Discovery of a Novel Potent STAT3 Inhibitor HP590 with Dual p-Tyr⁷⁰⁵/Ser⁷²⁷ Inhibitory Activity for Gastric Cancer Treatment

Abstract

Accumulating evidence has documented that STAT3 phosphorylation at Tyr705 and Ser727 jointly promotes the initiation and progression of gastric cancer. However, most reported STAT3 inhibitors have mainly focused on suppressing STAT3 phosphorylation at Tyr705 while ignoring the tumorigenic effects of phosphorylation at Ser727. Herein, we described the design, synthesis, and structure–activity relationship studies on a series of triaromatic heterocyclic derivatives as potent dual phosphorylation STAT3 inhibitors. These efforts led to the discovery of the best compound 3h (HP590) among the investigated ones, a novel, highly potent, and orally bioavailable STAT3 inhibitor possessing lower nanomolar inhibitory activity toward p-Tyr705 and p-Ser727. Target validation revealed that HP590 selectively targets STAT3 to remarkably inhibit its canonical and noncanonical activation and corresponding biological functions, thereby resulting in the growth inhibition of gastric cancer in vitro and in vivo, highlighting the therapeutic potential of dual phosphorylation STAT3 inhibitors for gastric cancer.

Directly Suppressing MYC Function with Novel Alkynyl-Substituted Phenylpyrazole Derivatives that Induce Protein Degradation and Perturb MYC/MAX Interaction

“…To assess the MYC engagement of 37 in native cellular environment, cellular thermal shift assay (CETSA), a new method based on the ligand-induced alteration in protein thermal stability, was employed in subsequent functional investigation (Figure A) . The results demonstrated that MYC expression in DMSO-treated PC-3 cells declined continuously as the incubation temperature increased.…”

Anti-IL23/12 agents and JAK inhibitors for inflammatory bowel disease

“…The influence of the STAT family of proteins on IBD pathology is also an area of active investigation. No clinical trials have been undertaken for the treatment of IBD to date, although the pharmacokinetics and safety/tolerability of inhibitors targeting dual phosphorylation or the SH2 domain of STAT3 have been evaluated in patients with solid tumors and natural killer/T-cell lymphoma ( 55 – 59 ) (ClinicalTrials.gov no: NCT03240939). As technology advances, such as for the degradation of STAT proteins, more drugs targeting STAT could enter clinical development, adding to the IBD treatment armamentarium ( 60 ).…”

Discovery of a Potent and Oral Available Complex I OXPHOS Inhibitor That Abrogates Tumor Growth and Circumvents MEKi Resistance

“…CYP Inhibition Assay. As previously reported, 49 the inhibition potency of HP661 for the CYP450 enzyme was evaluated by human liver microsomes (HLM). IC 50 values were calculated with GraphPad Prism software version 8.0.…”