Cancer is the second leading cause of death in the United States, contributing to one out of every four deaths. It is estimated that 555,500 people in the United States will die from cancer this year. Last year alone, cancer cost the United States' economy an amount of $156 billion in combined direct and indirect costs. This situation calls for the development of effective cancer therapies. The long-term goal of this research program is the discovery and preclinical development of compounds to target p53 pathway targets, specifically compounds that inhibit p53-Mdm2 interaction, using structure-based drug design and combinatorial chemistry in conjunction with mechanism-based assays. This grant proposal is designed to expand on biologically active lead compounds that were discovered through structure-based design using the reported X-ray crystallographic 3D atomic coordinates of the human p53 and Mdm2 binding complex. A series of compounds belonging to the beta-3-carboline class, that were among of lead compounds identified will be explore as potential novel molecularly target anticancer drugs, or as probes for cancer research. We have hypothesized that the observed effects of these compounds on elevation of cellular expression levels p53 and p21 stems from their inhibitory effect on p53-Mdm2 interaction.
The specific aims of this two-year R15 proposal are: 1) to test the hypothesis that this novel series of compounds exert their effect on p53 and p21 levels by inhibiting p53-Mdm2 interaction, and 2) to conduct structure-activity relationship (SAR) studies and generate combinatorial libraries for high throughput screening to optimize 13-carboline lead compounds as novel p53 potentiating agents. Traditional and combinatorial medicinal chemistry approaches, as well as 3D quantitative structure-activity relationship analyses will be employed together with p53-Mdm2 binding assays and high throughput antitumor assays to optimize lead compounds. This research program is planned to involve the participation of undergraduate students for the purpose of their training in biomedical research.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Academic Research Enhancement Awards (AREA) (R15)
Project #
3R15CA100102-01S1
Application #
6888478
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Rosenfeld, Bobby
Project Start
2003-06-01
Project End
2006-05-31
Budget Start
2004-03-01
Budget End
2006-05-31
Support Year
1
Fiscal Year
2004
Total Cost
$28,305
Indirect Cost
Name
University of Tennessee Health Science Center
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
941884009
City
Memphis
State
TN
Country
United States
Zip Code
38163
Patil, Shivaputra A; Addo, James K; Deokar, Hemantkumar et al. (2017) Synthesis, Biological Evaluation and Modeling Studies of New Pyrido[3,4-b]indole Derivatives as Broad-Spectrum Potent Anticancer Agents. Drug Des 6:
Nag, Subhasree; Qin, Jiang-Jiang; Voruganti, Sukesh et al. (2015) Development and validation of a rapid HPLC method for quantitation of SP-141, a novel pyrido[b]indole anticancer agent, and an initial pharmacokinetic study in mice. Biomed Chromatogr 29:654-63
Wang, Wei; Qin, Jiang-Jiang; Voruganti, Sukesh et al. (2014) The pyrido[b]indole MDM2 inhibitor SP-141 exerts potent therapeutic effects in breast cancer models. Nat Commun 5:5086
Nag, Subhasree; Qin, Jiang-Jiang; Patil, Shivaputra et al. (2014) A quantitative LC-MS/MS method for determination of SP-141, a novel pyrido[b]indole anticancer agent, and its application to a mouse PK study. J Chromatogr B Analyt Technol Biomed Life Sci 969:235-240
Chen, Qi; Buolamwini, John K; Smith, Jeremy C et al. (2013) Impact of resistance mutations on inhibitor binding to HIV-1 integrase. J Chem Inf Model 53:3297-307
Yang, Xinyi; Wang, Wei; Qin, Jiang-Jiang et al. (2012) JKA97, a novel benzylidene analog of harmine, exerts anti-cancer effects by inducing G1 arrest, apoptosis, and p53-independent up-regulation of p21. PLoS One 7:e34303
Buolamwini, John K; Addo, James; Kamath, Shantaram et al. (2005) Small molecule antagonists of the MDM2 oncoprotein as anticancer agents. Curr Cancer Drug Targets 5:57-68