Rac1 splicing variant Rac1b: Towards isoform selective inhibitors for the treatment of cancer

The pivotal role of Rac1, a member of the Rho family of small GTPases, has been well characterized in the genesis of many cancers. The aberrant activation of Rac1 promotes uncontrolled proliferation, invasion and metastatic properties of human cancer cells. Via ExonHit Therapeutics9 alternative splicing discovery plateform DATAS™, we identified a repertoire of genes deregulated in cancer. Among them, Rac1b, an alternative splice variant of Rac1, was found deregulated and overexpressed in diverse cancer types, including breast and colon. Rac1b is constitutively active and transforming, and since it was shown to sustain cancer cell survival, such as for colorectal cancer cells, there is considerable interest in the development of small molecule inhibitors of Rac1/Rac1b. We previously synthesized and fully characterized EHT 1864 as a pharmacological tool to study Rac1 functions(Shutes A et al. (2007). J Biol Chem. 282(49):35666‐78). Then, using molecular docking algorithms and ExonHit9s screening platform for nucleotide binding inhibitors, novel compounds were synthesized and characterized for Rac1/Rac1b inhibition and Rac1 versus Rac1b selectivity. Here, we describe new Rac1/Rac1b inhibitors with better pharmacological profile than EHT 1864 and better potency in various in vitro cancer cell models. Some of these pharmacological tools are good candidates for subsequent in vivo cancer studies to study Rac1 and Rac1b mediated cellular functions and to modulate pathological conditions in which Rac1 or Rac1b deregulation may play a role. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C89.