Research Project
6338049
DESCRIPTION (provided by applicant): Colon cancer is a common malignancy (140,000 cases in the USA) and about 50 percent of cases present metastatic disease within 5 years of diagnosis. Therefore, there is a need for improved therapies. The overall aim of this proposal is to develop a new agent for the treatment of human colon carcinoma. Previous studies with tiazofurin have shown that it is metabolized to an analogue of NAD, TAD (thiazole-4-carboxamide adenine dinucleotide) that is a potent inhibitor of IMPDH (inosine 5'-monophosphate dehydrogenase). Such inhibition causes selective reduction in guanylates, resulting in not only inhibition of RNA/DNA synthesis but also exhibiting significant antitumor activity. Benzamide riboside (BR), has recently been shown to be metabolized to an NAD analogue, BAD (benzamide adenine dinucleotide), a potent inhibitor of IMPDH that is more cytotoxic to human colon carcinoma HT-29 than tiazofurin. BR demonstrates in vivo antitumor activity. Moreover, unlike tiazofurin, BR induces apoptosis in human ovarian carcinoma N.1 cells. Our recent studies found that stable bis(phosphonate) analogues of TAD and BAD showed even better therapeutic potential than active metabolites TAD and BAD or parent nucleosides. On the basis of a recently solved crystal structure of an IMPDH Type II complex with our NAD analogue (SAD) we propose to synthesize bis(phosphonate) analogues of BAD which will be specific against IMPDH Type II. IMPDH Type I is ubiquitously expressed whereas, IMPDH Type II is expressed in cancer cells including colon carcinoma. In additon, we propose to prepare 4,2' -anhydro-BR as a conformationally "friendly" analogue of BR with improved affinity towards IMPDH in general. Its corresponding bis(phosphonate) analogue should have a better affinity towards IMPDH Type II than BR derivatives. In Phase I, the new compounds will be evaluated for their inhibitory activity against IMPDH Type I and II, and cytotoxic activity against HT-29 cells. The most active compounds will be examined for their apoptosis inducing activity and antitumor activity in human colon carcinoma HT-29 growing as a subcutaneous model and as an orthotopic model to mimic metastatic colon cancer to liver, in athymic mice. In Phase II, sufficient amounts of the candidate compounds will be prepared for examining antitumor activity inother tumor models, toxicologic and pharmacological studies required for an IND application. PROPOSED COMMERCIAL APPLICATION: Ribavirin (antiviral) and mycophenolic acid (immunosuppressant) are clinically used drugs that express their activity through inhibition of inosine monophosphate dehydrogenase (IMPDH). New inhibitors of IMPDH, tiazofurin-and benzamide riboside adenine dinucleotide (TAD and BAD) analogues, were developed by us and showed potent activity against human colon and ovarian cancer. These compounds are potential drugs for treatment of colon cancer.
