Dual mechanism MAP2K inhibitors bind MAP2Ks

Although mutations in MAP2K proteins are infrequent in human cancers, the position of these kinases downstream of RAS and RAF make them good candidates for therapeutic targeting. Dual mechanism inhibitors such as trametinib bind to non-phosphorylated MAP2K proteins, inhibiting their MAPK-directed kinase activity as well as preventing their phosphorylation by RAF proteins (Hatzivassiliou et al, 2013; Lito et al, 2014; Ishii et al, 2013; reviewed in Samatar and Poulikakos, 2014).

尽管MAP2K蛋白在人类癌症中的突变频率较低，但这些激酶位于RAS和RAF下游的位置，使其成为治疗性靶向的良好候选对象。如特拉米替尼等双机制抑制剂能够与未磷酸化的MAP2K蛋白结合，抑制其MAPK导向的激酶活性，并防止RAF蛋白对其磷酸化（参见Hatzivassiliou等，2013年；Lito等，2014年；Ishii等，2013年；由Samatar和Poulikakos，2014年综述）。