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

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.

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.

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.

scholarly journals Correlation Between Nasal Epithelial Injury and In Vitro Cytotoxicity Using a Series of Small Molecule Protein Tyrosine Phosphatase 1B Inhibitors Investigated for Reversal of Leptin Resistance in Obesity

2017 ◽  
Vol 36 (4) ◽  
pp. 303-313
Author(s):  
Alan P. Brown ◽  
Chandrassegar Saravanan ◽  
Patrick Devine ◽  
Maria Magnifico ◽  
Jiaping Gao ◽  
...  
Keyword(s):  
Food Consumption ◽  
Small Molecule ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Sodium Dodecylbenzene Sulfonate ◽  
Protein Tyrosine Phosphatase 1B ◽  
Protein Tyrosine ◽  
Nasal Injury ◽  
Ptp1b Inhibitors

This research provides a cautionary example when evaluating changes in behavioral end points with respect to postulated pharmacologic activity. Various small molecule substrate mimetic protein tyrosine phosphatase 1B (PTP1B) inhibitors were investigated as pharmacologic agents for decreasing food consumption using intranasal (IN) dosing as a means for direct nose-to-brain delivery along the olfactory/trigeminal nerve pathways. Although food consumption was decreased in diet-induced obese (DIO) mice, nasal discharge was observed. Studies were conducted to investigate local effects on the nasal airway and to develop structure–activity relationships. Intranasal administration of PTP1B inhibitors at ≥0.03 mg/d to DIO mice produced dose-dependent injury to various cell types of the nasal epithelia. Protein tyrosine phosphatase 1B inhibitors with calculated log octanol >3.0 were the most toxic. Whereas a pharmacologically inactive analog of a PTP1B inhibitor produced nasal injury, along with decreased food consumption, the marketed IN drug ketorolac produced no lesions at the same dose of 0.3 mg/d and only minor changes at 3 mg/d. Rat skin fibroblast cells were exposed in vitro to PTP1B inhibitors, ketorolac, paraquat, and the detergent sodium dodecylbenzene sulfonate (NDS) followed by measures of cytotoxicity. The most potent PTP1B inhibitors were similar to NDS, whereas ketorolac was the least toxic compound. Cytotoxic potency in vitro was similar to in vivo. In conclusion, PTP1B inhibitors injured nasal epithelium through a mechanism independent of PTP1B inhibition and likely due to nonspecific cytotoxicity such as disruption of the cell membrane. Decreased food consumption in DIO mice was due to toxicity rather than a pharmacologic mode of action.

scholarly journals Cocaine reward is reduced by decreased expression of receptor-type protein tyrosine phosphatase D (PTPRD) and by a novel PTPRD antagonist

2018 ◽  
Vol 115 (45) ◽  
pp. 11597-11602 ◽  
Author(s):  
George R. Uhl ◽  
Maria J. Martinez ◽  
Paul Paik ◽  
Agnieszka Sulima ◽  
Guo-Hua Bi ◽  
...  
Keyword(s):  
Conditioned Place Preference ◽  
Small Molecule ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Place Preference ◽  
Receptor Type ◽  
Self Administration ◽  
Preference Data ◽  
Protein Tyrosine ◽  
Type Protein

Receptor-type protein tyrosine phosphatase D (PTPRD) is a neuronal cell-adhesion molecule/synaptic specifier that has been implicated in addiction vulnerability and stimulant reward by human genomewide association and mouse cocaine-conditioned place-preference data. However, there have been no reports of effects of reduced expression on cocaine self-administration. There have been no reports of PTPRD targeting by any small molecule. There are no data about behavioral effects of any PTPRD ligand. We now report (i) robust effects of heterozygous PTPRD KO on cocaine self-administration (These data substantially extend prior conditioned place-preference data and add to the rationale for PTPRD as a target for addiction therapeutics.); (ii) identification of 7-butoxy illudalic acid analog (7-BIA) as a small molecule that targets PTPRD and inhibits its phosphatase with some specificity; (iii) lack of toxicity when 7-BIA is administered to mice acutely or with repeated dosing; (iv) reduced cocaine-conditioned place preference when 7-BIA is administered before conditioning sessions; and (v) reductions in well-established cocaine self-administration when 7-BIA is administered before a session (in WT, not PTPRD heterozygous KOs). These results add to support for PTPRD as a target for medications to combat cocaine use disorders. 7-BIA provides a lead compound for addiction therapeutics.

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