Discovery of a Highly Potent and Orally Bioavailable STAT3 Dual Phosphorylation Inhibitor for Pancreatic Cancer Treatment

Abstract

Increasing evidence has demonstrated that STAT3 phosphorylation at Tyr705 and Ser727 is closely associated with the progression and poor prognosis of pancreatic cancer. Herein, we report the function-based screening, SAR studies, and biological activity evaluation of a series of novel STAT3 dual phosphorylation inhibitors with an indole-containing tetra-aromatic heterocycle scaffold. Our efforts led to the discovery of optimal compound 4c among the investigated ones, showing desirable ADME properties and highly potent antitumor activities in vitro and in vivo. By targeting the STAT3 SH2 domain, 4c significantly blocked p-Tyr705 and p-Ser727 and caused the abrogation of the corresponding nuclear transcription and mitochondrial oxidative phosphorylation functions of STAT3 in the low nanomolar range. Except for nanomolar antiproliferation activities in vitro, oral treatment of 4c exhibited significant suppressive effects and tolerance in a pancreatic cancer xenograft model, indicating that 4c could be useful for pancreatic cancer treatment as a STAT3 dual phosphorylation inhibitor.

Preclinical characterization of WB737, a potent and selective STAT3 inhibitor, in natural killer/T‐cell lymphoma

“…In our previous studies, 32,33 we have used three functional assays to screen inhibitors that abolished STAT3 pTyr705 and pSer727 concurrently, including the MST assay (based on affinity for STAT3 protein), the STAT3-luciferase reporter assay (based on pTyr705 nuclear transcriptional function), and the mitochondrial respiration assay (based on pSer727 mitochondrial oxidative phosphorylation [OXPHOS] function). Interestingly, our preliminary screening results showed that a small molecule, WB737, exhibited the best inhibitory activity among the investigated compounds.…”

Medicinal chemistry approaches to target the MNK–eIF4E axis in cancer

“…[14][15][16][17] This aberrant phosphorylation to synthesize or activate oncogenic proteins is a common cause of many cancers, ultimately leading to tumorigenesis and metastasis. [18][19][20] Additionally, the translation of mRNAs regulated by the eIF4E complex also contributes to disease resistance. 11,21 While eIF4E phosphorylation has been shown to be critical for downstream signaling and mRNA translation in many circumstances, there have been some reports that this phosphorylation is dispensable for protein synthesis in some situations.…”

Design, synthesis, and biological evaluation of naphthoylamide derivatives as inhibitors of STAT3 phosphorylation

“…These compounds have antitumor proliferation, anticancer, antimetastatic, anti-invasive, and antiparasitic capabilities. [22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40] In this work, we designed a structurally simple and novel 5-R'-1-naphthylmethylamide based on nine different STAT3 phosphorylation inhibitors (Figure 1b). Derivatives 3D and 4D based on this structure showed excellent inhibition ability against CRC; they could also selectively target the phosphorylation and nuclear translocation of STAT3, significantly reducing tumor volume in a mouse tumor model without apparent damage to conventional organ tissues.…”