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In recent years, synthetic tyrosine kinase inhibitors have made a rapid transition from basic research to therapeutic application. These compounds represent a major clinical advance in the approach to cancer in their relative specificity of action and decreased toxicity. We report here the effects of a novel tyrosine kinase inhibitor CR4 that interferes with growthpromoting pathways to markedly inhibit the growth and survival of both Philadelphia-positive and -negative acute lymphoblastic leukemia (ALL) as well as acute myeloid leukemia (AML). While efficiently ablating leukemic cell growth, normal cell growth and differentiation remain unaffected by CR4. CR4 demonstrates an ability to inhibit the function of multiple growth-critical kinases and yet exhibits a low level of cytotoxicity. These findings suggest that CR4 may prove to be highly effective as a therapeutic agent. IntroductionTyrosine phosphorylation is often central to the development of unregulated proliferation. Mutation, hyperactivation, translocation, and overexpression of tyrosine kinases are all associated with tumorigenesis, and aberrant kinases such as the Bcr-Abl fusion product have been specifically identified and can play a driving role in unregulated growth. [1][2][3][4][5][6] The essential nature of Bcr-Abl and other tyrosine kinases to the growth process of transformed cells renders them ideal targets in attempting to prevent unregulated growth.A small number of compounds with structures based upon mimicry of either the adenosine triphosphate (ATP) moiety or tyrosine residues have been shown to be relatively selective inhibitors of tyrosine kinases. 7,8 As a result of their ability to inhibit tyrosine phosphorylation, these compounds can alter cell responses to growth factors or other processes driven by tyrosine kinase activity, including uncontrolled growth. The concept that tyrosine analogs act as anticancer agents was established by us and others using an inhibitor selective for the Jak kinases (AG-490) to kill by apoptosis human acute lymphoblastic leukemia (ALL) cells in vitro and in vivo. 9,10 Recent years have seen the rapid transition of tyrosine kinase inhibitors from the laboratory bench to therapeutic application, and there is currently much interest in the development of small synthetic molecules that inhibit tyrosine kinases for anticancer therapy. 7,8,11 The most noted success has been the development of the abl/kit kinase inhibitor STI571 (Gleevec; Novartis Pharmaceuticals, East Hanover, NJ), 12-17 which is highly effective in chronic myelogenous leukemia (CML) and possibly other malignancies. [11][12][13][14][15][16][17][18][19][20] However, the development of resistance to ST1571 has been reported recently in cultured cells 21,22 and, more importantly, in a number of patients treated with STI571. [23][24][25] Resistance to ST1571 appears to occur primarily through either increased expression of Bcr-Abl as the result of gene amplification 21 or the acquisition of Bcr-Abl mutations, 26 such that ST1571 binding is inhibit...