Medicinal chemistry strategies to discover P-glycoprotein inhibitors: An update

Dong, Junde; Qin, Zuodong; Zhang, Weidong; Cheng, Gang; Yehuda, Assaraf G.; Ashby, Charles R.; Chen, Zhe‐Sheng; Cheng, Xiangdong; Qin, Jiang‐Jiang

doi:10.1016/j.drup.2020.100681

Cited by 159 publications

(124 citation statements)

References 220 publications

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“…However, it has been reported that the down-regulation of USP7 expression also leads to the degradation of the p53 tumor suppressor (Tavana and Gu, 2017). Also, small molecules developed to inhibit the expression of molecular targets have been frequently found to have low specificity and selectivity (Qin et al, 2019a,b;Dong et al, 2020). The characterization of berberine as a USP7-MDM2 binding inhibitor provides novel strategies to develop specific inhibitors that selectively promote the degradation of oncoproteins.…”

Section: Discussionmentioning

confidence: 99%

Targeting USP7-Mediated Deubiquitination of MDM2/MDMX-p53 Pathway for Cancer Therapy: Are We There Yet?

Cheng

et al. 2020

Front. Cell Dev. Biol.

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The p53 tumor suppressor protein and its major negative regulators MDM2 and MDMX oncoproteins form the MDM2/MDMX-p53 circuitry, which plays critical roles in regulating cancer cell growth, proliferation, cell cycle progression, apoptosis, senescence, angiogenesis, and immune response. Recent studies have shown that the stabilities of p53, MDM2, and MDMX are tightly controlled by the ubiquitinproteasome system. Ubiquitin specific protease 7 (USP7), one of the most studied deubiquitinating enzymes plays a crucial role in protecting MDM2 and MDMX from ubiquitination-mediated proteasomal degradation. USP7 is overexpressed in human cancers and contributes to cancer initiation and progression. USP7 inhibition promotes the degradation of MDM2 and MDMX, activates the p53 signaling, and causes cell cycle arrest and apoptosis, making USP7 a potential target for cancer therapy. Several small-molecule inhibitors of USP7 have been developed and shown promising efficacy in preclinical settings. In the present review, we focus on recent advances in the understanding of the USP7-MDM2/MDMX-p53 network in human cancers as well as the discovery and development of USP7 inhibitors for cancer therapy.

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Section: Discussionmentioning

confidence: 99%

Targeting USP7-Mediated Deubiquitination of MDM2/MDMX-p53 Pathway for Cancer Therapy: Are We There Yet?

Cheng

et al. 2020

Front. Cell Dev. Biol.

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“…CRT has distinct domains important for its correct folding and immunogenic functions: the highly conserved amino-terminal domain and the close P domain constitute most of the extracellular portion of CRT interacting with other proteins [37]. On the other hand, Pgp is an integral membrane protein, characterized by 12 transmembrane helixes, connected by multiple extracellular loops and two large intracellular nucleotide binding domains [21]. The shift from an inward open conformation to an outward open conformation upon drug binding and efflux [21] makes Pgp a highly dynamic protein, able to transiently interact with other ecto-enzymes.…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, Pgp is an integral membrane protein, characterized by 12 transmembrane helixes, connected by multiple extracellular loops and two large intracellular nucleotide binding domains [21]. The shift from an inward open conformation to an outward open conformation upon drug binding and efflux [21] makes Pgp a highly dynamic protein, able to transiently interact with other ecto-enzymes. Such interactions can modulate Pgp activity, as in the case of Pgp-carbonic anhydrase XII interaction [25], or modulate the function of the client protein.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, we demonstrated that Pgp, which is synthesized within the ER, is transported to the plasma membrane, following the same mechanism of CRT: here, Pgp co-localizes with CRT and prevents cell phagocytosis by DCs [19]. In the last decades, three generations of Pgp/interacting compounds, including substrates, inhibitors, or modulators [20], have been developed with the aim of reversing chemoresistance in Pgp-expressing tumors [21]. Most of them failed because of heavy side effects, unexpected drug-drug interactions with chemotherapeutic agents, or poor pharmacokinetic profiles [20].…”

Section: Introductionmentioning

confidence: 98%

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Insights into P-Glycoprotein Inhibitors: New Inducers of Immunogenic Cell Death

Kopecka

Godel

Dei

et al. 2020

Cells

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Doxorubicin is a strong inducer of immunogenic cell death (ICD), but it is ineffective in P-glycoprotein (Pgp)-expressing cells. Indeed, Pgp effluxes doxorubicin and impairs the immunesensitizing functions of calreticulin (CRT), an “eat-me” signal mediating ICD. It is unknown if classical Pgp inhibitors, designed to reverse chemoresistance, may restore ICD. We addressed this question by using Pgp-expressing cancer cells, treated with Tariquidar, a clinically approved Pgp inhibitor, and R-3 compound, a N,N-bis(alkanol)amine aryl ester derivative with the same potency of Tariquidar as Pgp inhibitor. In Pgp-expressing/doxorubicin-resistant cells, Tariquidar and R-3 increased doxorubicin accumulation and toxicity, reduced Pgp activity, and increased CRT translocation and ATP and HMGB1 release. Unexpectedly, only R-3 promoted phagocytosis by dendritic cells and activation of antitumor CD8+T-lymphocytes. Although Tariquidar did not alter the amount of Pgp present on cell surface, R-3 promoted Pgp internalization and ubiquitination, disrupting its interaction with CRT. Pgp knock-out restores doxorubicin-induced ICD in MDA-MB-231/DX cells that recapitulated the phenotype of R-3-treated cells. Our work demonstrates that plasma membrane-associated Pgp prevents a complete ICD notwithstanding the release of ATP and HMGB1, and the exposure of CRT. Pharmacological compounds reducing Pgp activity and amount may act as promising chemo- and immunesensitizing agents.

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“…However, FOLFIRINOX has recently been associated with increased toxicity, mainly febrile neutropenia and diarrhea (Lambert et al, 2017). Numerous studies have unraveled the common molecular alterations occurring in PC, such as mutations in Kras, p53, and BRCA1 (Nag et al, 2013;Cicenas et al, 2017;Waters and Der, 2018), aberrant activation of wnt/bcatenin signaling and keap1/Nrf2 signaling (Qin et al, 2018;Kuo et al, 2019;Qin et al, 2019), and amplification and overexpression of MDM2, cyclin D1, USP7, and MDR1 (Qie and Diehl, 2016;Robey et al, 2018;Wang et al, 2019b;Dong et al, 2020;Qi et al, 2020), which play critical roles in the initiation, progression, metastasis, and chemoresistance of PC. Many targeted agents have been developed and evaluated in the preclinical and clinical settings (Karandish and Mallik, 2016).…”

Section: Introductionmentioning

confidence: 99%

Terphenyllin Suppresses Orthotopic Pancreatic Tumor Growth and Prevents Metastasis in Mice

et al. 2020

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Pancreatic cancer (PC) is an aggressive and fatal disease with high incidences of metastasis and recurrence. However, there are no effective treatment options for the majority of PC patients, especially for those with locally advanced tumors and metastatic diseases. Therefore, it is urgently needed to develop safe and effective anti-PC therapeutic agents. We have recently identified a novel marine-derived natural product terphenyllin with potent anti-PC activity. The present study was designed to investigate the efficacy and mechanisms of action of terphenyllin in several human PC cell lines and an orthotopic PC mouse model. The results showed that terphenyllin significantly inhibited the viability of all PC cell lines with minimal effects on a normal human pancreatic cell line (HPNE). We next demonstrated the effects of terphenyllin on colony formation, apoptosis, migration, and invasion in both Panc1 and HPAC cell lines in a concentration-dependent manner. Terphenyllin also suppressed the tumor growth and metastasis in the Panc1 orthotopic mouse model. We further showed the profound effects of terphenyllin on the expression of apoptosis-associated proteins, including Bax, Bad, Puma, Bim L , Bcl-2, phos-Bcl-2 (Ser70), Bcl-xL, caspase 7, and PARP, which contributed to its anti-PC activity. In summary, terphenyllin suppressed the PC cell growth and metastasis in vitro and in vivo and may be developed as an anti-PC therapeutic agent in the future.

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Medicinal chemistry strategies to discover P-glycoprotein inhibitors: An update

Cited by 159 publications

References 220 publications

Targeting USP7-Mediated Deubiquitination of MDM2/MDMX-p53 Pathway for Cancer Therapy: Are We There Yet?

Targeting USP7-Mediated Deubiquitination of MDM2/MDMX-p53 Pathway for Cancer Therapy: Are We There Yet?

Insights into P-Glycoprotein Inhibitors: New Inducers of Immunogenic Cell Death

Terphenyllin Suppresses Orthotopic Pancreatic Tumor Growth and Prevents Metastasis in Mice

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