The overall objective is to develop potent anti-CXCR4 drugs that are specific and safe. Even though CXCR4 is a good target for intervening various diseases, especially, cancer metastasis, there is no safe drug in the clinic until now. Metastasis is an end result for many solid tumor types and is the leading cause of cancer related deaths. This has attracted an increasing amount of attention from research groups over the last decade in both academia and industry, as a target for metastatic disease intervention and life extension. To date, a number of target molecules have been addressed that are linked mechanistically to the various sub- steps associated with metastasis including: i) establishment of angiogenesis at the primary site; ii) locomotion; iii) chemoattraction, homing, and adhesion of the metastatic cells to the defined organs; and iv) establishment of metastatic tumor growth and angiogenesis. The CXCR4/SDF-1 interaction, and the resulting cell signaling cascade, has recently emerged as one of the most relevant such targets as it has been shown to play a key role in all four steps outlined above. A set of small molecule CXCR4 antagonists has been discovered and we are currently in the process of evaluating specificity and potency. We are simultaneously designing and generating new analogs to optimize efficacy as well as expand our structural scope. WZ40 is currently the most advanced, which potently bind to CXCR4, thus, blocking the CXCR4/SDF-1 signaling process. We have followed this discovery by demonstrating that WZ40 inhibits tumor metastasis by inhibiting the CXCR4/SDF-1 interaction in both in vitro and in vivo studies. Our underlying hypothesis is that WZ40 and its analogs are specific inhibitors of CXCR4/SDF-1 interaction.
The specific aims are: 1. Design and prepare improved inhibitors with increasingly diverse chemical scaffolds; 2. Determine the Specificity of selected compounds against other chemokine receptors; and 3. Select and progress suitable candidates based on plasma stability, oral availability, and in vivo efficacy. The intended outcome of this proposal is the identification of small molecules that will attenuate tumor metastasis in vivo by blocking CXCR4 function whilst demonstrating a sufficient pharmacokinetic and specificity profile to merit advancement into human clinical evaluation. ? ? ?
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