Discovery of 2-Amino-3-cyanothiophene Derivatives as Potent STAT3 Inhibitors for the Treatment of Osteosarcoma Growth and Metastasis

Yang

Computational and Mathematical Methods in Medicine

et al. 2022

Objective. A case-control study was conducted to explore the efficacy of cohort study and value of CT perfusion imaging in patients with metastatic osteosarcoma after chemotherapy. Methods. Eighty patients with metastatic osteosarcoma treated in our hospital from March 2020 to December 2021 were divided into two groups. According to their different treatment methods, the chemotherapy+antiangiogenesis group had 36 cases and the chemotherapy group had 44 cases. All patients were scanned by 64-slice spiral CT before and after treatment. The differences of tumor volume and perfusion parameters before and after treatment were compared, and the correlation between perfusion parameters and tumor microvessel density (MVD) was analyzed. The receiver working curve (ROC curve) was used to evaluate the efficacy of the two groups after chemotherapy. Results. Blood flow (BF), blood volume (BV), Pallak blood volume (PBV), and time to start (TTS) in the antitumor angiogenesis+chemotherapy group were significantly lower than those before treatment ( P < 0.05 ). Microvessel density was positively correlated with PS, BF, BV, and PBV ( P < 0.05 ). The reduction rate of BV and BF in the remission group after treatment was significantly higher than that in the nonremission group. When the BV and BF decline rates were 47.37% and 21.53% and the areas under the curve were 0.968 and 0.916, respectively, the diagnostic effect was the best. When the decrease rate of BV was 47.48% and the decrease rate of BF was 21.55%, the sensitivity was 94.72% and 89.56% and the specificity was 91.31% and 91.31%. Conclusion. The reduction rate of BV and BF in CT perfusion imaging is of high value in evaluating the efficacy of radiotherapy and chemotherapy in patients with NSCLC and can provide more objective basis for observing the changes and judging the prognosis of osteosarcoma after treatment.

Section: Discussionmentioning

confidence: 99%

A Cohort Study to Evaluate the Efficacy and Value of CT Perfusion Imaging in Patients with Metastatic Osteosarcoma after Chemotherapy

Yang

Computational and Mathematical Methods in Medicine

et al. 2022

“…To date, there is a range of STAT3 inhibitors under preclinical development and in clinical trials. , For instance, Stattic , STA-21 , BP-1-102 , S31-201 , HJC0152 , HJC0123 , and HJC0416 , as orally bioavailable STAT3 inhibitors, exhibit promising antitumor effects against various cancers in preclinical models in vitro and in vivo. Additionally, a few STAT3 inhibitors, such as TTI-101 and OPB-111077 , have advanced to phase I clinical trials in patients with diverse types of cancers, including GC.…”

Section: Introductionmentioning

confidence: 99%

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

Miao

Sun

et al. 2022

J. Med. Chem.

Self Cite

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.

“…In addition to STAT3 inhibitors entering clinic studies, many preclinical STAT3 inhibitors have been reported. For instance, compounds 1d (BP-1-102), 1e (HJC0416), and 1f display potent antitumor activities by inhibiting STAT3 activation (Figure ). Most STAT3 inhibitors so far, however, mainly focus on inhibiting STAT3 phosphorylation at Tyr 705 while ignoring the tumorigenicity of Ser 727 phosphorylation. , It is worth noting that the STAT3 PROTAC molecule SD-36 ( 1g ) remarkably inhibits STAT3 phosphorylation at Tyr 705 and Ser 727 by degrading STAT3 protein, leading to complete and durable tumor regression in vivo , indicating that concurrently inhibiting STAT3 dual phosphorylation might block STAT3 activation to a greater extent than suppression of phosphorylation at either site alone …”

Section: Introductionmentioning

confidence: 99%

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

Bian

Miao

et al. 2022

J. Med. Chem.

Self Cite

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.