Potent Benzimidazole Sulfonamide Protein Tyrosine Phosphatase 1B Inhibitors Containing the Heterocyclic (<i>S</i>)-Isothiazolidinone Phosphotyrosine Mimetic

Combs, Andrew P.; Zhu, Wenyu; Crawley, Matthew L.; Glass, Brian; Polam, Padmaja; Sparks, Richard B.; Modi, Dilip; Takvorian, Amy; McLaughlin, Erin; Yue, Eddy W.; Wasserman, Zelda R.; Bower, Michael J.; Wei, Min; Rupar, Mark; Paul, Jean-Claude; Reid, Brian; Ellis, Dawn M.; Gonneville, Lucie; Emm, Thomas; Taylor, Nancy; Yeleswaram, Swamy; Li, Yanlong; Wynn, Richard; Burn, Timothy C.; Hollis, Gregory; Liu, Phillip C.C.; Metcalf, Brian W.

doi:10.1021/jm0600904

Cited by 83 publications

(36 citation statements)

References 14 publications

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“…Among them, compound VII displayed high inhibition potency, with an IC 50 of 35 nM. It also exhibited significant cellular activity, increasing the insulin receptor phosphorylation level at 80 μM [53]. Collectively, these results illustrate that it is highly feasible to obtain potent and selective PTP1B inhibitors.…”

Section: Ptp1bmentioning

confidence: 76%

Targeting PTPs with small molecule inhibitors in cancer treatment

Jiang

Zhang

2008

Cancer Metastasis Rev

114

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Protein tyrosine phosphorylation plays a major role in cellular signaling. The level of tyrosine phosphorylation is controlled by protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). Disturbance of the normal balance between PTK and PTP activity results in aberrant tyrosine phosphorylation, which has been linked to the etiology of several human diseases, including cancer. A number of PTPs have been implicated in oncogenesis and tumor progression and therefore are potential drug targets for cancer chemotherapy. These include PTP1B, which may augment signaling downstream of HER2/Neu; SHP2, which is the first oncogene in the PTP superfamily and is essential for growth factor-mediated signaling; the Cdc25 phosphatases, which are positive regulators of cell cycle progression; and the PRL phosphatases, which promote tumor metastases. As PTPs have emerged as drug targets for cancer, a number of strategies are currently been explored for the identification of various classes of PTP inhibitors. These efforts have resulted many potent, and in some cases selective, inhibitors for PTP1B, SHP2, Cdc25 and PRL phosphatases. Structural information derived from these compounds serves as a solid foundation upon which novel anti-cancer agents targeted to these PTPs can be developed.

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Section: Ptp1bmentioning

confidence: 76%

Targeting PTPs with small molecule inhibitors in cancer treatment

Jiang

Zhang

2008

Cancer Metastasis Rev

114

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“…A related approach employed an isothiazolidinone (IZD)-based phosphoryl mimetic, which had previously been shown to be a superior for this use against PTP1B [82][83][84][85][86]. In the aforementioned study, a 3-formylphenyl group was introduced at the 5-position of the IZD ring to give intermediate 20 and then this was reacted with excess 1,3-diaminooxypropane to give the monomeric adduct 21 Fig.…”

Section: Oxime-based Click Chemistrymentioning

confidence: 99%

Yersinia pestis and Approaches to Targeting its Outer Protein H Protein-Tyrosine Phosphatase (YopH)

Bahta¹,

Burke²

2012

CMC

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Plague is an infectious disease with a high mortality rate that has repeatedly impacted human society. It remains a threat in many parts of the world today. Plague is caused by the bacterium, Yersinia pestis (Y. pestis), which has as one of its required virulence factors, the protein-tyrosine phosphatase, YopH. Therefore, YopH represents a potential target for the treatment of Y. pestis infection. Recent recognition of Y. pestis as a possible bioterrorism agent and the fact that it is still the cause of endemic disease around the world make it an important object of study and heighten the need for new anti-plague agents. The current review covers aspects of plague and its historical occurrence and summarizes approaches to developing YopH inhibitors.

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“…This group has gone on to incorporate the (S)-IZD pTyr mimetic into more druglike molecules and have demonstrated that benzimidazole sulfonamide containing (S)-IZD PTP1B inhibitors (Fig. 4B) can potently inhibit the enzyme, have cell permeability, and increase insulin signaling [Combs et al, 2006].…”

Section: Ptp1b Inhibitors For Metabolic Diseasesmentioning

confidence: 99%

Toward the discovery of small molecule PTP1B inhibitors for the treatment of metabolic diseases

Nichols¹,

Mashal²,

Balkan

2006

Drug Development Research

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PTP1B is a protein tyrosine phosphatase involved in insulin and leptin signaling and is a primary mechanism for down-regulating both the insulin and leptin receptor signaling pathways. Animals deficient in PTP1B have improved glucose regulation and lipid profiles and are resistant to weight gain when treated with a high fat diet. Thus, PTP1B inhibitors are expected to be useful in the treatment of type 2 diabetes, obesity, and the metabolic syndrome. Progress toward the design of potent and orally active PTP1B inhibitors has been hindered by the highly charged nature of the tyrosine phosphate mimetics used to date. Recent progress in the design of more drug-like molecules holds promise for the eventual discovery and development of clinically useful PTP1B inhibitors. Drug Dev. Res. 67:559-566, 2006.

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Potent Benzimidazole Sulfonamide Protein Tyrosine Phosphatase 1B Inhibitors Containing the Heterocyclic (S)-Isothiazolidinone Phosphotyrosine Mimetic

Cited by 83 publications

References 14 publications

Targeting PTPs with small molecule inhibitors in cancer treatment

Targeting PTPs with small molecule inhibitors in cancer treatment

Yersinia pestis and Approaches to Targeting its Outer Protein H Protein-Tyrosine Phosphatase (YopH)

Toward the discovery of small molecule PTP1B inhibitors for the treatment of metabolic diseases

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