C-Acylations of Polymeric Phosphoranylidene Acetates for C-Terminal Variation of Peptide Carboxylic Acids

El-Dahshan, Adeeb; Weik, Steffen; Rademann, Jörg

doi:10.1021/ol062754+

Cited by 23 publications

(14 citation statements)

References 26 publications

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“…Good drug-like properties and membrane permeability (logP Ͻ5, H bond donors Ͻ5, H bond acceptors Ͻ10, molecular weight Ͻ500) (31) can be predicted for PHPS1. A four-step procedure for the synthesis of PHPS compounds was developed based on the C-acylation of triphenylphosphoranylidene acetate (32) [see supporting information (SI) Text, Materials and Methods, and Scheme S1] and used to vary its chemical structure for structure-activity studies and further lead optimization. Therefore, we focused on the PHPS compound class throughout this study.…”

Section: Identification Of the Phps Compound Class Of Shp2 Inhibitorsmentioning

confidence: 99%

Specific inhibitors of the protein tyrosine phosphatase Shp2 identified by high-throughput docking

Hellmuth

Grosskopf

Lum

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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The protein tyrosine phosphatase Shp2 is a positive regulator of growth factor signaling. Gain-of-function mutations in several types of leukemia define Shp2 as a bona fide oncogene. We performed a high-throughput in silico screen for small-molecular-weight compounds that bind the catalytic site of Shp2. We have identified the phenylhydrazonopyrazolone sulfonate PHPS1 as a potent and cellpermeable inhibitor, which is specific for Shp2 over the closely related tyrosine phosphatases Shp1 and PTP1B. PHPS1 inhibits Shp2-dependent cellular events such as hepatocyte growth factor/scatter factor (HGF/SF)-induced epithelial cell scattering and branching morphogenesis. PHPS1 also blocks Shp2-dependent downstream signaling, namely HGF/SF-induced sustained phosphorylation of the Erk1/2 MAP kinases and dephosphorylation of paxillin. Furthermore, PHPS1 efficiently inhibits activation of Erk1/2 by the leukemia-associated Shp2 mutant, Shp2-E76K, and blocks the anchorage-independent growth of a variety of human tumor cell lines. The PHPS compound class is therefore suitable for further development of therapeutics for the treatment of Shp2-dependent diseases.chemical biology ͉ growth factor signaling ͉ phosphatase inhibition ͉ virtual drug screening

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Section: Identification Of the Phps Compound Class Of Shp2 Inhibitorsmentioning

confidence: 99%

Specific inhibitors of the protein tyrosine phosphatase Shp2 identified by high-throughput docking

Hellmuth

Grosskopf

Lum

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

206

182

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“…Synthetic procedures and analytical data (HRMS; 1 H, 13 C NMR) of all new compounds are given in the Supporting Information.…”

Section: Methodsmentioning

confidence: 99%

Metal‐Free, Regioselective Triazole Ligations that Deliver Locked cis Peptide Mimetics

et al. 2009

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“…Enzymatic cleavage of the peptidic substrate released a fluorophore, which served as an indicator for protease activity. The chemically reactive protein ligand, a peptide aldehyde [45,54], was then incubated with an excess of a nucleophilic fragment in the presence of the enzyme. Following addition of the fluorogenic substrate, rate differences in substrate turnover were quantified to identify active inhibitory fragments.…”

Section: Reviewmentioning

confidence: 99%

Dynamic template-assisted strategies in fragment-based drug discovery

Schmidt

Rademann

2009

Trends in Biotechnology

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Fragment-based methods for drug discovery are increasingly popular because they provide drug leads with greater ligand efficiency than conventional high-throughput screening. However, established methods for fragment detection do not address the central question in fragment-based ligand discovery: how can a primary ligand be optimally extended by a secondary fragment? Dynamic screening methods solve this issue by using a protein target as a template for ligand assembly, thus yielding high-affinity binders from low-affinity fragments. This review summarizes recent work on dynamic screening methodology, which resulted in the development of several high-affinity binders for various targets. Strengths and limitations of the published approaches are discussed and possible contributions of dynamic screening methodology to the drug discovery process are highlighted.

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C-Acylations of Polymeric Phosphoranylidene Acetates for C-Terminal Variation of Peptide Carboxylic Acids

Cited by 23 publications

References 26 publications

Specific inhibitors of the protein tyrosine phosphatase Shp2 identified by high-throughput docking

Specific inhibitors of the protein tyrosine phosphatase Shp2 identified by high-throughput docking

Metal‐Free, Regioselective Triazole Ligations that Deliver Locked cis Peptide Mimetics

Dynamic template-assisted strategies in fragment-based drug discovery

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