Though anitumor antimitotic agents are some of the most successful anticancer agents, such as taxanes, these agents are plagued by numerous drawbacks that are the cause of chemotherapy failure. In Preliminary Studies we have discovered a unique set of antitumor antimitotics that: 1) possess a broad spectrum of potent antitumor activity (60 tumor cell lines at nanomolar GI50);2) circumvent tumor resistance due to overexpression of P-glycoprotein (MDR) and/or ?III-tubulin, two of the major clinically relevant tumor resistance mechanisms that hinder antitubule activity of the taxanes and other antimitotics;3) are highly water soluble, thus overcome the lack of water solubility that continue to plague a large number of antimitotics including the newly approved ixabepilone;4) are selective for tumor cells over normal cells;5) bind to or near the colchicine-site in tubulin;and 6) are highly efficacious in tumor xenograft without toxicity. The analogs proposed for optimization of the lead compounds are easily synthesized as water soluble salts. The analogs will be evaluated as inhibitors of tumor cells and tubulin assembly in vitro and active compounds will be prioritized for further studies in three xenograft models and in Taxol resistant tumors in vivo murine tumor models. These results will allow the development of pharmacophores that will provide other molecules to be synthesized.
The Specific Aims of this project are: 1) to synthesize and optimize the activities of lead compounds;2) to evaluate the activities of the synthesized analogs as inhibitors of tumor cells in culture and of tubulin assembly and mechanistic studies;3) to evaluate prioritized, selected analogs in vivo in sensitive and resistant murine tumor models. The broad long term goals of this project are to optimize these novel agents to allow the selection of a candidate or candidates for Phase I clinical trials as antitumor agent(s) to be used alone or in combination with other antitumor agents (including other antimitotics) as well as radiation for the treatment of a broad spectrum of cancers and to fill an unmet need for patients with antitubulin resistant diseases.

Public Health Relevance

Tumor resistance, lack of selectivity and poor water solubility are three of the most important factors responsible for cancer treatment failures. We have discovered new agents with potent antitumor activity, water soluble agents that overcome tumor resistance to some of the most widely used anticancer drugs. This study intends to develop an understanding of the important parts of these drugs to its anticancer activity and its ability to overcome resistance and to develop new drugs with better properties that can be advanced to human trials against a variety of tumors including resistant tumors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA142868-04
Application #
8641327
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Fu, Yali
Project Start
2011-06-01
Project End
2016-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
4
Fiscal Year
2014
Total Cost
$304,291
Indirect Cost
$56,389
Name
Duquesne University
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
004501193
City
Pittsburgh
State
PA
Country
United States
Zip Code
15282