This proposal describes our efforts toward the synthesis of peptide mimetic molecules against chronic myelogenous leukemia (CML). In collaboration with the Deisseroth laboratory, we will target the p210/bcrabl protein kinase. Specifically, we are interested in the design of small-molecules that will specifically bind to and potentially inhibit the proliferation of myelogenous leukemia cells in vivo. Researchers on this project will synthesize a number of small-molecules, based on a general-binding scaffold, which will be tested for binding to and inhibition of p210/bcrabl. The library proposed here has been designed on the principle of a general- binding scaffold, and involves the random presentation of amino acid side chains, or "natural functionality", around a rigid molecular scaffold. The philosophy behind a general-binding scaffold is that nature's functionality can be radially displayed, preferable in a random and diverse fashion, to mimic both peptide and signaling molecules which may bind to and affect a protein of interest. We propose that the functionality displayed ont the molecular scaffold will have the ability to sample many local conformations,t hereby increasing the changes of identifying a small molecule inhibitor. Each of the compounds synthesized will be forwarded to the Deisseroth Laboratory for in vitro binding constants and in vivo activity. Lead compounds from these assays will then be further subjected to design and randomization in an effort to improve inhibition and gain beneficial pharmacophoric properties needed for their development as chemotherapeutic drug candidates.
NIH ExPorter
NIH ExPorter