scholarly journals Biomolecular Interactions of Small-molecule Inhibitors Affecting the YopH Protein Tyrosine Phosphatase

2013 ◽  
Vol 81 (3) ◽  
pp. 323-333 ◽  
Author(s):  
Megan Hogan ◽  
Medhanit Bahta ◽  
Scott Cherry ◽  
George T. Lountos ◽  
Joseph E. Tropea ◽  
...  
Keyword(s):  
Small Molecule ◽  
Protein Tyrosine Phosphatase ◽  
Small Molecule Inhibitors ◽  
Tyrosine Phosphatase ◽  
Biomolecular Interactions ◽  
Protein Tyrosine

Structure-Based Discovery of Small Molecule Inhibitors Targeted to Protein Tyrosine Phosphatase 1B

2000 ◽  
Vol 43 (2) ◽  
pp. 146-155 ◽  
Author(s):  
Mauro Sarmiento ◽  
Li Wu ◽  
Yen-Fang Keng ◽  
Li Song ◽  
Zhaowen Luo ◽  
...  
Keyword(s):  
Small Molecule ◽  
Protein Tyrosine Phosphatase ◽  
Small Molecule Inhibitors ◽  
Tyrosine Phosphatase ◽  
Protein Tyrosine Phosphatase 1B ◽  
Protein Tyrosine

scholarly journals PAIN-less identification and evaluation of small molecule inhibitors against protein tyrosine phosphatase 1B

MedChemComm ◽  
2017 ◽  
Vol 8 (6) ◽  
pp. 1220-1224 ◽  
Author(s):  
Hamid R. Nasiri ◽  
Philipp Mracek ◽  
Steffen K. Grimm ◽  
Janine Gastaldello ◽  
Adrian Kolodzik ◽  
...  
Keyword(s):  
Natural Products ◽  
Small Molecule ◽  
Protein Tyrosine Phosphatase ◽  
Small Molecule Inhibitors ◽  
Tyrosine Phosphatase ◽  
Protein Tyrosine Phosphatase 1B ◽  
Protein Tyrosine ◽  
Set Up ◽  
Assay Interference

A miniaturized assay was set up to test a set of natural products against protein tyrosine phosphatase 1B (PTP1B). By using several read-out and counter assays, berberine and palmatine were identified as PAINS (pan-assay interference compounds) and α-TOS as a novel inhibitor of PTP1B.

Abstract A83: Profiling potent, novel protein tyrosine phosphatase 4A3 small molecule inhibitors for ovarian cancer.

2016 ◽  
Author(s):  
Elizabeth R. Sharlow ◽  
Joseph M. Salamoun ◽  
Kelley E. McQueeney ◽  
Sophie Lewandowski ◽  
Jennifer Bryant ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Small Molecule ◽  
Protein Tyrosine Phosphatase ◽  
Small Molecule Inhibitors ◽  
Tyrosine Phosphatase ◽  
Protein Tyrosine ◽  
Novel Protein

Tapping the therapeutic potential of protein tyrosine phosphatase 4A with small molecule inhibitors

2019 ◽  
Vol 29 (16) ◽  
pp. 2008-2015 ◽  
Author(s):  
Nikhil R. Tasker ◽  
Ettore J. Rastelli ◽  
James C. Burnett ◽  
Elizabeth R. Sharlow ◽  
John S. Lazo ◽  
...  
Keyword(s):  
Small Molecule ◽  
Protein Tyrosine Phosphatase ◽  
Small Molecule Inhibitors ◽  
Therapeutic Potential ◽  
Tyrosine Phosphatase ◽  
Protein Tyrosine

Inhibitor Binding Sites in the Protein Tyrosine Phosphatase SHP-2

2020 ◽  
Vol 20 (11) ◽  
pp. 1017-1030
Author(s):  
Haonan Zhang ◽  
Zhengquan Gao ◽  
Chunxiao Meng ◽  
Xiangqian Li ◽  
Dayong Shi
Keyword(s):  
Small Molecule ◽  
Protein Tyrosine Phosphatase ◽  
Binding Sites ◽  
Drug Target ◽  
Tyrosine Phosphatase ◽  
Cancer Drug ◽  
Cellular Activity ◽  
Binding Modes ◽  
Inhibitor Binding ◽  
Protein Tyrosine

Protein tyrosine phosphatase 2 (SHP-2) has long been proposed as a cancer drug target. Several small-molecule compounds with different mechanisms of SHP-2 inhibition have been reported, but none are commercially available. Pool selectivity over protein tyrosine phosphatase 1 (SHP-1) and a lack of cellular activity have hindered the development of selective SHP-2 inhibitors. In this review, we describe the binding modes of existing inhibitors and SHP-2 binding sites, summarize the characteristics of the sites involved in selectivity, and identify the suitable groups for interaction with the binding sites.

Small Molecule Interactions with Protein−Tyrosine Phosphatase PTP1B and Their Use in Inhibitor Design†

Biochemistry ◽  
1996 ◽  
Vol 35 (50) ◽  
pp. 15989-15996 ◽  
Author(s):  
Terrence R. Burke, ◽  
Bin Ye ◽  
Xinjian Yan ◽  
Shaomeng Wang ◽  
Zongchao Jia ◽  
...  
Keyword(s):  
Small Molecule ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Inhibitor Design ◽  
Protein Tyrosine ◽  
Molecule Interactions

A Small Molecule Inhibitor of Protein Tyrosine Phosphatase-Sigma (PTPσ) Promotes Hematopoietic Stem Cell (HSC) Regeneration

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 822-822
Author(s):  
Yurun Zhang ◽  
Mamle Quarmyne ◽  
Heather A Himburg ◽  
Xiao Yan ◽  
William McBride ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Small Molecule ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Receptor Protein ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Protein Tyrosine ◽  
Protein Tyrosine Phosphatase Sigma

Abstract Receptor tyrosine kinases (RTKs), such as c-kit, Flt-3 and Tie2, regulate hematopoietic stem cell (HSC) proliferation, differentiation and maintenance. Substantially less is known regarding the function of receptor protein tyrosine phosphatases (PTPs) in regulating HSC fate. We recently discovered that receptor protein tyrosine phosphatase sigma (PTPσ) is highly expressed by murine and human HSCs. Interestingly, constitutive deletion of PTPσ caused a marked increase in HSC repopulating capacity as measured in primary and secondary competitive repopulation assays (J Clin Invest 2015;125:177-182). Further, negative selection of human cord blood (CB) HSCs for PTPσ surface expression (PTPσ - negative CB HSCs) conferred more than 10-fold increased human CB hematopoietic engraftment through 20 weeks in transplanted NSG mice. Additionally, PTPσ-deficient mice displayed significantly augmented recovery of phenotypic bone marrow (BM) HSCs and colony forming cells at day +10 following 550 cGy total body irradiation. Based on these observations, we hypothesized that PTPσ may function as a negative regulator of HSC self-renewal and regeneration. We sought to develop pharmacologic strategies to inhibit PTPσ function as a means to augment HSC functional capacity. Based on structure-activity-relationship analysis of PTPσ, we screened candidate small molecules for ability to modulate PTPσ function on BM HSCs. We identified a small molecule, 5483071 (Chembridge), as a candidate PTPσ inhibitor. In silico simulation indicated that 5483071 rigidly docked into the binding site of PTPσ intracellular domain through hydrogen bonding and electrostatic interactions. In a model of HSC injury and regeneration, we irradiated C57Bl6 mice with 700 cGy TBI and treated mice systemically with either 10 μcg of 5483071 or water subcutaneously every other day from day +1 to day +14. Irradiated mice treated with 5483071 displayed significantly increased 60 day survival compared to controls (P=0.0007). Irradiated mice treated with 5483071 showed accelerated recovery of BM SLAM+kit+sca-1+lin- HSCs (P=0.02), BM KSL cells (P=0.01), and colony forming cells (CFCs) (P=0.0003). In vitro culture of BM KSL cells with 5483071 significantly increased the levels of activated Rac1 (P=0.0004), which recapitulated the effects of PTPσ deletion on Rac1 activation in HSCs. Importantly, treatment of BM KSL cells from PTPσ -/- mice with 5483071 caused no change in Rac1 activation, suggesting that 5483071 acted specifically on PTPσ and was not mediating effects via inhibition of other phosphatases. Systemic administration of 5483071 to irradiated mice caused an increase in BM KSL cell cycling at 72 hours compared to irradiated control mice (p=0.02), while also decreasing BM KSL cell apoptosis at 24 hours after TBI (p=0.02). Subsequent to these findings, we have generated several new small molecule inhibitors of PTPσ with novel composition of matter and have taken a lead compound into pre-clinical studies for investigational new drug (IND) development. PTPσ represents a novel receptor tyrosine phosphatase that regulates HSC self-renewal and regeneration. Targeted inhibition of PTPσ has high therapeutic potential to promote hematopoietic regeneration in patients receiving myelosuppressive chemotherapy and/or radiotherapy or undergoing myeloablative hematopoietic cell transplantation. Disclosures No relevant conflicts of interest to declare.

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