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 (, ), which displays improved MEK1 and PI3K isoform inhibition, is described. 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 (; ) in enzymatic inhibition assays. demonstrated superior tumoricidal efficacy over in an A375 melanoma spheroid tumor model. was comparatively more effective than 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 MEK1/PI3K inhibition.

Ocular Toxicity Profile of ST-162 and ST-168 as Novel Bifunctional MEK/PI3K Inhibitors

“…In our previous studies, we investigated the systemic toxicity of the bifunctional inhibitors and found that the side effect profiles of ST-162 and ST-168 are much less significant as compared with single-pathway inhibition (PD0325901 or ZSTK474) or inhibition of both signaling pathways with PD0325901 and ZSTK474 cocktail. 20,42 Moreover, treatment with ST-162 in colorectal and melanoma mouse xenograft models has demonstrated no significant systemic toxicity (assessed as more than 10% of body weight loss posttreatment). 42 Since earlier preclinical and clinical studies of MEK inhibitors focused on pathological changes largely in the outer retina, we used outer retinal cell line models of photoreceptors and RPE for in vitro toxicity analysis.…”

“…16,18 ZSTK474 is very potent, displaying IC 50 values between 3.9 and 20.8 nM for the 4 PI3K isoforms. 20 PD0325901 is a second-generation inhibitor of both MEK1 and MEK2 isoforms that has been evaluated in phase 1 clinical trials for the treatment of several different solid tumors. 21 This early phase clinical study of PD0325901, which enrolled 66 patients with various late-stage cancers, revealed numerous ocular adverse events, including transient blurred vision (7 patients), optic neuropathy (1 patient), and retinal vein occlusion (2 patients), which developed after 4 months of treatment.…”

“…41,42 A structural analog of ST-162, ST-168, demonstrates higher inhibitory activity toward MEK1 and all 4 class I PI3K isoforms. 20 The side effect profile of both ST-168 and ST-162 is much less significant as compared with single-pathway inhibition (PD0325901 or ZSTK474) or cocktail inhibition. 20,42 In this study, we characterized the in vitro and in vivo toxicity profiles of bifunctional MEK/PI3K inhibitors, ST-162 and ST-168, in retinal cells and in a rabbit preclinical model.…”

“…20 The side effect profile of both ST-168 and ST-162 is much less significant as compared with single-pathway inhibition (PD0325901 or ZSTK474) or cocktail inhibition. 20,42 In this study, we characterized the in vitro and in vivo toxicity profiles of bifunctional MEK/PI3K inhibitors, ST-162 and ST-168, in retinal cells and in a rabbit preclinical model. Our results show that these novel inhibitors demonstrate favorable in vitro and in vivo ocular toxicity profiles compared with PD0325901, supporting their further development as potential therapies for diverse tumors.…”

A conjugated mTOR/MEK bifunctional inhibitor as potential polypharmacological anticancer agent: the prototype compound discovery

“…Nonetheless, to our knowledge, no mTOR/MEK bifunctional inhibitors have been disclosed so far. Bifunctional inhibitors of this kind and the recently reported PI3K/MEK dual inhibitors (Van Dort et al 2017) have the potential to provide novel remedies for cancer treatment.…”