Description
TAK-733 is a potent and selective MEK allosteric site inhibitor for MEK1 with IC50 of 3.2 nM, inactive to Abl1, AKT3, c-RAF, CamK1, CDK2, c-Met, etc. Phase 1.
In vitro
TAK-733 is highly potent and selective MEK allosteric site inhibitor with IC50 of 3.2 nM. TAK-733 shows potent enzymatic and cell activity with an EC50 of 1.9 nM against ERK phosphorylation in cells.
In vivo
TAK-733 demonstrates broad antitumor activity in mouse xenograft models of human cancer including models of melanoma, colorectal, NSCLC, pancreatic and breast cancer. TAK-733 is well tolerated with pharmacokinetics and pharmacodynamics that support once-daily oral dosing in humans. TAK-733 shows maximally efficacious doses at once daily orally doses of 10 mg/kg.
Biological Activity
tak-733 is a potent, atp-noncompetitive and selective inhibitor of mek allosteric site with the ic50 value of 3.2nm [1].tak-733 has been shown potent enzymatic and cell activity with an ic50 value of 3.2nm against constitutively active mek enzyme and an ec50 of 1.9nm against erk phosphorylation in cells. in addition, tak-733 has also shown the low clearance and high oral bioavailability based on the pharmacokinetics of tak-733 in all species (mouse, rat, dog and monkey). furthermore, tak-733 has been reported to broad inhibit tumor activity in mouse xenograft models of human cancer (melanoma, colorectal, nsclc, pancreatic and breast cancer) [1].
References
[1] dong q1, dougan dr, gong x, halkowycz p, jin b, kanouni t, o'connell sm, scorah n, shi l, wallace mb, zhou f. discovery of tak-733, a potent and selective mek allosteric site inhibitor for the treatment of cancer. bioorg med chem lett. 2011 mar 1;21(5):1315-9. doi: 10.1016/j.bmcl.2011.01.071. epub 2011 jan 22.
