Sex steroids play important roles in a number of cancers including breast, ovarian, endometrial and prostate cancers. In this proposal, we are planning to investigate means to modulate steroid levels in an effort to suppress tumor growth. During the Phase I of this proposal we will design inhibitors for 17beta-dehydrogenase, the enzyme that catalyzes the last step of 17beta-estradiol biosynthesis. There is strong literature evidence that modulation of this biosynthetic pathway is an effective treatment strategy, particularly for estrogen sensitive breast cancers. Small molecule inhibitors will be developed as potential clinical candidates and as biological probes to further study the pharmacological effects of inhibiting enzymes involved in the biosynthesis of 17beta-estradiol, a key steroid involved in the stimulation of breast cancer cell growth. ? ? The workplan is composed of four steps: 1) the structure guided design of inhibitors for this enzyme; 2) selection, synthesis and characterization potential inhibitors; 3) enzymological evaluation of the ligands; 4) evaluation of promising inhibitors in cellular assays. During the Phase I we plan to demonstrate that selective inhibitors can be designed for this enzyme using structure guided design starting from the structure of the endogenous ligand. In the process we will generate a small library of compounds that can be used as probes to study their effect on other steroid sensitive cancers. ? ? The second phase of these studies will evaluate the compounds in ex-vivo and in-vivo studies, with the ultimate purpose of identifying candidates for drug development. ? ?
