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

Abstract

The structure-based design of a new single entity, MEK/PI3K bifunctional inhibitor (<b>7</b>, <b>ST-168</b>), which displays improved MEK1 and PI3K isoform inhibition, is described. <b>ST-168</b> 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 (<b>4</b>; <b>ST-162</b>) in <i>in vitro</i> enzymatic inhibition assays. <b>ST-168</b> demonstrated superior tumoricidal efficacy over <b>ST-162</b> in an A375 melanoma spheroid tumor model. <b>ST-168</b> was comparatively more effective than <b>ST-162</b> 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 <i>in vivo</i> MEK1/PI3K inhibition.