There is often little hope for patients with chronic myeloid leukemia (CML) once the patient enters blast crisis (BC) stage. Currently there are only two agents that are in clinical use for CML-BC, tiazofurin (IMP dehydrogenase inhibitor) and Gleevec (tyrosine kinase inhibitor). Patients develop resistance to both these agents after several cycles of treatment and therefore this condition is exceptionally difficult to treat. Cancer cells, including CML, require IMP dehydrogenase for their uncontrolled growth and overexpress the type II isoform of the enzyme. The type I isoform, called a "housekeeping" enzyme, is dominant in normal cells. We propose to synthesize a specific inhibitor(s) of the type II isoform. Such a compound(s) should show antileukemic effects without affecting normal cells that use the type I isoform. Although the two isoforms are very similar (they share 84% of amino acids sequences), we recently discovered that there are substantial differences. These differences are located in the cofactor binding domain of the enzyme. IMP-dehydrogenase uses a small molecule, nicotinamide adenine dinucleotide (NAD cofactor), that is crucial for the proper enzymatic activity of the enzyme. In the last decade, we synthesized a number of the cofactor analogues that bind strongly at the cofactor binding domain but cannot participate in the enzymatic activity, resulting in potent inhibition of IMP dehydrogenase. Our novel mycophenolic adenine dinucleotide (MAD) analogues are highly specific for IMP-dehydrogenase (they do not inhibit other NAD-dependent enzymes). However, like other clinically used inhibitors, they inhibit both isoforms of IMPDH with equal potency. Recently, we solved the crystal structure of the complex of IMPDH type II with our MAD analogue, which clearly shows that a modified MAD analogue with an appropriate substituent at the C2 position of adenine ring should be strongly bound to and inhibit the type II isoform; whereas, it should not fit to the binding domain of the type I of IMP-dehydrogenase. Tiazofurin, an approved CML drug, is converted by cellular enzymes into tiazofurin adenine dinucleotide, TAD, which inhibits the enzyme as a cofactor mimic. Resistance to tiazofurin is quickly developed due to diminished ability of resistant cells to synthesize TAD and increased enzymatic degradation of TAD. Our MAD analogues are metabolically stable cofactor mimics that do not require metabolic activation and are resistant to enzymatic degradation. Therefore, the proposed compounds will show potent antileukemic activity in tiazofurin-resistant cells. The differentiation of cancer cells, the process that converts proliferating cancer cells into mature non-dividing cells without killing them, is the best scenario for treatment of cancer diseases. Not all malignant cells differentiate easily, but leukemic cells do. Tiazofurin was reported to be the most potent differentiation inducer among several compounds studied, and its welcomed differentiation activity was confirmed in clinical studies. It is important to note that our MAD analogues were found to be an even more potent (10-fold) differentiation inducer than tiazofurin (in vitro, human K562 leukemic cells). It is likely that the proposed type II specific MAD analogues would be a much better alternative for treatment of CML than tiazofurin.