Structure-Guided Design and Initial Studies of a Bifunctional MEK/PI3K Inhibitor (ST-168)

The structure-based design of a new single entity, MEK/PI3K bifunctional inhibitor (7, ST-168), which displays improved MEK1 and PI3K isoform inhibition, is described. ST-168 demonstrated a 2.2-fold improvement in MEK1 inhibition and a 2.8-, 2.7-, 23-, and 2.5-fold improved inhibition toward the PI3Kα, PI3Kβ, PI3Kδ, and PI3Kγ isoforms, respectively, as compared to a previous lead compound (4; ST-162) in in vitro enzymatic inhibition assays. ST-168 demonstrated superior tumoricidal efficacy over ST-162 in an A375 melanoma spheroid tumor model. ST-168 was comparatively more effective than ST-162 in promoting tumor control when administrated orally in a tumor therapy study conducted in an A375 melanoma mouse model confirming its bioavailability and efficacy toward combined in vivo MEK1/PI3K inhibition.