An allosteric Cdc42 inhibitor
ML141(CID-2950007) is a potent, selective and reversible non-competitive inhibitor of Cdc42 GTPase(IC50=200 nM) with low micromolar potency and selectivity against other members of the Rho family of GTPases (Rac1, Rab2, Rab7). IC50 value: 200 nM [1]Target: Cdc42 inhibitorin vitro: In the primary HTS bead-based assay using 1 mM EDTA and 100 nM BODIPY-FL-GTP, potency for CID2950007 was IC50 = 2.6 and 5.4 μM for Cdc42 wild type and activated mutant, respectively [1]. ML141 exposure also enhanced the ability of TMX to suppress BLBC cell growth, through both induction of cell death and suppression of cell division [2]. in vivo: Treatment with ML141 + TMX caused a suppression of further tumour growth in vivo [2]. Parallel suppression of the conserved brain CDC42 activity by intracerebroventricular ML141 injection caused acute anxiety in mice [3]. using a pilocarpine-induced epileptic model, we found that pretreatment with ML141, a specific inhibitor of Cdc42, reduces seizure severity [4].
参考文献:
[1]. Surviladze Z, et al. A Potent and Selective Inhibitor of Cdc42 GTPase. Probe Reports from the NIH Molecular Libraries Program
[2]. Chen HY, et al. Inhibition of redox/Fyn/c-Cbl pathway function by Cdc42 controls tumour initiation capacity and tamoxifen sensitivity in basal-like breast cancer cells. EMBO Mol Med. 2013 May;5(5):723-36.
[3]. Hanin G, et al. Competing targets of microRNA-608 affect anxiety and hypertension. Hum Mol Genet. 2014 Sep 1;23(17):4569-80.
[4]. Zhang Y, et al. Inhibition of the small GTPase Cdc42 in regulation of epileptic-seizure in rats. Neuroscience. 2015 Mar 19;289:381-91.
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