Cryptotanshinone was identified by screening a library

Is a potent and highly selective MEK1 and MEK2, which was identified by screening a library of compounds with in vitro reactivation of ERK1. PD98059 Cryptotanshinone and U0126 like, CI 1040, and its analogs inhibit MEK1 / 2 in a non-ATP and not ERK1 / 2 in a competitive manner. Structural studies have shown that CI 1040 analogues bind adjacent in a hydrophobic pocket, however. Not overlapping with the position of the Mg ATP binding MEK1 and MEK2 Of inhibitor binding induces a conformational Change of phosphorylated MEK1 / 2, that the kinase in a catalytically inactive form blocks eventually en. This binding pocket in an area with low sequence homology to other kinases that the high selectivity t These compounds and their non-competitive inhibition kinetics explained Is explained in more detail.
In previous clinical studies, IC has been shown in 1040 to inhibit the growth of colon GSK2126458 cancer by more than 80% of the mouse xenograft models. Particularly, the anti-tumor activity of t at doses well tolerated Resembled and correlates with reduced levels of phosphorylated ERK1 / 2 is performed in distant tumors. A Phase I study oral CI 1040 was conducted in 77 patients with advanced cancers. The results of this study indicate that entered the compound at a dose tolerated waswell Ing median 73% inhibition of phospho ERK 1/2 expression in biopsies. About 60% of the incidence of adverse events, mostly grade 1 or 2, no patients with grade 4 drug events. The h Common side effects go Ren Diarrh, Fatigue, rash, nausea and vomiting.
Interestingly, one patient with pancreatic cancer achieved a partial response with significant improvement of symptoms, which lasted 12 months, and 19 other patients with various cancers had stable disease duration of 4 to 17 months. This encouraging study provided the first evidence that MEK1 / 2 can be prevented in humans in vivo, and the first signs of clinical activity T this class of drugs. On this basis, a phase II study in 67 patients with breast cancer has been initiated, the pancreas moved lon heart and non-small cell lung cancer. Unfortunately, the results of this study were disappointed Uschend. No patient presented a completely Ndiges or partial response and stable disease was observed in 8 patients. The anti-tumor activity T sufficient small L Solubility and low bioavailability of CI 1040 prohibits the further clinical development of this compound.
PD0325901 PD0325901 The IC 1040 is a structural analogue of the second generation MEK1 / 2 inhibitor with significantly improved pharmaceutical properties. Diphenylamine-based optimization and modification of the side chain hydroxamate not l Sen PD0325901 increases performance, the L Solubility and bioavailability. PD0325901 has an IC50 value of 1 nM against purified MEK1/MEK2 and inhibits the proliferation of various tumor cell lines in subnanomolar concentrations. In vivo studies have shown that PD0325901 inhibited the growth of human tumor xenografts with activating mutations of B Raf, together with suppression of ERK1 / 2 phosphorylation. Tumor growth was also inhibited mutant ras partially. The clinical efficacy of PD0325901 was first called in a phase I-II, 35 patients with advanced solid tumors growing using doses