The overall aim of this proposal is to develop novel new agents for treatment of acute myeloid leukemia (AML) and chronic myeloid leukemia (CML). In myeloid leukemia several constitutive tyrosine kinase oncogenes are involved in activating RAS signaling pathway. Previous studies with tiazofurin have shown that selective reduction of the levels of guanine nucleotides by inhibition of inosine monophosphate dehydrogenase (IMPDH) not only results in inhibition of RNA/DNA synthesis, but also affects RAS signaling. Tiazofurin induces remissions in adult AML and CML and its curative effect was found to be due to induction of myeloid leukemia cells differentiation into mature non- proliferating cells. However, the remissions were for short duration (3-4 weeks) and toxic side effects prevent the broader application of tiazofurin. We found that mycophenolic adenine dinucleotide (MAD) analogues, which mimic tiazofurin adenine dinucleotide (TAD), an active metabolite of tiazofurin, showed as potent inhibition of IMPDH as TAD but they were an order of magnitude more potent than tiazofurin as differentiation inducers of human myeloid leukemia. In Phase I, we will evaluate cytotoxic, differentiation, IMPDH activity, GTP concentration, and antileukemic activity of the novel MAD analogues in vitro in human myelogeneous leukemias K562 and HL-60 cells, and in human colon carcinoma HT-29 cells. The most active compounds will be examined for the antileukemic activity in vivo in systemic leukemia model in SCID mice. In Phase II, sufficient amounts of the candidate compound(s) will be prepared for toxicological and pharmacological studies required for an IND application.
Ribavirin (antiviral) and mycophenolic acid (immunosuppressant) are clinically useful drugs expressing their activity due to inhibition of inosine monophosphate dehydrogenase (IMPDH). New inhibitors of IMPDH developed by us, mycophenolic adenine dinucleotides (MAD) analogues, showed potent activity against human leukemias. These compounds should be of great commercial interest as potential drugs for treatment of acute myeloid leukemia (AML) in adults and chronic myeloid leukemia (CML).
| Pankiewicz, Krzysztof W; Patterson, Steven E; Black, Paul L et al. (2004) Cofactor mimics as selective inhibitors of NAD-dependent inosine monophosphate dehydrogenase (IMPDH)--the major therapeutic target. Curr Med Chem 11:887-900 |
| Pankiewicz, Krzysztof W; Lesiak-Watanabe, Krystyna B; Watanabe, Kyoichi A et al. (2002) Novel mycophenolic adenine bis(phosphonate) analogues as potential differentiation agents against human leukemia. J Med Chem 45:703-12 |
| Yalowitz, Joel A; Pankiewicz, Krzysztof; Patterson, Steven E et al. (2002) Cytotoxicity and cellular differentiation activity of methylenebis(phosphonate) analogs of tiazofurin and mycophenolic acid adenine dinucleotide in human cancer cell lines. Cancer Lett 181:31-8 |
| Yalowitz, J A; Jayaram, H N (2000) Molecular targets of guanine nucleotides in differentiation, proliferation and apoptosis. Anticancer Res 20:2329-38 |
