An Isoform-Selective PTP1B Inhibitor Derived from Nitrogen-Atom Augmentation of Radicicol

Shi, Taoda; Wijeratne, E. M. Kithsiri; Solano, Cristian; Ambrose, Andrew J.; Ross, Alison B.; Norwood, Charles; Orido, Charles K.; Grigoryan, Tigran; Tillotson, Joseph; Kang, Minjin; Luo, Gang; Keegan, Bradley M.; Hu, Wenhao; Blagg, Brian S. J.; Zhang, Donna D.; Gunatilaka, A. A. Leslie; Chapman, Eli

doi:10.1021/acs.biochem.9b00499

Cited by 9 publications

(3 citation statements)

References 57 publications

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“…Celastrol also blocks the enzyme activity of SHP2 and PTEN, which is also relevant for hypothalamic leptin action. Shi et al, 78 screened a library of natural products and their derivatives for refinement of the most potent PTP1B inhibitors. Among the screened compounds, SN1 has discovered as pyrrolopyrazoloisoquinolone derivative.…”

Section: Natural Plant Products As Ptp1b Allosteric Inhibitorsmentioning

confidence: 99%

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Recent advances in the development of allosteric protein tyrosine phosphatase inhibitors for drug discovery

Elhassan

Hou

Fang

2021

Medicinal Research Reviews

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Protein tyrosine phosphatases (PTPs) superfamily catalyzes tyrosine de-phosphorylation which affects a myriad of cellular processes. Imbalance in signal pathways mediated by PTPs has been associated with development of many human diseases including cancer, metabolic, and immunological diseases. Several compelling evidence suggest that many members of PTP family are novel therapeutic targets. However, the clinical development of conventional PTP-based active-site inhibitors originally was hampered by the poor selectivity and pharmacokinetic properties. In this regard, PTPs has been widely dismissed as "undruggable." Nonetheless, allosteric modulation has become increasingly an influential and alternative approach that can be exploited for drug development against PTPs. Unlike active-site inhibitors, allosteric inhibitors exhibit a remarkable targetselectivity, drug-likeness, potency, and in vivo activity. Intriguingly, there has been a high interest in novel allosteric PTPs inhibitors within the last years. In this review, we focus on the recent advances of allosteric inhibitors that have been explored in drug discovery and have shown an excellent result in the development of PTPs-based therapeutics. A special emphasis is placed on the structure-activity relationship and molecular

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Section: Natural Plant Products As Ptp1b Allosteric Inhibitorsmentioning

confidence: 99%

“…Shi et al, 78 screened a library of natural products and their derivatives for refinement of the most potent PTP1B inhibitors. Among the screened compounds, SN1 has discovered as pyrrolopyrazoloisoquinolone derivative.…”

Section: Discovery and Development Of Ptps Allosteric Inhibitorsmentioning

confidence: 99%

Recent advances in the development of allosteric protein tyrosine phosphatase inhibitors for drug discovery

Elhassan

Hou

Fang

2021

Medicinal Research Reviews

View full text Add to dashboard Cite

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“…The inhibition mode was determined by variation patterns of the kinetic parameters ( V max and K m ). The Lineweaver–Burk plots produced a set of double-reciprocal curves illustrating the decrease of V max and the increase of K m values with increasing inhibitor concentration typical of a mixed-type inhibitory behavior for both 4 and 7 . , In addition, the K i values of 4 and 7 were determined by Dixon plots as 1.21 and 3.02 μM, respectively (Figure S84). The mixed-type inhibition with obvious selectivity hinted at an allosteric effect.…”

Section: Resultsmentioning

confidence: 99%

Selective Inhibition of PTP1B by New Anthraquinone Glycosides from Knoxia valerianoides

et al. 2022

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Protein tyrosine phosphatase 1B (PTP1B) is highly validated as a therapeutic target for type 2 diabetes. However, active site-directed PTP1B inhibitors generally suffer from poor selectivity and bioavailability. Inspired by the identification of a unique anthraquinone-coumarin hybrid from Knoxia valerianoides exhibiting good specificity for PTP1B over the highly homologous T-cell protein tyrosine phosphatase (TCPTP), further chemical investigation of this plant species led to the isolation of nine new anthraquinone glycosides (1–9) and two known ones (10 and 11). Structures were characterized by a combination of spectroscopic analyses and chemical methods. All compounds showed PTP1B inhibitory activities with IC50 values ranging from 1.05 to 13.74 μM. Compounds 4 and 8 exhibited greater than 64-fold selectivity over TCPTP. Enzyme kinetic studies revealed that compounds 4 and 7 behaved as mixed-type inhibitors. Docking studies predicted similar binding modes of these compounds at the allosteric site positioned between helices α3 and α6.

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Fungal metabolites as anti-diabetic agents: emphasis on PTP1B inhibitors

et al. 2021

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An Isoform-Selective PTP1B Inhibitor Derived from Nitrogen-Atom Augmentation of Radicicol

Cited by 9 publications

References 57 publications

Recent advances in the development of allosteric protein tyrosine phosphatase inhibitors for drug discovery

Recent advances in the development of allosteric protein tyrosine phosphatase inhibitors for drug discovery

Selective Inhibition of PTP1B by New Anthraquinone Glycosides from Knoxia valerianoides

Fungal metabolites as anti-diabetic agents: emphasis on PTP1B inhibitors

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