Cdc42, a member of the Rho family of GTPases, has been shown to play a role in cell adhesion, cytoskeletal arrangement, phagocytosis and cell motility and migration. ML141 is a potent, selective and reversible non-competitive inhibitor of Cdc42 GTPase with low micromolar potency and selectivity against other members of the Rho family of GTPases (Rac1, Rab2, Rab7)[3]. Pharmacological inhibition of Cdc42 with ML141 was similarly effective as genetic knockdown at enabling TMX-induced reductions in levels of EGFR (epidermal growth factor receptor). Co-exposure to 20 µM ML141 (a concentration that selectively inhibits Cdc42 function in BLBC cells) enabled TMX (tamoxifen) to cause a ∼45% reduction in EGFR levels. ML141 exposure also enhanced the ability of TMX to suppress BLBC cell growth, through both induction of cell death and suppression of cell division. Tumour bearing animals were treated with 1 mg/day ML141 and 125 µg/day TMX. Pharmacological inhibition of Cdc42 with ML141 enabled TMX to suppress growth of MDA-MB 231 derived tumours. Moreover, the tumour sizes resulting from ML141 pre-treated cells were markedly smaller than those of the control group[4]. Moreover, both the absolute numbers of KL (Lin− c-Kit+ sca-1−) and KSL (Lin− c-Kit+ sca-1+) population in ML141 treated mice were increased as compared to these in DMSO vehicle control mice. Mice treated with 10 μg ML141 presented higher KL and KSL counts than those in mice with 5 μg ML141[5].
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