PTP1B Inhibitors Research Articles

Allosteric inhibition of PTP1B by bromocatechol-chalcone derivatives

Allosteric inhibition of PTP1B by bromocatechol-chalcone derivatives

Structure-Agnostic Bioactivity-Driven Combinatorial Biosynthesis Reveals New Antidiabetic and Anticancer Triterpenoids.

Although combinatorial biosynthesis can dramatically expand the chemical structures of bioactive natural products to identify molecules with improved characteristics, progress in this direction has been hampered by the difficulty in isolating and characterizing the numerous produced compounds. This challenge could be overcome with improved designs that enable the analysis of the bioactivity of the produced metabolites ahead of the time-consuming isolation procedures. Herein, we showcase a structure-agnostic bioactivity-driven combinatorial biosynthesis workflow that introduces bioactivity assessment as a selection-driving force to guide iterative combinatorial biosynthesis rounds towards enzyme combinations with increasing bioactivity. We apply this approach to produce triterpenoids with potent bioactivity against PTP1B, a promising molecular target for diabetes and cancer treatment. We demonstrate that the bioactivity-guided workflow can expedite the combinatorial process by enabling the narrowing down of more than 1000 possible combinations to only five highly potent candidates. By focusing the isolation and structural elucidation effort on only these five strains, we reveal 20 structurally diverse triterpenoids, including four new compounds and a novel triterpenoid-anthranilic acid hybrid, as potent PTP1B inhibitors. This workflow expedites hit identification by combinatorial biosynthesis and is applicable to many other types of bioactive natural products, therefore providing a strategy for accelerated drug discovery.

PTP1B inhibitor alleviates deleterious septic lung injury through Src signaling.

Septic lung injury is an unmet clinical challenge due to its high mortality, and there is a lack of effective treatment. Accumulating evidence suggests that an uncontrolled pulmonary inflammatory response is important in the pathogenesis of lung injury in sepsis. Therefore, limiting excessive early inflammatory responses may be an effective strategy. We established a septic lung injury model using cecal ligation and puncture. Western blotting and immunofluorescence analyses were performed to assess the expression of PTP1B and endoplasmic reticulum (ER) stress and pyroptosis. Co-immunoprecipitation was used to analyze the binding of PTP1B and Src molecules. PTP1B is upregulated in both in vivo and in vitro models of septic lung injury. PTP1B directly binds to Src and aggravates inflammation by regulating the ER stress-pyroptosis axis. The inhibition of PTP1B alleviates inflammation and improves the prognosis of septic mice. Our study suggesting that PT1B inhibitors have clinical application value in the treatment of septic lung injury. This may provide a new strategy for the treatment of septic lung injury.

Discovery of Novel PTP1B Inhibitors by High-throughput Virtual Screening.

To Discover novel PTP1B inhibitors by high-throughput virtual screening Background: Type 2 Diabetes is a significant global health concern. According to projections, the estimated number of individuals affected by the condition will reach 578 million by the year 2030 and is expected to further increase to 700 million deaths by 2045. Protein Tyrosine Phosphatase 1B is an enzymatic protein that has a negative regulatory effect on the pathways involved in insulin signaling. This regulatory action ultimately results in the development of insulin resistance and the subsequent elevation of glucose levels in the bloodstream. The proper functioning of insulin signaling is essential for maintaining glucose homeostasis, whereas the disruption of insulin signaling can result in the development of type 2 diabetes. Consequently, we sought to utilize PTP1B as a drug target in this investigation. The purpose of our study was to identify novel PTP1B inhibitors as a potential treatment for managing type 2 diabetes. To discover potent PTP1B inhibitors, we have screened the Maybridge HitDiscover database by SBVS. Top hits have been passed based on various drug-likeness rules, toxicity predictions, ADME assessment, Consensus Molecular docking, DFT, and 300 ns MD Simulations. Two compounds have been identified with strong binding affinity at the active site of PTP1B along with drug-like properties, efficient ADME, low toxicity, and high stability. The identified molecules could potentially manage T2DM effectively by inhibiting PTP1B, providing a promising avenue for therapeutic strategies.

Design, synthesis and enzymatic inhibition evaluation of novel 4-hydroxy Pd–C-Ⅲ derivatives as α-glucosidase and PTP1B dual-target inhibitors

A library of 4-Hydroxy Pd–C-Ⅲ derivatives (5a-5p and 8a-8h) as α-glucosidase inhibitors was prepared and the activity of these compounds against α-glucosidase was evaluated. The outcomes displayed that most of the derivatives had moderate to potent α-glucosidase inhibition with IC50 values ranging from 66.3 ± 2.4 to 299.7 ± 6.0 μM. Amongst these compounds, 8a had the strongest α-glucosidase inhibition than others with an IC50 value of 66.3 ± 2.4 μM. Therefore, 8a was chosen to detect the inhibitory activities on PTP1B and α-amylase, the results revealed that 8a had the potential to be PTP1B (IC50 = 47.0 ± 0.5 μM) and α-amylase (IC50 = 30.62 ± 2.13 μM) inhibitor. Additionally, the enzyme kinetic study displayed that 8a was a mixed-type inhibitor. Moreover, the results of the spectroscopy experiments proved that 8a could quench the fluorescence intensity of α-glucosidase in a dose-dependent manner, destroy the secondary structure of α-glucosidase and change the conformation of the enzyme. Significantly, the investigation of cellular thermal shift assay exhibited that 8a could target the PTP1B protein, and the in vitro cytotoxicity discovered compound 8a had no significant toxicity to normal HEK-293 cells. Additionally, the results of molecular docking found that 8a could both bind the active sites of the α-glucosidase and PTP1B. Importantly, the in vivo sucrose-loading test displayed 8a had potential to reduce the postprandial blood glucose. All results proved that compound 8a had great potential as a dual-target inhibitor in treating Type 2 diabetes mellitus.

Medicinal Aspects of PTP 1B Inhibitors as Anti-Breast Cancer Agents: An Overview.

Protein tyrosine phosphatase 1B (PTP1B) has gained interest as a therapeutic target for type 2 diabetes and obesity. Besides metabolic signalling, PTP1B is a positive regulator of signalling pathways linked to ErbB2-induced breast tumorigenesis. Substantial evidence proves that its overexpression is involved in breast cancer, which suggests that selective PTP1B inhibition might be effective in breast cancer treatment. Therefore, huge research is being carried out on PTP1B inhibitors and their activity against breast cancer development. To date, only two PTP1B inhibitors, viz. ertiprotafib and trodusquemine, have entered clinical trials. The discovery of selective inhibitors of PTP1B could open a new avenue in breast cancer treatment. In this review, we provide an extensive overview on the involvement of PTP1B in breast cancer, its pathophysiology, with special attention on the discovery and development of various natural as well as synthetic PTP1B inhibitors. This study will provide significant information to the researchers developing PTP1B inhibitors for breast cancer treatment.

Inhibition of PTP1b via Milk Exosome-Mediated Small Interfering RNA (siRNA) Delivery Is a Novel Therapeutic Approach for AKI

Inhibition of PTP1b via Milk Exosome-Mediated Small Interfering RNA (siRNA) Delivery Is a Novel Therapeutic Approach for AKI

Lanostane triterpenoids from Ganoderma calidophilum exhibit potent anti-tumor activity by inhibiting PTP1B

The species Ganoderma calidophilum represents a distinct variety within the genus Ganoderma and used by the indigenous Li ethnic group as a medicinal agent for the prevention and treatment of cancer. However, the precise biological activity and role of G. calidophilum in antitumor treatment remain largely unresolved. Several lanostane triterpenoids have been isolated from G. calidophilum. The enzyme activity analysis revealed that four lanostane triterpenoids exhibited PTP1B inhibition activity, with minimal inhibition towards SHP2, SHP1, PTPN5, PTPRA, STEP and TCPTP. Molecular docking analysis demonstrated that these compounds primarily bind to the substrate recognition and entry regions of PTP1B. Further analysis indicated that among them, ganoderic aldehyde A (GAA) is a selective and non-competitive PTP1B inhibitor. GAA inhibited the proliferation, colony formation and migration of C33A and MDA-MB-231 cells in a dose-dependent manner. GAA has the capacity to induce apoptosis in a cell-type-specific manner, both in a caspase-dependent and -independent manner. PTP1B siRNA significantly reduced the cytotoxic effect of GAA, while overexpression of PTP1B significantly increased cell growth after GAA treatment. These findings confirm that PTP1B is a functional target of GAA. Research into the mechanisms of action of GAA has revealed that it could inhibit the activation of AKT by inhibiting PTP1B, while simultaneously activating p38, which promotes cell death. It is possible to develop specific PTP1B inhibitors based on the lanosterol triterpene skeleton. G. calidophilum has the potential to be developed into functional foods or drugs with the aim of preventing and treating cancer.

Structure‐Agnostic Bioactivity‐Driven Combinatorial Biosynthesis Reveals New Antidiabetic and Anticancer Triterpenoids

Although combinatorial biosynthesis can dramatically expand the chemical structures of bioactive natural products to identify molecules with improved characteristics, progress in this direction has been hampered by the difficulty in isolating and characterizing the numerous produced compounds. This challenge could be overcome with improved designs that enable the analysis of the bioactivity of the produced metabolites ahead of the time‐consuming isolation procedures. Herein, we showcase a structure‐agnostic bioactivity‐driven combinatorial biosynthesis workflow that introduces bioactivity assessment as a selection‐driving force to guide iterative combinatorial biosynthesis rounds towards enzyme combinations with increasing bioactivity. We apply this approach to produce triterpenoids with potent bioactivity against PTP1B, a promising molecular target for diabetes and cancer treatment. We demonstrate that the bioactivity‐guided workflow can expedite the combinatorial process by enabling the narrowing down of more than 1000 possible combinations to only five highly potent candidates. By focusing the isolation and structural elucidation effort on only these five strains, we reveal 20 structurally diverse triterpenoids, including four new compounds and a novel triterpenoid‐anthranilic acid hybrid, as potent PTP1B inhibitors. This workflow expedites hit identification by combinatorial biosynthesis and is applicable to many other types of bioactive natural products, therefore providing a strategy for accelerated drug discovery.

Assessing the potential fasting and postprandial mechanisms involved in the acute hypoglycemic and anti-hyperglycemic effects of four selected plants from Iran used in traditional Persian medicine

Ethnopharmacological relevanceIn traditional Persian medicine (TPM), people often use herbal infusions as a dosage form to treat diseases related to hyperglycemia, known as 'dam-kardeh'. Traditionally, herbal preparations of Eryngium bungei Boiss. (E. b), Tragopogon buphthalmoides (DC.) Boiss. (T. b), Salvia hydrangea DC. ex Benth. (S. h), and Juniperus polycarpos K. Koch. (J. p) are used to manage diabetes in Iran. However, there is no evidence of their effectiveness in controlling glucose levels and their mechanisms remain unclear.Aim of the study: This study aimed to investigate whether traditional doses of plant infusions can have hypoglycemic and/or anti-hyperglycemic effects during fasting and/or postprandial states and establish the basis for future research on their potential mechanisms of action. Materials and methodsThe effects of traditional doses of herbal extracts on blood glucose levels in STZ-NA-induced hyperglycemic rats were investigated in 2-h acute tests during fasting and postprandial states (with a glucose load). In addition, the potential inhibitory effect in vitro of enzymes involved in relevant pathways, such as gluconeogenesis (fructose-1,6-bisphosphatase, FBPase and glucose-6-phosphatase, G6Pase), carbohydrate breakdown (intestinal α-glucosidases), and insulin sensitivity (protein tyrosine phosphatase 1B, PTP-1B) was evaluated. Acute toxicity tests were carried out and HPLC-SQ-TOF was used to analyze the chemical profiles of the plant extracts. ResultsIn the fasting state, T. b, S. h, and E. b were as effective as glibenclamide in lowering blood glucose levels in hyperglycemic rats. Moreover, all three suppressed G6Pase and FBPase enzymatic activity by 90–97% and 80–91%, respectively. On the other hand, significant postprandial hypoglycemic efficacy was observed for E. b, S. h, and T. b. Based on the AUC values, T. b caused a reduction comparable to the therapeutic efficacy of repaglinide. When investigating the possible mechanisms of action involved in this activity, E. b, S. h, and T. b showed significant inhibition of PTP-1B in vitro (>70%). Finally, all plant extracts showed no signs of acute toxicity. Several compounds that may contribute to biological activities were identified, including phenolic acids and flavonoid glycosides. ConclusionsThe present study supports the traditional use of T. b, E. b and S. h for the control of diabetes in the fasting and postprandial state. Moreover, these plants were found to be rich in bioactive compounds with hypoglycemic and antihyperglycemic activities. On the other hand, J. p, showed a modest effect only in the fasting state and after 90 min. Further studies are needed to expand these results by analyzing the chemical composition and using complementary experimental models.

Revealing the potential hypoglycaemic ingredients of Terminalia chebula Retz. by spectrum–effect relationship combining molecular docking and experimental validation

Terminalia chebula Retz. is commonly used in the treatment of diabetes, but its specific ingredients and hypoglycaemic mechanisms remain unclear. In this study, spectrum-effect relationships between common peaks of fingerprint and DPPH, ABTS, PTP1B, α-glucosidase, were used to screen six compounds as the potential hypoglycemic ingredients. Molecular docking studies were conducted on chebulagic acid, chebulinic acid and punicalagin, which were identified by reference standard, revealing the potent in teractions between these bioactive substances and the PTP1B, α-glucosidase protein. Additionally, the cellular level results showed that punicalagin displayed stronger inhibition of PTP1B and α-glucosidase, with IC50 values of 0.0236 and 0.335 μg/mL, respectively, while improving glucose consumption and intracellular glycogen content of insult-resistant L6 muscle cell, and the hypoglycemic effect was achieved by activating the PI3K/AKT signaling pathway. This study demonstrated that T. chebula has the potential to become a hypoglycemic functional food, and offers a strategy for characterization hypoglycemic ingredients.

Exploring Plant-Derived Bioactive Compounds in Olea Europaea L. Leaves as Potent Inhibitors of PTP-1B Using an In silico Approach

In this study, we focus on exploring the medicinal potential of Olea Europaea L., a commonly used plant with diverse indigenous medicinal applications. The main aim is to identify promising phytoconstituents from Olea Europaea L. leaves that can act as inhibitors for the PTP-1B target, utilizing an in silico approach. The phytoconstituents were sourced from the IMMPAT database, and molecular docking was employed to assess their binding affinities. The docking results revealed that rutin (−10.05 kcal/mol) and quercetin (−8.28 kcal/mol) displayed the highest binding scores against PTP-1B, outperforming reference compounds. Furthermore, MM-GBSA calculations indicated favorable free binding energy. To ensure stability, 200 ns Molecular Dynamics simulations were conducted on the 2QBS-Rutin complex. The results revealed that the 2QBS-Rutin complex showed stable conformation throughout the simulation, maintaining consistency with RMSD values below 1 Å. This study highlights rutin and quercetin as promising phytoconstituents from Olea Europaea L. leaves, demonstrating potent-binding affinities against PTP-1B inhibitors.

Molecular Docking and Dynamic Simulation Analysis of Natural Polyphenols for Identifying Potential PTP1B Inhibitors for Type 2 Diabetes

Molecular Docking and Dynamic Simulation Analysis of Natural Polyphenols for Identifying Potential PTP1B Inhibitors for Type 2 Diabetes

New phenylthiosemicarbazide-phenoxy-1,2,3-triazole-N-phenylacetamides as dual inhibitors against α-glucosidase and PTP-1B for the treatment of type 2 diabetes.

This study describes the design, synthesis, and evaluation of a novel series of phenylthiosemicarbazide-phenoxy-1,2,3-triazole-N-phenylacetamide derivatives (7a-l) as dual inhibitors of α-glucosidase and protein tyrosine phosphatase 1-B (PTB-1B). The latter enzymes are two important targets in the treatment of type 2 diabetes. The in vitro obtained data demonstrated that all title compounds 7a-l were more potent than the standard inhibitor acarbose against α-glucosidase while only four derivatives (7a, 7g, 7h, and 7h) were more potent than the standard inhibitor suramin against PTP-1B. Furthermore, these data showed that the most potent α-glucosidase inhibitor was compound 7i, with sixfold higher inhibitory activity than acarbose, and the most potent PTP-1B inhibitor was compound 7a with 3.5-fold higher inhibitory activity than suramin. Kinetic studies of compounds 7i and 7a revealed that they inhibited their target enzymes in a competitive mode. The docking study demonstrated that compounds 7i and 7a well occupied the active site pockets of α-glucosidase and PTP-1B, respectively. In silico pharmacokinetic and toxicity assays of the most potent compounds were performed, and the obtained results were compared with those of the standard inhibitors.

Abstract LB052: PTP1B inhibitors activate a novel hypoxia-induced inflammatory cell death pathway in breast cancer

Abstract Dual PTP1B/TC-PTP (PTPN1/2) inhibitors are in clinical trials for multiple cancer types, primarily because they augment anti-tumor immunity, but they can also have cancer cell-autonomous effects. Hypoxic cancer cells resist many anti-neoplastic therapies and can seed recurrence. We found previously that PTP1B deficiency/inhibition promotes HER2+ breast cancer cell death in hypoxia by activating RNF213, an ~600kDa protein containing AAA-ATPase domains and two ubiquitin ligase domains (RING and RZ) that also is implicated in Moyamoya disease (MMD), lipotoxicity, and innate immunity. We now report that PTP1B and ABL1/2 reciprocally control RNF213 phosphorylation on tyrosine-1275. This phosphorylation promotes RNF213 oligomerization and RZ domain activation. The RZ domain ubiquitylates CYLD/SPATA2, and together with the LUBAC complex, induces their degradation. Decreased CYLD/SPATA2 causes NF-κB activation, which together with hypoxia-induced ER-stress triggers GDSMD-dependent pyroptosis. Mutagenesis experiments show that the RING domain negatively regulates the RZ domain. CYLD-deleted HER2+ cell-derived xenografts phencopy the effects of PTP1B deficiency, and reconstituting RNF213 knockout lines with RNF213 mutants shows that the RZ domain mediates PTP1B-dependent tumor cell death. Our results identify a novel, potentially targetable PTP1B/RNF213/CYCLD/SPATA pathway critical for controlling inflammatory cell death in hypoxic tumors that could be exploited to target hypoxic tumor cells, potentially turning “cold” tumors “hot”, thereby increasing the potential clinical utility of PTP1B inhibitors. Citation Format: Benjamin G. Neel, Abhishek Bhardwaj, Maria Antonelli, Beatrix Ueberheide. PTP1B inhibitors activate a novel hypoxia-induced inflammatory cell death pathway in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB052.

PTP1B Inhibitors from Indonesian Plants and Its Structure-Activity Relationship: A Review

PTP1B Inhibitors from Indonesian Plants and Its Structure-Activity Relationship: A Review

In silico De Novo Discovery of Novel Target-specific Drug-like Bidentate Inhibitors of PTP 1B

Background: Protein tyrosine phosphatase 1B (PTP 1B) is a recognized legitimate target for type 2 diabetes and obesity, collectively designated as ‘diabesity’, even though first-in-class inhibitor is still awaited. The main cause behind the unachieved target selectivity of investigated inhibitors is the high degree of sharing of structural homology between PTP 1B and other members of the PTP family. Objective: The present work aimed to discover target-specific inhibitors of PTP 1B with bidentate binding features on both the allosteric and active sites. Materials and Methods: We have implicated the amalgamated de novo designing, ADMET screening, and molecular docking simulations to discover novel drug-like allosteric inhibitors of PTP 1B. The LEA3D de novo designing platform was used to design novel thiazolidinediones (TZDs) from scratch in the core of the target on the strict constraints of defined molecular properties of drug-likeness. Molecular modelling and geometry optimization were done using the ChemOffice package. The druglikeness/ ADMET screening was performed using the TSAR package based on Lipinski’s filter. Molegro Virtual Docker (MVD) was used for the prediction of binding cavities in the target, estimation of ligandtarget binding affinities as well as mode of binding interactions. Results and Discussion: Novel TZDs (Molecules 1-8) were de novo designed successfully as drug-like target-specific inhibitors of PTP 1B. The interaction pattern and the energy contribution of ligand (Etotal, Eintra, Epair) and target (Epair) supported that the generated TZDs showed bidentate inhibition. Conclusion: The discovered TZDs can be developed as novel target-specific allosteric inhibitors of PTP 1B after the accomplishment of synthetic and pre-clinical interventions.

Eutypellaolides A–J, Sesquiterpene diversity expansion of the polar fungus Eutypella sp. D-1

Eight new 12,8-eudesmanolide sesquiterpenes, eutypellaolides A–H (1–8), and two new eudesmane-type sesquiterpenes, eutypellaolides I–J (9–10), along with four known 12,8-eudesmanolide compounds 11–14, were isolated from the culture extract of the polar fungus Eutypella sp. D-1 by one strain many compounds (OSMAC) approach. The structures of these compounds were determined through comprehensive spectroscopic data and experimental and calculated ECD analysis. Antibacterial, immunosuppressive, and PTP1B inhibition activities of these compounds were evaluated. Compounds 1 and 11 exhibited strong inhibitory activities against Bacillus subtilis and Staphylococcus aureus, with each showing an MIC value of 2 μg/mL. Compound 9 displayed weak immunosuppressive activity against ConA-induced T-cell proliferation with an inhibitory rate of 61.7% at a concentration of 19.8 μM. Compounds 5, 11, and 14 exhibited weak PTP1B inhibition activities with IC50 values of 44.8, 43.2, and 49.5 μM, respectively.

Eremane, viscidane and isozizaene diterpenoids from the leaves of Eremophila rigida and their absolute configurations

Previously undescribed eremane, viscidane, and isozizaene diterpenoids, eremorigidanes A-F, along with six known O-methylated flavonoids and three known triterpenoids were isolated and identified from the leaves of Eremophila rigida Chinnock by combined use of high-resolution PTP1B inhibition profiling, semipreparative- and analytical-scale HPLC separations, HPLC-PDA-HRMS analysis, and NMR spectroscopy. The absolute configuration of the unreported diterpenoids were determined by comparison of their experimental and calculated ECD spectra as well as by biosynthetic arguments. All isolates were evaluated for their PTP1B inhibitory activities, which revealed the flavonoid penduletin (3) to show inhibition with an IC50 value of 18.3 μM, and the triterpenoids 3,4-seco-olean-12-ene-3,28-dioic acid (15), oleanolic acid (16), and 3-oxo-oleanolic acid (17) to show inhibition with IC50 values of 55.7, 9.9, and 6.3 μM, respectively. The preliminary structure-activity relationship (SAR) of isolated flavonoids and triterpenoids is discussed. Plausible biosynthetic steps involved in eremane and isozizaene metabolism are presented and discussed.

Discovery and biological evaluation of novel dual PTP1B and ACP1 inhibitors for the treatment of insulin resistance

In this study, a virtual screening pipeline comprising ligand-based and structure-based approaches was established and applied for the identification of dual PTP1B and ACP1 inhibitors. As a result, a series of benzoic acid derivatives was discovered, and compound H3 and S6 demonstrated PTP1B and ACP1 inhibitory activity, with IC50 values of 3.5 and 8.2 μM for PTP1B, and 2.5 and 5.2 μM for ACP1, respectively. Molecular dynamics simulations illustrated that H3 interacted with critical residues in the active site, such as Cys215 and Arg221 for PTP1B, and Cys17 and Arg18 for ACP1. Enzymatic kinetic research indicated that identified inhibitors competitively inhibited PTP1B and ACP1. Additionally, cellular assays demonstrated that H3 and S6 effectively increased glucose uptake in insulin-resistant HepG2 cells while displaying very limited cytotoxicity at their effective concentrations. In summary, H3 and S6 represent novel dual-target inhibitors for PTP1B and ACP1, warranting further investigation as potential agents for the treatment of diabetes.