Fragment Screening and Assembly:  A Highly Efficient Approach to a Selective and Cell Active Protein Tyrosine Phosphatase 1B Inhibitor

Liu, Gang; Xin, Zhili; Pei, Zhonghua; Hajduk, Philip J.; Abad‐Zapatero, Celerino; Hutchins, Charles W.; Zhao, Hongyu; Lübben, Thomas; Ballaron, Stephen J.; Haasch, Deanna L.; Kaszubska, Wiweka; Rondinone, Cristina M.; Trevillyan, James M.; Jirousek, Michael R.

doi:10.1021/jm034122o

Cited by 159 publications

(95 citation statements)

References 23 publications

(40 reference statements)

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“…These results suggest that increasing the lipophilicity of the B ring improved inhibitory potency against PTP1B. This is consistent with earlier studies in which lipophilic moieties stabilized the enzyme-compound complex via hydrophobic interactions with the active site and surrounding subpockets, a common feature of PTP1B-inhibitor complexes 40,41 . This concept is also supported by our docking simulations described below.…”

Section: Biological Evaluationsupporting

confidence: 91%

Synthesis and characterization of 5,7-dihydroxyflavanone derivatives as novel protein tyrosine phosphatase 1B inhibitors

Sun

Gao

et al. 2012

Journal of Enzyme Inhibition and Medicinal Chemistry

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Section: Biological Evaluationsupporting

confidence: 91%

Synthesis and characterization of 5,7-dihydroxyflavanone derivatives as novel protein tyrosine phosphatase 1B inhibitors

Sun

Gao

et al. 2012

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…Various approaches to fragment binding detection have been adopted, among them mass spectrometry [81], NMR [82,83], crystallography [84,85] and combinations there-from [86,87]. Special considerations for fragment based discovery using X-ray crystallography include the necessity for obtaining a well characterized crystal form of the target protein which diffracts well (d min < 2.5Å), possesses a lattice amenable to soaking experiments (i.e., without occlusion of the target site), and is able to withstand exposure to modest quantities of organic solvents (e.g., ethanol and DMSO are popular solvents for chemical fragments).…”

Section: Fragment Condensationmentioning

confidence: 99%

Structural genomics of protein phosphatases

Almo

Bonanno

Sauder³

et al. 2007

J Struct Funct Genomics

152

117

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The New York SGX Research Center for Structural Genomics (NYSGXRC) of the NIGMS Protein Structure Initiative (PSI) has applied its high-throughput X-ray crystallographic structure determination platform to systematic studies of all human protein phosphatases and protein phosphatases from biomedically-relevant pathogens. To date, the NYSGXRC has determined structures of 21 distinct protein phosphatases: 14 from human, 2 from mouse, 2 from the pathogen Toxoplasma gondii, 1 from Trypanosoma brucei, the parasite responsible for African sleeping sickness, and 2 from the principal mosquito vector of malaria in Africa, Anopheles gambiae. These structures provide insights into both normal and pathophysiologic processes, including transcriptional regulation, regulation of major signaling pathways, neural development, and type 1 diabetes. In conjunction with the contributions of other international structural genomics consortia, these efforts promise to provide an unprecedented database and materials repository for structureguided experimental and computational discovery of inhibitors for all classes of protein phosphatases.

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“…Such inhibitors often show greatly improved potency and selectivity. 26,27 Other peripheral residues, such as Arg47, Asp48, Lys41, Phe52, and Ala27, also can be targeted by extended inhibitors. 14, 16, 17, 28-31 Our research group has recently developed two libraries of extended bidentate PTP inhibitors that are derived from α-ketocarboxylic acids.…”

Section: Ptp Inhibitorsmentioning

confidence: 99%

A two stage click-based library of protein tyrosine phosphatase inhibitors

Xie

Seto

2007

Bioorganic & Medicinal Chemistry

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Protein tyrosine phosphatases (PTPs) are important regulators of signal transduction pathways. Potent and selective PTP inhibitors are useful for probing these pathways and also may serve as drugs for the treatment of a variety of diseases including type 2 diabetes and infection by the bacterium Yersinia pestis. In this report Cu(I)-catalyzed 'click' cycloaddition reactions between azides and alkynes were employed to generate two sequential libraries of PTP inhibitors. In the first round library methyl 4-azidobenzoylformate was reacted with 56 mono-and diynes. After hydrolysis of the methyl esters, the resulting α-ketocarboxylic acids were assayed in crude form against the Yersinia PTP and PTP1B. Four compounds were selected for further evaluation, and one compound was chosen as the lead for generation of the second round library. This lead compound was modified by conversion of an alcohol into an azide group, and the resulting azide was reacted with the same 56 mono-and diynes that were used in the first generation library. After screening the crude inhibitors against the Yersinia PTP and PTP1B, four compounds were selected and evaluated in pure form against the Yersinia PTP, PTP1B, TCPTP, LAR and CD45. The best bis(α-ketocarboxylic acid) inhibitor 34 had an IC 50 value of 550 nM against the Yersinia PTP, and an IC 50 value of 710 nM against TCPTP. The most potent inhibitor containing a single α-ketocarboxylic acid group 32 had IC 50 values of 2.1, 5.7 and 2.6 μM against the Yersinia PTP, PTP1B and TCPTP, respectively.

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Fragment Screening and Assembly: A Highly Efficient Approach to a Selective and Cell Active Protein Tyrosine Phosphatase 1B Inhibitor

Cited by 159 publications

References 23 publications

Synthesis and characterization of 5,7-dihydroxyflavanone derivatives as novel protein tyrosine phosphatase 1B inhibitors

Synthesis and characterization of 5,7-dihydroxyflavanone derivatives as novel protein tyrosine phosphatase 1B inhibitors

Structural genomics of protein phosphatases

A two stage click-based library of protein tyrosine phosphatase inhibitors

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