The long-term goal of our research program is to establish a platform targeting protein arginine methyltransferases (PRMTs) that develops small-molecule probes to investigate PRMTs as viable therapeutic targets and to provide lead compounds toward developing PRMT-based new diagnosis and treatment in cancers. The objective of this proposal is to validate a general structure-based approach for developing inhibitors of various PRMTs and to identify selective small-molecule inhibitors of CARM1 for investigating therapeutic potentials of chemical inhibition of CARM1 in cancer. The proposed approach builds upon our existing expertise in synthetic chemistry, assay development, and molecular and cell biology, and leverages our strong collaboration with experts in cancer biology, computation and proteomics. The central hypothesis of this proposal is that small molecules could modulate the function of specific PRMTs by interfering the selective binding of individual PRMT with co-factor SAM methyl donor or arginine substrate. To accomplish the objective of this application the following two specific aims will be pursued.
Aim 1) Construct a collection of SAM-mimic and arginine mimic compounds targeting chemical inhibition of PRMTs.
Aim 2) Identify CARM1 inhibitors and validate therapeutic potentials of chemical inhibition of CARM1 in cancers. Through this exploratory grant, the identification of novel small-molecule inhibitors of CARM1 will validate the general applicability of the proposed structure-based approach for developing inhibitors for various PRMTs of promising cancer-therapeutic targets. Furthermore, the identified small-molecule inhibitors of CARM1 will, for the first time, provide cell-active lead compounds for the discovery of new diagnostic biomarkers and therapeutic treatment for CARM1-assoscaited breast and prostate cancers.

Public Health Relevance

Protein arginine methyltransferases (PRMTs) represent an emerging class of viable therapeutic targets for cancers. This project explores a novel structure-based strategy for the development of small-molecule inhibitors of PRMTs and centers on the identification of selective inhibitors of CARM1 for the development of new diagnostic biomarkers and treatment for CARM1-assoscaited breast and prostate cancers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21CA198643-01
Application #
8959432
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Fu, Yali
Project Start
2015-07-01
Project End
2017-06-30
Budget Start
2015-07-01
Budget End
2016-06-30
Support Year
1
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Duke University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705