Development of novel selective Rac inhibitors for refractory leukemias

点击翻译按钮获取中文摘要

Project summary/abstract Rac belongs to the family of Rho GTPases, proteins that regulate critical cellular functions by integrating extracellular signals and coordinating activation of downstream effectors. In several models of leukemia (BCR-ABL, MLL-rearranged and RAS-mutated leukemia), Rac is aberrantly activated and its genetic deletion can attenuate the transforming effect of driver oncogenes. Moreover, increased activation of Rac due to the expression of an alternative splicing version or to mutations in its coding sequence has been shown to play a critical role in the malignant progression of some solid tumors, including breast, lung and colon cancer as well as melanoma. Due to its biochemical properties, Rac has not been fully exploited as a therapeutic target in cancer. However, a tool compound (NSC 23766) that inhibits Rac activation at high concentration in mammalian cells has been previously developed and inhibits malignant transformation mediated by BCR-ABL in vitro and in vivo. In the present project, the Williams laboratory, a leader in Rho GTPase biology in hematopoietic stem cells, is partnering with Evotec (a medicinal chemistry company with deep expertise in drug discovery) to carry out orthogonal approaches to develop small molecule inhibitors of Rac for the treatment of refractory leukemias (in particular, MLL- rearranged and RAS-mutated). We propose the following approaches to identify new inhibitors and develop recently identified compounds into lead molecules: 1) Optimization of DW_0069, the lead compound previously identified by a virtual screening for Rac inhibitors. This compound inhibits Rac activation in vitro and in vivo, and is well tolerated in leukemia xenograft models. We have already identified several analogues with increased potency. In this project, we propose to further optimize this compound and to investigate its mechanism of action. 2) Expansion of a fragment-based drug discovery program for Rac inhibitors, and development of additional hits identified by a fragment-based NMR screen. Criteria for prioritization of compound development will involve extended SAR studies, good absorption, distribution, metabolism, and excretion- (ADME) properties, and activity in advanced cellular and animal models of RAS-mutated and MLL-rearranged leukemias. The project proposal includes a timeline for nomination of lead compounds for human testing and an outline of a proposed phase I human trial.