individually, while indirect, non-affinity based approaches are dependent on the drug's ability to induce specific biochemical or cellular readouts. This project presents a novel, universally applicable target identification approach (DARTS) that analyzes direct small-molecule binding to its protein target without requiring modification or immobilization of the small molecule.
The specific aims are to 1) establish a robust DARTS protocol for identifying the molecular targets of bioactive food components, and 2) to use DARTS to determine the molecular targets of bioactive food compounds that explain their inhibition of human cancer cell growth. If successful, the studies will have a major impact on our understanding of the linkage between diet and cancer, and shed light on new mechanisms and targets for cancer prevention and aging intervention.

Public Health Relevance

Cancer preventive agents in our food are well documented. A clear understanding of the molecular targets for these bioactive food components is challenging but fundamental to the development of effective diet strategies against cancer. This project develops a novel and universal method to identify the molecular targets for anti-cancer food components.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21CA149774-02
Application #
8020054
Study Section
Chemo/Dietary Prevention Study Section (CDP)
Program Officer
Seifried, Harold E
Project Start
2010-02-03
Project End
2013-01-31
Budget Start
2011-02-01
Budget End
2013-01-31
Support Year
2
Fiscal Year
2011
Total Cost
$162,451
Indirect Cost
Name
University of California Los Angeles
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Pai, Melody Y; Lomenick, Brett; Hwang, Heejun et al. (2015) Drug affinity responsive target stability (DARTS) for small-molecule target identification. Methods Mol Biol 1263:287-98
Lomenick, Brett; Olsen, Richard W; Huang, Jing (2011) Identification of direct protein targets of small molecules. ACS Chem Biol 6:34-46
Lomenick, Brett; Jung, Gwanghyun; Wohlschlegel, James A et al. (2011) Target identification using drug affinity responsive target stability (DARTS). Curr Protoc Chem Biol 3:163-180
Watanabe, Ryosuke; Wei, Liu; Huang, Jing (2011) mTOR signaling, function, novel inhibitors, and therapeutic targets. J Nucl Med 52:497-500
Aghajan, Mariam; Jonai, Nao; Flick, Karin et al. (2010) Chemical genetics screen for enhancers of rapamycin identifies a specific inhibitor of an SCF family E3 ubiquitin ligase. Nat Biotechnol 28:738-42
Lomenick, Brett; Hao, Rui; Jonai, Nao et al. (2009) Target identification using drug affinity responsive target stability (DARTS). Proc Natl Acad Sci U S A 106:21984-9