Compound 23 was shown to have little effect on the phosphorylation state of ERK1/2, implying the reductions in ERK substrate phosphorylations was not due to a reduction in active ERK
Compound 23 was shown to have little effect on the phosphorylation state of ERK1/2, implying the reductions in ERK substrate phosphorylations was not due to a reduction in active ERK. growth factor, RTK = receptor tyrosine kinase, Grb2 = growth factor receptor-bound protein 2; Sos = child of sevenless; P indicates a phosphorylated serine, threonine or tyrosine residue. There is now considerable evidence that links the dysregulation of the RasRafMEKERK pathway to the oncogenesis of human cancers. Ras is usually hyperactivated in around 30% of human cancers, most commonly the K-Ras isoform. More specifically, Ras activating mutations have been reported in about 90% of pancreatic carcinomas, 50% of colon carcinomas, 30% of lung cancers and in around 30% of myeloid leukaemia cases. Activating mutations of Raf have also been reported in around 7% of human cancers.[5,6] In particular, mutations of B-Raf have been observed in over 60% of melanomas, around 30% of ovarian malignancy and in approximately 20% of colorectal carcinomas, as well as in several other malignancies at lower frequencies.[5,6] Constitutively activate MEK1/2 and ERK1/2 proteins are present in a relatively high number of human tumours, particularly those from your colon, lung, pancreas, ovary and kidney. Since mutations of the MEK1/2 and ERK1/2 genes have not been observed in human tumours, it seems probable that this hyperactivity of these proteins is a consequence of their constitutive phosphorylation due to hyperactivation of upstream effectors, including 3′,4′-Anhydrovinblastine receptors, Ras and B-Raf. In summary, the RasRafMEK1/2ERK1/2 pathway is an appealing target for the development of potential anti-cancer therapeutics. Moreover, the pathway offers several junctures for transmission transduction blockade; due to the converging functions of MEK1/2 and 3′,4′-Anhydrovinblastine ERK1/2, specific inhibition of these proteins is particularly desired. In this mini-review, some of the more prominent small molecule inhibitors of the ERK pathway will be ACTB offered, with a particular emphasis on those discovered within the last ten to fifteen years. In the first section, we shall discuss those inhibitors that target proteins upstream of ERK1/2, specifically Raf and MEK1/2. We will then shift to the main focus of this review, which is the direct inhibition of ERK1/2 through targeting either the ATP-binding site (ATP-competitive inhibitors) or the surface of ERK and blocking its proteinCprotein interactions with its substrates (non-ATP-competitive inhibitors). Indirect Inhibition of ERK Raf Inhibitors Constitutive activation of the ERK pathway, which has been observed in many human cancers, is usually predominantly due to gain-of-function mutations of Ras or Raf.[4C6] The large number of published 3′,4′-Anhydrovinblastine Ras inhibitors, in particular the farnesyltransferase inhibitors, along with their diverse and mostly disappointing results in clinical trials, is beyond the scope of this review, and the authors direct the reader 3′,4′-Anhydrovinblastine elsewhere for any discussion on this topic. Of the three Raf isoforms in mammals (A-Raf, B-Raf and Raf-1), it is predominantly the B-Raf isoform that is mutated.[5,6] However, the quest for potent B-Raf inhibitors is very much in its infancy, probably since it was originally considered that Raf-1 was the Raf isoform with the greatest oncogenic potential. In that regard, GW5074 and sorafenib, two potent, ATP-competitive inhibitors of Raf-1, were recognized through various screening techniques. Experts at GlaxoSmithKline synthesized and screened a series of over 2000 benzylidene oxindole compounds in a Raf1/MEK/ERK2 cascade assay. Optimization of an initial hit led to the discovery of GW5074 (1), which blocks Raf-1 kinase activity with an IC50 value of 9 nM. The inspiration for the benzylidene oxindole scaffold came from previous research that had shown such compounds inhibited tyrosine-specific protein kinase activity of the epidermal growth factor receptor (EGFR). Moreover, the NH/CO of the oxindole is usually a hydrogen bond donor/acceptor motif that is.