The dual specific threonine/tyrosine kinase, map kinase kinase (MEK), is a key component of the RAS/RAF/MEK/ERK signaling pathway that is frequently activated in human tumors. CI-1040 is a benzhydroxamate compound that potently inhibits MEK in an in vitro mitogen-activated protein kinase cascade assay with an IC50 value of 2.3 nM (Kd = 74 nM when activated with adenosine triphosphate). It can suppress phosphorylation of ERK in mouse colon 26 tumors with an IC50 value of 35 nM and demonstrates in vivo activity with oral administration in a mouse tumor model. The second-generation MEK inhibitor PD 0325901 is a structural derivative of CI-1040 that was developed for improved solubility.
