Recently, we discovered EHop-016 as a novel small molecule inhibitor of Vav2-Rac1 interactions in MDA-MB-435 metastatic cancer cells at low micromolar concentrations.By inhibiting Rac, Ehop-016 reduced lamellipodia formation, cell migration, and metastasis. Preliminary in vivo experiments in xenograft mice implanted with MD-MBA-435 demonstrated that EHop-016 reduced tumor growth and metastasis. Nevertheless, the therapeutic index (in vitro activity in tumor cells vs toxicity against epithelial cells) is quite low. Therefore, there was a need to develop new derivatives of EHop-016 in order to further optimize the activity, reduce the toxicity, and improve physicochemical parameters. EHop-016 consists of three major building blocks, and via synthesis and testing of novel derivatives, the carbazole group was demonstrated to be important for maintaining inhibitory activity. Molecular docking was utilized to aid in the design of additional new compounds with modifications in the central core and the pending morpholine group. Compounds with promising binding energies and favorable physicochemical parameters were synthesized and tested for activity. The synthetic procedures and the analysis of the Structure Activity relationships will be presented. The presented improved inhibitors of Rac activity could possibly be used for treatment of metastatic breast cancer.

Structural optimization of the Rac GTPase inhibitor EHop-016

248th National Meeting (2014)

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