NOT-OD-09-058: NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications. The goal of this project is to apply the mechanistic insights of the interaction between Rac GTPases and their regulatory guanine nucleotide exchange factors (GEFs), to the design of novel small molecule inhibitors targeting deregulated Rac activities in human lymphoma. The GEF-Rac signaling axis lies in the crossroads of many signaling events initiated by growth factors, cytokines, stress, and adhesion molecules. Their functional interaction leads to the activation of Rac and a variety of Rac-mediated physiological responses including actin and microtubule cytoskeletal reorganization, adhesion, migration, and proliferation. In the parental grant, we seek to define the role of Rac GTPase signaling in p53 deficient mouse and human lymphoma models and to implicate Rac signaling as a useful anti-cancer target. Our track record and preliminary data provide strong credential in studying the structure-function relationship of Rac1 in regard of its interaction with GEFs, in deriving structural and kinetic information of several functional interactions involving Rac1, and in studying the role of Rac1 by conditional gene targeting approach in mice. In particular, we have discovered a first generation small molecule inhibitor, NSC23766, that is effective in targeting Rac in vitro and in vivo, and have utilized it to study a number of physiological and pathological functions of Rac GTPases ranging from hematopoietic stem cell mobilization, platelet regulation, schwannoma phenotype reversion, to lymphoma suppression. In this supplemental proposal, we will (1) pursue structure-function based rational design and improvement of Rac-targeting small molecule inhibitors by virtual screening based on a newly resolved Rac1-NSC23766 crystal structure, (2) seek to improve the structure-activity relations of the Rac inhibitors by medicinal chemistry, and (3) validate the new Rac inhibitors in purified in vitro systems and in cells, and apply the Rac-targeting small molecule inhibitors to p53 deficient lymphoma where Rac activity is abnormally high. These mechanism-based studies of small molecule inhibitor design and pre- clinical validation in a novel pathologic context will accelerate the tempo of the research project to synergize with the parental grant funding to move an innovative and mechanism based, basic science hypothesis closer to translational applications, and will retain and create jobs in US. The end point of these studies will provide an improved generation of Rac GTPase inhibitors for a wide range of usage in cancer research, particularly for effective eradication of lymphoma.
Project Narrative The proposed work will pursue structure-based design of new chemical inhibitors of Rac GTPases by translating the mechanistic information obtained from the decade-long biochemical, structural, cell biological, and animal studies of Rac GTPases for anti-cancer therapy. Further, the proposed work will help establish a novel therapeutic concept that targeting Rac in p53 deficient lymphoma cells could be beneficial to conventional, chemoresistant cancer. The studies will accelerate the tempo of the research project to synergize with the parental grant funding to move an innovative and mechanism based, basic science hypothesis closer to translational applications, and will retain and create jobs in US.
