Drugs for Breast Cancer: A Novel Mechanistic Approach

DESCRIPTION (provided by applicant): The objective of this project is to develop a new class of breast cancer drugs that act by inhibiting the enzyme CoA-Independent Transacylase (CoA-IT). This enzyme is involved in the remodeling of arachidonic acid (AA) in membrane phospholipids and recent studies suggest that disruption of this remodeling may represent a novel therapeutic strategy to block cancer cell proliferation. The prototype CoA-IT inhibitor 2-[2-[3-(4-chloro-3 (trifluoromethyl)phenyl]-ureido]-4-(trifluTp -4,5-dichlorobenzenesulfonic acid (PLT 25130) inhibits the proliferation of estrogen receptor-negative and positive human breast cancer cell lines (MDA-MB-231 and MCF-7) as well as a number of other tumor and leukemia cell lines. Cell cycle synchronization experiments reveal that CoA-IT inhibition results in the blockade of cell replication in the early to mid G1 phase. Growth inhibition is accompanied by an increase in free intracellular AA. The principle goal of Phase I is to determine the anti-tumor potential of PLT 25130. In these studies, the selectivity of PLT 25130 against normal cells and a variety of cancers will be examined. Additionally, the pharmacokinetic properties and effacacy of PLT 25130 on human breast cancer xenographs in nude mice will be assessed. In Phase II, a series of structural analogs of PLT 25130 will be synthesized and evaluated to identify a clinical candidate with the appropriate drug-like attributes (pharmacokinetics, safety, stability, solubility). Once a clinical candidate is selected, all studies needed to support IND filing will be conducted. PROPOSED COMMERCIAL APPLICATION: Breast cancer is the most common form of cancer in women. The National Cancer Institute estimates that the overall annual health care costs for all types of cancer is $104 billion with breast, lung and prostate cancer accounting for over half of this appending. The safe treatment of these and other cancers is still an unmet medical need and large commercial opportunity. The target of this research, CoA-independent transacylase, is a novel target for inducing apoptosis of tumor cells. The successful outcome of this research project will be a viable clinical drug candidate for the treatment of breast cancer.