| Target Validation Information | |||||
|---|---|---|---|---|---|
| Target ID | T99031 | ||||
| Target Name | Dual specificity mitogen-activated protein kinase kinase | ||||
| Target Type | Clinical Trial |
||||
| Drug Potency against Target | PD-0325901 | Drug Info | IC50 = 0.34 nM | [552513] | |
| AZD6244 | Drug Info | IC50 = 14 nM | [552842] | ||
| Action against Disease Model | AZD6244 | AZD6244 is effective in colorectal cancer cell lines with BRAF or KRAS mutations. Sensitivity to MEK1/2 inhibition correlates with a biochemical signature; those cells with highERK1/2 activity (whether mutant for BRAF or KRAS) evolve a dependency upon that pathway and tend to be sensitive to AZD6244 but this can be offset by high PI3K-dependent signalling. | [552965] | Drug Info | |
| The Effect of Target Knockout, Knockdown or Genetic Variations | Although the null cells resembled the wild-type cells regarding in vitro viability and proliferation in plastic dishes, there was a marked difference in a more relevant in vivo model of experimental metastasis and t uMorigenesis.MKK4-/- clones injected i.v. produced fewer lung metastases than syngeneic MKK4-competent cells (P = 0.0034). | [552965] | |||
| References | |||||
| Ref 552965 | Intrinsic resistance to the MEK1/2 inhibitor AZD6244 (ARRY-142886) is associated with weak ERK1/2 signalling and/or strong PI3K signalling in colorectal cancer cell lines. Int J Cancer. 2009 Nov 15;125(10):2332-41. doi: 10.1002/ijc.24604. | ||||
| Ref 552513 | Progress towards therapeutic small molecule MEK inhibitors for use in cancer therapy. Curr Top Med Chem. 2005;5(2):215-29. | ||||
| Ref 552842 | Therapeutic strategies for inhibiting oncogenic BRAF signaling. Curr Opin Pharmacol. 2008 Aug;8(4):419-26. doi: 10.1016/j.coph.2008.06.014. Epub 2008 Aug 3. | ||||
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