Discovery of novel pyrazolopyrimidine derivatives as potent mTOR/HDAC bi-functional inhibitors via pharmacophore-merging strategy

Zhang, Mingming; Wei, Wei; Peng, Chengjun; Ma, Xiaodong; He, Xiao; Zhang, Heng; Zhou, Mingkang

doi:10.1016/j.bmcl.2021.128286

Cited by 15 publications

(11 citation statements)

References 26 publications

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“…HDACs can participate in epigenetic regulation of transcription, cell cycle and cell metabolism by catalyzing post-translational modifications of histones. 16 HDAC inhibitors may potentially provide a way to alleviate visceral hypersensitivity related to irritable bowel syndrome. 17 Compared with the control group, the fecal water content of the model group was significantly increased, but was significantly reduced after SAHA administration ( Figure 2A ).…”

Section: Resultsmentioning

confidence: 99%

SAHA Alleviates Diarrhea-Predominant Irritable Bowel Syndrome Through Regulation of the p-STAT3/SERT/5-HT Signaling Pathway

Shen¹,

Zhang²,

Chen³

et al. 2022

JIR

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Objective Irritable bowel syndrome (IBS) is characterized by abdominal pain, bloating, and stool irregularity. However, its pathophysiological mechanisms, which trigger intestinal motility disorders and diarrhea leading to diarrhea-predominant IBS (D-IBS), remain largely unknown. Methods In the present study, we established a D-IBS rat model by mother–infant separation combined with restraint stress. Then we exposed the modelled rats to suberoylanilide hydroxamic acid (SAHA) treatment, followed by determination of their visceral sensitivity. Toluidine blue staining served to reveal the effects of SAHA treatment on mast cells of D-IBS model rats. Then we measured the expression of serotonin (5-hydroxytryptamine; 5-HT) and its receptors by ELISA. Results Construction of short hairpin RNA (sh)-serotonin transporter (SERT) lentivirus vectors verified the regulation of the 5-HT signaling pathway by phosphorylated (p)-STAT/SERT. SAHA treatment of D-IBS model rats reduced the fecal water content, electromyography integral change rate, abdominal withdrawal reflex score, and number of mast cells, as well as the expression of 5-HT type 3A (5-HT3AR), 3B receptor (5-HT3BR), and 4 receptor (5-HT4R) receptors. The treatment also elevated the expression of signal transducer and activator for transcription 3 (STAT3) and SERT. Activation of p-STAT3 may reverse the inhibitory effect of SAHA on the elevated visceral sensitivity of D-IBS model rats. Moreover, SAHA promoted the transcription of SERT through repression of the p-STAT3/5-HT signaling, thereby inhibiting the visceral sensitivity of D-IBS model rats. Conclusion This study highlights that SAHA treatment can alleviate D-IBS through regulation of the p-STAT3/SERT/5-HT signaling pathway.

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Section: Resultsmentioning

confidence: 99%

SAHA Alleviates Diarrhea-Predominant Irritable Bowel Syndrome Through Regulation of the p-STAT3/SERT/5-HT Signaling Pathway

Shen¹,

Zhang²,

Chen³

et al. 2022

JIR

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“…Incorporating a hydroximic acid into an mTOR′ solvent-exposed area via a linker led to the identification of compounds 78 – 80 as HDAC/mTOR dual inhibitors . Compound 78 comprised a pyrazolopyrimidine core (pharmacophore of mTOR inhibitor 16 ) and hydroxamic acid with different linkers. − Compound 78 had a piperidine-containing linker and showed mTOR inhibitory activity (IC 50 = 0.49 nM) comparable to that of compound 16 (IC 50 = 0.63 nM) and greater HDAC1 inhibitory activity (IC 50 = 0.91 nM) than vorinostat.…”

Section: Co-targeting Inhibitors With the Pi3k/akt/mtor Pathwaymentioning

confidence: 99%

“…Compound 78 with a hydrocarbon linker showed antiproliferative effects against HCT116 (IC 50 = 17 nM), Raji (IC 50 = 1.9 nM), MM1S (IC 50 = 7.3 nM), MV4-11 (IC 50 = 4.0 nM), OCI-AML2 (IC 50 = 9.0 nM), and OCI-AML3 (IC 50 = 10 nM) cell lines and antitumor activity (dosing at 20 mg/kg through intravenous injection induced TGI of 72%) against the MM1S xenograft NOD/SCID mouse model. 170 Recently, we designed and synthesized a new HDAC/mTOR dual inhibitor (79) by introducing a pharmacophore of vorinostat into mTOR inhibitor (16) solvent-exposed groups via different optimized linkers. 171 Compound 79 significantly inhibited mTOR kinase and HDACs with more selective cytotoxicity against HepG2 cells (IC 50 = 1.6 μM) than normal L-02 cells (IC 50 = 25 μM) and good metabolic stability.…”

Section: Co-targeting Inhibitors With the Pi3k/akt/mtor Pathwaymentioning

confidence: 99%

Targeting the PI3K/AKT/mTOR Signaling Pathway in the Treatment of Human Diseases: Current Status, Trends, and Solutions

Huang

Chen

et al. 2022

J. Med. Chem.

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The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway is one of the most important intracellular pathways involved in cell proliferation, growth, differentiation, and survival. Therefore, this route is a prospective biological target for treating various human diseases, such as tumors, neurodegenerative diseases, pulmonary fibrosis, and diabetes. An increasing number of clinical studies emphasize the necessity of developing novel molecules targeting the PI3K/AKT/mTOR pathway. This review focuses on recent advances in ATP-competitive inhibitors, allosteric inhibitors, covalent inhibitors, and proteolysis-targeting chimeras against the PI3K/AKT/mTOR pathway, and highlights possible solutions for overcoming the toxicities and acquired drug resistance of currently available drugs. We also provide recommendations for the future design and development of promising drugs targeting this pathway.

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“…[45] Considering these, Zhang et al achieved the synthesis of pyrazolopyrimidine derivatives, followed by anticancer evaluation. [46] In the case of initial mTOR and HDAC1 inhibition, some of the compounds exerted remarkable activity. The strongest activity (Table 2) was found for compound 26 (Figure 3) and it was found to be a dual inhibitor.…”

Section: Pyrazolopyrimidine-azole Derivativesmentioning

confidence: 99%

Pyrazolopyrimidines as attractive pharmacophores in efficient drug design: A recent update

Dorababu¹

2022

Archiv der Pharmazie

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Among the menacing diseases, cancer needs the most attention as millions of people are affected by it worldwide. Genetic and environmental factors play a pivotal role in causing cancer. Although a wide range of underlying mechanisms of cancer has been discovered, efficient treatments have not been discovered to date. Additionally, diseases caused by microbes such as viruses, bacteria, protozoa, and so forth, persistently result in several deaths. Also, inflammation is a major factor that leads to several health issues. For decades, drug design has become a major part of drug discovery and development for curing various diseases. Among the large number of pharmacological agents that have been synthesized, only very few have emerged as efficient drug molecules. Most of them are heterocyclic compounds, which are promising candidates for the design of efficient drug molecules. Furthermore, fused heterocycles showed comparatively stronger pharmacological activities than monocyclic heterocycles. The literature reveals that pyrazolopyrimidines have outstanding biological activity. Hence, here, the diverse pharmacological activities shown by pyrazolopyrimidine derivatives reported in the last 5 years are collated and reviewed systematically. This review is classified into various sections focusing on anticancer, antimicrobial, anti-inflammatory, and enzyme inhibitors.Structure-activity relationships are discussed in brief, which will help researchers design potent pharmacological agents.

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Discovery of novel pyrazolopyrimidine derivatives as potent mTOR/HDAC bi-functional inhibitors via pharmacophore-merging strategy

Cited by 15 publications

References 26 publications

SAHA Alleviates Diarrhea-Predominant Irritable Bowel Syndrome Through Regulation of the p-STAT3/SERT/5-HT Signaling Pathway

SAHA Alleviates Diarrhea-Predominant Irritable Bowel Syndrome Through Regulation of the p-STAT3/SERT/5-HT Signaling Pathway

Targeting the PI3K/AKT/mTOR Signaling Pathway in the Treatment of Human Diseases: Current Status, Trends, and Solutions

Pyrazolopyrimidines as attractive pharmacophores in efficient drug design: A recent update

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