FIGURE 5.

Allosteric MEK inhibitors. (a) Structure of the MEK1 kinase in its inactive state in complex with early MEK inhibitor PD318088 and Mg²⁺ ATP. The inhibitor and ATP are shown in spacefill to indicate the respective locations of the ATP and allosteric inhibitor binding sites (PDB ID 1S9J). ¹⁰⁷ (b) Detailed view of inhibitor interactions in the structure shown in Panel A. (c) Crystal structure of a MEK1: BRAF dimer, with inhibitor GDC‐0623 bound in the MEK allosteric site (PDB ID 6PP9). ⁷⁷ (d) Detail of the interactions of GDC‐0623 in the MEK allosteric site. (e) Crystal structure of a KSR:MEK1 dimer, with inhibitor trametinib bound in the MEK allosteric site (PDB ID 7JUX). ¹⁰⁸ (f) Detailed view of the interactions of trametinib in the MEK1 allosteric site