Preclinical studies of the triazolo[1,5-a]pyrimidine derivative WS-716 as a highly potent, specific and orally active P-glycoprotein (P-gp) inhibitor

Wang, Saiqi; Teng, Quincy; Wang, Shuai; Lei, Zinning; Hu, Huihui; Lv, Haiyan; Chen, Beibei; Wang, Jianzheng; Shi, Xiaojing; Xu, Weifeng; Liu, Hong‐Min; Chen, Xiaobing; Chen, Zhe‐Sheng

doi:10.1016/j.apsb.2022.03.023

Cited by 16 publications

(10 citation statements)

References 53 publications

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“…Many previously investigated inhibitors are believed to bind to drug binding sites and to limit chemotherapeutic export by competing for transport cycles as P-gp transport substrates. Because of this property, extremely large systemic dosages were almost certainly necessary, which resulted in off-target damage [113].…”

Section: Authors' Perspectivementioning

confidence: 99%

Multidrug Resistance of Cancer Cells and the Vital Role of P-Glycoprotein

Karthika

Sureshkumar

Zehravi

et al. 2022

Life

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P-glycoprotein (P-gp) is a major factor in the multidrug resistance phenotype in cancer cells. P-gp is a protein that regulates the ATP-dependent efflux of a wide range of anticancer medicines and confers resistance. Due to its wide specificity, several attempts have been made to block the action of P-gp to restore the efficacy of anticancer drugs. The major goal has been to create molecules that either compete with anticancer medicines for transport or function as a direct P-gp inhibitor. Despite significant in vitro success, there are presently no drugs available in the clinic that can “block” P-gp–mediated resistance. Toxicity, unfavourable pharmacological interactions, and a variety of pharmacokinetic difficulties might all be the reason for the failure. On the other hand, P-gp has a significant effect in the body. It protects the vital organs from the entry of foreign bodies and other toxic chemicals. Hence, the inhibitors of P-gp should not hinder its action in the normal cells. To develop an effective inhibitor of P-gp, thorough background knowledge is needed in this field. The main aim of this review article was to set forth the merits and demerits of the action of P-gp on cancer cells as well as on normal cells. The influence of P-gp on cancer drug delivery and the contribution of P-gp to activating drug resistance were also mentioned.

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Section: Authors' Perspectivementioning

confidence: 99%

Multidrug Resistance of Cancer Cells and the Vital Role of P-Glycoprotein

Karthika

Sureshkumar

Zehravi

et al. 2022

Life

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show abstract

“…As a member of ATP-binding cassette (ABC) transporters, P-glycoprotein (P-gp) can promote the efflux of drugs and make the drugs lose their therapeutic effect, inhibition of P-gp can significantly reverse drug resistance. [6][7][8][9][10] Additionally, cytoprotective autophagic response often counteracts apoptosis triggered by anticancer drugs, potentially contributing to acquired drug resistance. 11,12 Notably, it is generally believed that eliminating cancer stem cells (CSCs) and reversing epithelial-mesenchymal transition (EMT) are also effective means to overcome drug resistance.…”

Section: Introductionmentioning

confidence: 99%

Targeting epigenetic regulators to overcome drug resistance in cancers

Wang

2023

Sig Transduct Target Ther

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Drug resistance is mainly responsible for cancer recurrence and poor prognosis. Epigenetic regulation is a heritable change in gene expressions independent of nucleotide sequence changes. As the common epigenetic regulation mechanisms, DNA methylation, histone modification, and non-coding RNA regulation have been well studied. Increasing evidence has shown that aberrant epigenetic regulations contribute to tumor resistance. Therefore, targeting epigenetic regulators represents an effective strategy to reverse drug resistance. In this review, we mainly summarize the roles of epigenetic regulation in tumor resistance. In addition, as the essential factors for epigenetic modifications, histone demethylases mediate the histone or genomic DNA modifications. Herein, we comprehensively describe the functions of the histone demethylase family including the lysine-specific demethylase family, the Jumonji C-domain-containing demethylase family, and the histone arginine demethylase family, and fully discuss their regulatory mechanisms related to cancer drug resistance. In addition, therapeutic strategies, including small-molecule inhibitors and small interfering RNA targeting histone demethylases to overcome drug resistance, are also described.

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“…Therefore, targeting P-gp has been employed as a promising strategy to overcome MDR by co-administration with anticancer drugs. − Until now, the development process of P-gp inhibitors or modulators has experienced four generations, and the representative member of each generation includes verapamil (VPL), , dexverapamil, encequidar, and peptidomimetics. − Although they had been extensively investigated in clinical trials in hope of overcoming MDR for more than 40 years, the progress in this field was unsatisfactory due to poor therapeutic efficacy and non-negligible toxicity. Consequently, it is urgent and desirable to develop nontoxic, more effective, and structurally new molecules for the treatment of P-gp-mediated MDR. − …”

Section: Introductionmentioning

confidence: 99%

Modular Biomimetic Strategy Enabled Discovery of Simplified Pseudo-Natural Macrocyclic P-Glycoprotein Inhibitors Capable of Overcoming Multidrug Resistance

Liu

Wang

et al. 2023

J. Med. Chem.

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Natural macrocycles have shown impressive activity to overcome P-glycoprotein (P-gp)-mediated multidrug resistance (MDR). However, the total synthesis and structural modification of natural macrocycles are challenging, which would hamper the deeper investigations of their structure–activity relationship (SAR) and drug likeness. Herein, we describe a modular biomimetic strategy to expeditiously achieve a new class of macrocycles featuring polysubstituted 1,3-diene, which efficiently inhibited P-gp and reversed MDR in cancer cells. The SAR analysis revealed that the size and linker of the macrocycles are important structural characteristics to restore activity. Particularly, 32 containing a naphthyl group and (d)-Phe moiety has higher potency with an excellent reversal fold than verapamil at a concentration of 5 μM, which induces conformational change of P-gp and inhibits its function instead of altering P-gp expression. Furthermore, 23 and 32 were identified to be attractive leads, which possess a good pharmacokinetic profile and antitumor activity in a KBV200 xenograft mouse model.

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Preclinical studies of the triazolo[1,5-a]pyrimidine derivative WS-716 as a highly potent, specific and orally active P-glycoprotein (P-gp) inhibitor

Cited by 16 publications

References 53 publications

Multidrug Resistance of Cancer Cells and the Vital Role of P-Glycoprotein

Multidrug Resistance of Cancer Cells and the Vital Role of P-Glycoprotein

Targeting epigenetic regulators to overcome drug resistance in cancers

Modular Biomimetic Strategy Enabled Discovery of Simplified Pseudo-Natural Macrocyclic P-Glycoprotein Inhibitors Capable of Overcoming Multidrug Resistance

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