Skip to main content
NCBI home page
ACS Medicinal Chemistry Letters logoLink to ACS Medicinal Chemistry Letters
. 2021 May 19;12(6):1017–1023. doi: 10.1021/acsmedchemlett.1c00174

Discovery of Novel PTP1B Inhibitors Derived from the BH3 Domain of Proapoptotic Bcl-2 Proteins with Antidiabetic Potency

Chuanliang Zhang †,‡,§,*, Lijuan Wu ‡,§, Xiaochun Liu ‡,§, Jiangming Gao ‡,§, Shan Liu ‡,§, Juan Wu ‡,§, Dingmin Huang †, Zhenwei Wang †, Xianbin Su †,*
PMCID: PMC8201754  PMID: 34141087

Abstract

graphic file with name ml1c00174_0007.jpg

BH3 peptide analogues are generally believed to exhibit great potency as cancer therapeutics via targeting antiapoptotic Bcl-2 proteins. Here, we describe the synthesis and identification of a new class of palmitoylated peptide BH3 analogues derived from the core region (h1–h4) of BH3 domains of proapoptotic Bcl-2 proteins and as alternative PTP1B inhibitors with antidiabetic potency in vitro and in vivo. PTP1B inhibitors are attractive for treatment of type 2 diabetes. We design the analogues using a simple lipidation approach and discovered novel lead analogues with promising antidiabetic potency in vitro and in vivo. The results presented here expanded the alternative target and function for the BH3 peptide analogues from one member Bim to other members of the proapoptotic Bcl-2 proteins and emphasize their therapeutic potential in T2DM. Furthermore, our findings may provide new proof of the regulatory function of Bcl-2 family proteins in mitochondrial nutrient and energy metabolism.

Keywords: BH3 domains, palmitoylated peptide analogues, PTP1B inhibitors, pro27 apoptotic Bcl-2 proteins, antidiabetic potency

It is generally believed that peptide analogues derived from the BH3 domain of proapoptotic Bcl-2 proteins exhibited great potency as cancer therapeutics via targeting antiapoptotic Bcl-2 proteins (such as Bcl-2, Bcl-XL, Mcl-1).1−7 Here, we describe the application of the lipidation strategy of the core region of the BH3 domain of nine proapoptotic Bcl-2 proteins (Table 1) for the discovery of novel peptide BH3 mimetics with alternative PTP1B inhibitory activity and antidiabetic potency in vitro and in vivo.

Table 1. Homology Alignment of the Core Region (h1–h4) of Various BH3 Domains.

graphic file with name ml1c00174_0006.jpg

Open in a new tab

The Bcl-2 family consists of anti- and proapoptotic proteins and serves as essential regulators of the intrinsic or mitochondrial pathway of apoptosis via interactions among different members.1,8 The family members share sequence homology within conserved α-helical regions known as Bcl-2 homology (BH) domains. The antiapoptotic Bcl-2 family (such as Bcl-2 and Bcl-XL) and the Bax subfamily (such as Bax and Bak) are “multidomain” proteins that contain about three to four BH domains (BH1, BH2, BH3, and BH4). The “BH3-only” proapoptotic members, including Bim, Bad, Bid, Noxa, Bik, Hrk, Bmf, and Puma, show sequence homology only within the BH3 domain. The capacity of different members to form highly selective interactions is integral to their regulation of apoptosis. The BH3 domain plays a critical role in these interactions via binding to long, complementary grooves displayed by antiapoptotic family members such as Bcl-xL, Mcl-1, and Bcl-2. Binding to the prosurvival members of this family and neutralizing their functional activity (sequestration of the proapoptotic Bcl-2 family members) can trigger apoptosis. The release of proapoptotic factors triggers mitochondrial membrane permeabilization, cytochrome c release, and caspase activation.1,9−11 A “BH3 mimetic” concept has been prompted as an attractive approach in the development of molecules capable of mimicking BH3 domains and thus inducing apoptosis in cancer therapy.2,12−15 Many research groups3−7 have make extensive efforts of research and development of these peptide analogues but had yielded hardly any peptide candidates into clinical trials. In addition, recent studies have expanded functional networks of Bcl-2 proteins beyond the regulation of cell death and survival in other physiologic pathways, such as metabolism,16−19 Ca2+ homeostasis,20 and mitochondrial morphology.21 Of particular interest, a series of studies have demonstrated that the BH3-only proapoptotic protein Bad was involved in the regulation of mitochondrial nutrient and energy metabolism.16,18,19 Further evidence uncovered an alternative target and function for the phosphorylated Bad-BH3 domain and/or hydrocarbon-stapled Bad-BH3 mimetics and emphasized the therapeutic potential in diabetes through targeting glucokinase, restoring glucose-driven mitochondrial respiration, and correcting the insulin secretory.22,23 Moreover, phospho-Bad-BH3 mimicry could protect β cells and restore functional β cell mass, thus improving islet engraftment in transplanted diabetic mice.24 Glucokinase activators (GKAs) hold therapeutic promise in type 2 diabetes mellitus (T2DM), and interest in the GKA class has been renewed.25 These results are exciting but also unfortunate, because the reported Bad-BH3-domain-derived BH3 analogues did not exhibit in vivo antidiabetic potency.

Similarly, we discovered a BimBH3 analogue (also showed BcL-2/Bcl-XL binding affinity,26Figure 1) derived from the BH3 core sequence peptide of another proapoptotic Bcl-2 family member Bim and its PTP1B inhibitory and glucose uptake stimulatory activities in our previous work.27 Protein-tyrosine phosphatase 1B (PTP1B) was regarded as a therapeutic target for metabolic diseases such as diabetes and obesity.28,29 Plenty of biological, genetic, and pharmacological evidence have validated that PTP1B played a role as a negative regulator in both insulin and leptin signaling to dephosphorylate the activated insulin receptor (IR) or insulin receptor substrate (IRS).30−33 PTP1B knockout mice displayed enhanced insulin sensitivity as well as lower plasma glucose and insulin levels with increased or prolonged tyrosine phosphorylation of IR in muscle and liver.34,35 Genetic studies also revealed that aberrant expression of PTP1B could contribute to diabetes and obesity.36,37 Additionally, accumulating evidence has indicated that PTP1B could be targeted for cancer therapy38−45 and Alzheimer’s therapy46,47 as well as improving islet transplantation outcomes.48

Figure 1.

Figure 1

Open in a new tab

Peptide analogues of the BH3 domain derived from proapoptotic Bcl-2 proteins via the same lipidation modification with Pal-BimBH3, a Bim-BH3 analogue described in our previous work.27

The biological and pharmacological evidence have validated the alternative function and therapeutic potency of proapoptotic Bcl-2 proteins in metabolism and related diseases. The proapoptotic Bcl-2 family, including Bax subfamily and BH3-only proteins, all share the conserved BH3 domain core region with four similar hydrophobic residues (h1–h4, Table 1). Herein, we inferred that the BH3 domain peptide analogues (Figure 1) with similar and conserved sequences derived from the proapoptotic members might exhibit the same PTP1B inhibitory activity according to the similarity property principle (SPP), which established that drugs with a similar molecular structure were likely to exhibit the same biological activity induced by interaction with targets.49,50 To validate the guess, a variety of BH3 domain peptide analogues (Figure 1) derived from proapoptotic Bcl-2 proteins including Bad, Bid, Noxa, Bik, Hrk, Bmf, Puma, Bax, and Bak via the same lipidation approach with Bim27 and their PTP1B binding affinity, inhibitory activity, glucose uptake stimulatory activity, and antidiabetic potency in vivo have been described.

In the present study, the analogues maintain the 12-mer core region of the BH3 domains from h1–h4, and the N-terminal ends were palmitoylated. Lipidation has become an important chemical strategy for the development of half-life extended protein/peptide therapeutics.51−53 Fatty acids such as palmitic acid have proved to be successful lipidation agents with strong albumin binding affinity, resulting in prolonged action in the development of peptide therapeutics such as liraglutide.51,52 Direct binding affinity of the palmitoylated peptide BH3 analogues to PTP1B (Table 1) was determined using the previously described surface plasmon resonance (SPR) technique.27 Analogues Pal-PumaBH3, Pal-BidBH3, Pal-BikBH3, Pal-BakBH3, and Pal-BaxBH3 bound to PTP1B with affinity KD = 105.0 nmol/L, KD = 77.8 nmol/L, KD = 15.1 nmol/L, KD = 60.7 nmol/L, and KD = 86.3 nmol/L, respectively. Meanwhile, other analogues did not exhibit specific PTP1B binding affinity in the SPR assay. These binding affinity data show the binding ability of molecules to a receptor/target but cannot reveal whether these analogues exhibit target inhibition activity. Thus, the in vitro enzyme-based inhibitory activity against human recombinant PTP1B of the BH3 peptide mimetics with good PTP1B binding affinity (Table 2) was evaluated using a previously described procedure. Based on the results in Figure 2, analogues Pal-PumaBH3, Pal-BidBH3, Pal-BikBH3, Pal-BakBH3, and Pal-BaxBH3 could be validated as PTP1B inhibitors with IC50 values of 6.84, 2.15, 0.937, 1.28, and 5.25 μmol/L, respectively. The natural proapoptotic Bcl-2 family members share a conserved α-helical BH3 region. To gain insight into the impact of the modification/truncation on the analogue conformation in solution and the conformation–activity relationship, we determined the far-UV circular dichroism (CD) spectra of BH3 domain peptide analogues (Figure 3). All the analogues showed little evidence of a typical α-helical signature in buffer solution. These results indicate that the palmitoylated and sequence-truncated analogues of BH3 domains do not inherit the helicity. These results are consistent with our previous report that the Pal-BimBH3 showed little evidence of helicity in buffer solution either.27 Therefore, the α-helical conformation might be unnecessary to the PTP1B inhibitory activity of these BH3 peptide analogues. The 12-mer BH3 peptide analogues may not be able to form typical second structures (such as α-helix, β-turn), so there might be a need to obtain the cocrystallization of the BH3 analogue/PTP1B complex to determine the active conformation or orientation to explain the structure–activity relationship (SAR), which will be a new project with great challenges in the further studies.

Table 2. Binding Affinity to Human Recombinant PTP1B Determined by SPR.

  PTP1B binding affinity
analogue Kon (1/M·s) Koff (1/s) affinity KD (M)
Pal-PumaBH3 1.45 × 104 1.52 × 10–4 1.05 × 10–7
Pal-BadBH3 \ \ \
Pal-BidBH3 1.02 × 104 7.97 × 10–4 7.78 × 10–8
Pal-NoxaBH3 \ \ \
Pal-BikBH3 1.67 × 104 2.53 × 10–4 1.51 × 10–8
Pal-BmfBH3 \ \ \
Pal-HrkBH3 \ \ \
Pal-BakBH3 9.48 × 103 5.75 × 10–4 6.07 × 10–8
Pal-BaxBH3 9.73 × 103 8.39 × 10–4 8.63 × 10–8
Open in a new tab

Figure 2.

Figure 2

Open in a new tab

Dose–response curves for PTP1B inhibition of the BH3 analogues.

Figure 3.

Figure 3

Open in a new tab

Far-UV CD spectra of the peptide BH3 analogues in solution (0.5 mg/mL in 50 mM Tris and 100 mM NaCl buffer, 25 °C).

A characteristic feature of obesity and diabetes mellitus is insulin resistance, and evaluation of glucose uptake ability in cells plays a fundamental role for the treatment of diabetes as well as obesity. We examined the ability of the selected BH3 peptide analogues to stimulate glucose uptake using a 2-NBDG uptake assay in insulin-resistant HepG2 cells induced by palmitic acid (PA). As illustrated in Figure 4, administration of selected analogues resulted in a dose-dependent increase of 2-NBDG uptake, yielding ∼2 fold greater 2-NBDG uptake for Pal-BakBH3 and Pal-BikBH3 at 10 μM compared with vehicle (p < 0.01).

Figure 4.

Figure 4

Open in a new tab

Effect of selected analogues on insulin-stimulated glucose uptake in insulin-resistant HepG2 cells. A glucose uptake assay was performed using the fluorescent d-glucose analogue 2-NBDG. The insulin-resistant HepG2 cells were treated with different concentration analogues or liraglutide for 24 h, and the vehicle group was administered an equivalent volume of dimethyl sulfoxide (DMSO) as a control. Relative fluorescence intensity minus background was used for subsequent statistical analyses. The results shown are mean ± SD (n = 4). *, P < 0.05, **, P < 0.01 when compared with vehicle.

The favorable glucose uptake ability in cells of analogues Pal-BakBH3, Pal-BikBH3, Pal-BidBH3, and the previously described Pal-BimBH3 (SM-6) motivated us to evaluate their in vivo efficacy in db/db mice, a hyperglycemic, hyperinsulinemic, and obese model of type 2 diabetes used during the initial in vivo screening studies of analogues to investigate the antihyperglycemic efficacy. Diabetic db/db mice were treated with a daily s.c. dose of analogue Pal-BakBH3 (2 μmol/kg, MW = 1507.9, i.e., 3.02 mg/kg), Pal-BikBH3 (2 μmol/kg, MW = 1543.6, i.e., 3.09 mg/kg), Pal-BidBH3 (2 μmol/kg, MW = 1535.9, i.e., 3.07 mg/kg), Pal-BimBH3 (2 μmol/kg, MW = 1685.0, i.e., 3.37 mg/kg), and liraglutide (0.5 μmol/kg, MW = 3751.2, i.e., 1.88 mg/kg) or vehicle for a week. The antihyperglycemic activity profile was illustrated in Table 3; all of the selected four analogues were active in vivo at a 2 μmol/kg s.c. dose, decreasing the blood glucose level in the db/db mice by 40.1, 43.9, 31.6, and 37.9%, respectively. The positive drug liraglutide showed 72.6% blood glucose lowering activity at a dose of 0.5 μmol/kg. The following blood glucose monitoring over 12 h (Figure 5A) on day 8 showed that the selected BH3 analogues had a duration of action of up to 10 h. The four selected BH3 analogues exhibited certain antihyperglycemic potency at this dose (2 μmol/kg s.c.), while their glycemic control ability was still far weaker than that of liraglutide (0.5 μmol/kg s.c.)

Table 3. In Vivo Antihyperglycemic Activity Profile of Selected Analogues in db/db Mice Model.

    blood glucose (mmol/L)
  
group dose (μmol/kg) baseline 1 week % decrease of blood glucose
vehicle / 25.6 ± 4.2 26.7 ± 2.1 /
liraglutide 0.5 24.8 ± 3.1 6.8 ± 1.2** 72.6
Pal-BidBH3 2 25.0 ± 1.8 17.1 ± 4.0* 31.6
Pal-BikBH3 2 25.5 ± 2.7 14.3 ± 4.3** 43.9
Pal-BakBH3 2 26.2 ± 3.7 15.7 ± 3.8** 40.1
Pal-BimBH3 2 25.8 ± 4.6 16.0 ± 3.2** 37.9
Open in a new tab

Figure 5.

Figure 5

Open in a new tab

Palmitoylated peptide analogues Pal-BakBH3, Pal-BikBH3, Pal-BidBH3, and Pal-BimBH3 demonstrate blood glucose lowering duration and improvement of glucose tolerance in vivo. (A) After a 1 week intervention, diabetic db/db mice were treated with a single s.c. dose of analogue Pal-BakBH3, Pal-BikBH3, Pal-BidBH3, and Pal-BimBH3, liraglutide, or vehicle followed by a blood glucose monitoring over 12 h on day 8. (B) On day 9, GTT after overnight fast for the indicated peptides, liraglutide, or vehicle (s.c. dosing) followed by glucose (2 g/kg, i.g.) 0.5 h later. (C) Average area under the curve (AUC) values for the GTT data shown in part B. Data are mean ± SD for n = 5 mice per treatment condition. *, P < 0.05, **, P < 0.01 vs vehicle.

The following glucose tolerance test (GTT) after fasting overnight on day 9 indicated that the selected BH3 analogues exhibited the potential to normalize circulating glucose levels. As illustrated in Figure 5B, after an overnight fast, the vehicle group mice showed mild symptoms of hypoglycemia compared with the treatment groups. The subsequent glucose challenge caused a rapid rise in blood glucose concentration at 0.5 h except that liraglutide (0.5 μmol/kg s.c.) and Pal-BakBH3(2 μmol/kg s.c.) showed a dramatic suppression in the rise of blood glucose concentration relative to vehicle-treated mice. During 0.5 to 2 h, mice injected with Pal-BakBH3 (2 μmol/kg), PalBikBH3 (2 μmol/kg), Pal-BimBH3 (2 μmol/kg), and liraglutide (0.5 μmol/kg) all exhibited a lowering/suppression effect relative to vehicle-treated mice.

In summary, we have described a new class of palmitoylated peptide BH3 analogues derived from the core region of the BH3 domains of proapoptotic Bcl-2 proteins as novel PTP1B inhibitors with promising therapeutic activity in mouse models. The results are highly in accordance with our hypothesis that the BH3 domain peptide analogues with similar and conserved sequences derived from the proapoptotic members might exhibit the same PTP1B inhibitory activity. Traditionally, peptide BH3 analogues are regarded as potential cancer therapeutics capable of mimicking BH3-only proteins and thus inducing apoptosis of cancer cells. In the present work, we designed and synthesized nine palmitoylated peptide analogues maintaining the h1–h4 core sequence of BH3 domains and demonstrated their PTP1B inhibitory activity and glucose uptake ability in insulin-resistant HepG2 cells. The further in vivo study demonstrated that the selected compounds Pal-BakBH3, Pal-BikBH3, Pal-BidBH3, and Pal-BimBH3 showed a promising antihyperglycemic potency and duration of action in db/db mice. The results presented here uncover and expand the alternative target and function for the peptide BH3 analogues from one member Bim to the other three members Bak, Bik, and Bid of proapoptotic Bcl-2 proteins and emphasize their therapeutic potential in T2DM based on our previous work. Our findings agree with findings from past studies that the phosphorylated Bad-BH3 domain and/or hydrocarbon-stapled Bad-BH3 mimetics showed therapeutic potential in diabetes through activating glucokinase, restoring glucose-driven mitochondrial respiration, and correcting the insulin secretory via protecting β cells and restoring functional β cell mass.22−24 These results all provide evidence for the regulatory function of Bcl-2 family proteins in mitochondrial nutrient and energy metabolism by different routes.

Acknowledgments

We are grateful for support from the National Natural Science Foundation of China (21907086) and the Natural Science Foundation of Shandong Province (ZR2019BH088).

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsmedchemlett.1c00174.

  • Experimental procedures for the peptide synthesis and purification and full characterization of the peptide BH3 analogues. A description of the protein binding affinity measurement, PTP1B enzymatic activity assay, cell glucose uptake assay, antidiabetic activity and glucose tolerance tests in vivo and detailed results thereafter (PDF)

The authors declare no competing financial interest.

Supplementary Material

ml1c00174_si_001.pdf (1.2MB, pdf)

References

  1. Cory S.; Adams J. M. The Bcl2 family: regulators of the cellular life-or-death switch. Nat. Rev. Cancer 2002, 2 (9), 647–656. 10.1038/nrc883. [DOI] [PubMed] [Google Scholar]
  2. Delbridge A. R. D.; Strasser A. The BCL-2 protein family, BH3-mimetics and cancer therapy. Cell Death Differ. 2015, 22 (7), 1071–1080. 10.1038/cdd.2015.50. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Checco J. W.; Lee E. F.; Evangelista M.; Sleebs N. J.; Rogers K.; Pettikiriarachchi A.; Kershaw N. J.; Eddinger G. A.; Belair D. G.; Wilson J. L.; Eller C. H.; Raines R. T.; Murphy W. L.; Smith B. J.; Gellman S. H.; Fairlie W. D. α/β-Peptide Foldamers Targeting Intracellular Protein–Protein Interactions with Activity in Living Cells. J. Am. Chem. Soc. 2015, 137 (35), 11365–11375. 10.1021/jacs.5b05896. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Boersma M. D.; Haase H. S.; Peterson-Kaufman K. J.; Lee E. F.; Clarke O. B.; Colman P. M.; Smith B. J.; Horne W. S.; Fairlie W. D.; Gellman S. H. Evaluation of Diverse α/β-BackbonePatterns for Functional α-Helix Mimicry: Analogues of the Bim BH3 Domain. J. Am. Chem. Soc. 2012, 134 (1), 315–323. 10.1021/ja207148m. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Sadowsky J. D.; Fairlie W. D.; Hadley E. B.; Lee H.-S.; Umezawa N.; Nikolovska-Coleska Z.; Wang S.; Huang D. C. S.; Tomita Y.; Gellman S. H. (α/β+α)-Peptide Antagonists of BH3 Domain/Bcl-xL Recognition: Toward General Strategies for Foldamer-Based Inhibition of Protein–Protein Interactions. J. Am. Chem. Soc. 2007, 129 (1), 139–154. 10.1021/ja0662523. [DOI] [PubMed] [Google Scholar]
  6. Walensky L. D.; Kung A. L.; Escher I.; Malia T. J.; Barbuto S.; Wright R. D.; Wagner G.; Verdine G. L.; Korsmeyer S. J. Activation of Apoptosis in Vivo by a Hydrocarbon-Stapled BH3 Helix. Science 2004, 305 (5689), 1466–1470. 10.1126/science.1099191. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Peterson-Kaufman K. J.; Haase H. S.; Boersma M. D.; Lee E. F.; Fairlie W. D.; Gellman S. H. Residue-Based Preorganization of BH3-Derived α/β-Peptides: Modulating Affinity, Selectivity and Proteolytic Susceptibility in α-Helix Mimics. ACS Chem. Biol. 2015, 10 (7), 1667–1675. 10.1021/acschembio.5b00109. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Green D. R.; Kroemer G. The Pathophysiology of Mitochondrial Cell Death. Science 2004, 305 (5684), 626–629. 10.1126/science.1099320. [DOI] [PubMed] [Google Scholar]
  9. Czabotar P. E.; Lessene G.; Strasser A.; Adams J. M. Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy. Nat. Rev. Mol. Cell Biol. 2014, 15 (1), 49–63. 10.1038/nrm3722. [DOI] [PubMed] [Google Scholar]
  10. Youle R. J.; Strasser A. The BCL-2 protein family: opposing activities that mediate cell death. Nat. Rev. Mol. Cell Biol. 2008, 9 (1), 47–59. 10.1038/nrm2308. [DOI] [PubMed] [Google Scholar]
  11. Danial N. N.; Korsmeyer S. J. Cell Death: Critical Control Points. Cell 2004, 116 (2), 205–219. 10.1016/S0092-8674(04)00046-7. [DOI] [PubMed] [Google Scholar]
  12. Billard C. BH3Mimetics: Status of the Field and New Developments. Mol. Cancer Ther. 2013, 12 (9), 1691–1700. 10.1158/1535-7163.MCT-13-0058. [DOI] [PubMed] [Google Scholar]
  13. Labi V.; Grespi F.; Baumgartner F.; Villunger A. Targeting the Bcl-2-regulated apoptosis pathway by BH3 mimetics: a breakthrough in anticancer therapy?. Cell Death Differ. 2008, 15 (6), 977–987. 10.1038/cdd.2008.37. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Sarosiek K. A.; Letai A. Directly targeting the mitochondrial pathway of apoptosis for cancer therapy using BH3 mimetics – recent successes, current challenges and future promise. FEBS J. 2016, 283 (19), 3523–3533. 10.1111/febs.13714. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Vela L.; Marzo I. Bcl-2 family of proteins as drug targets for cancer chemotherapy: the long way of BH3 mimetics from bench to bedside. Curr. Opin. Pharmacol. 2015, 23, 74–81. 10.1016/j.coph.2015.05.014. [DOI] [PubMed] [Google Scholar]
  16. Danial N. N.; Gramm C. F.; Scorrano L.; Zhang C.-Y.; Krauss S.; Ranger A. M.; Robert Datta S.; Greenberg M. E.; Licklider L. J.; Lowell B. B.; Gygi S. P.; Korsmeyer S. J. BAD and glucokinase reside in a mitochondrial complex that integrates glycolysis and apoptosis. Nature 2003, 424 (6951), 952–956. 10.1038/nature01825. [DOI] [PubMed] [Google Scholar]
  17. Plas D. R.; Thompson C. B. Cell metabolism in the regulation of programmed cell death. Trends Endocrinol. Metab. 2002, 13 (2), 75–78. 10.1016/S1043-2760(01)00528-8. [DOI] [PubMed] [Google Scholar]
  18. Giménez-Cassina A.; Danial N. N. Regulation of mitochondrial nutrient and energy metabolism by BCL-2 family proteins. Trends Endocrinol. Metab. 2015, 26 (4), 165–175. 10.1016/j.tem.2015.02.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Giménez-Cassina A.; Garcia-Haro L.; Choi C. S.; Osundiji M. A.; Lane E. A.; Huang H.; Yildirim M. A.; Szlyk B.; Fisher J. K.; Polak K.; Patton E.; Wiwczar J.; Godes M.; Lee D. H.; Robertson K.; Kim S.; Kulkarni A.; Distefano A.; Samuel V.; Cline G.; Kim Y.-B.; Shulman G. I.; Danial N. N. Regulation of Hepatic Energy Metabolism and Gluconeogenesis by BAD. Cell Metab. 2014, 19 (2), 272–284. 10.1016/j.cmet.2013.12.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Pinton P.; Rizzuto R. Bcl-2 and Ca2+ homeostasis in the endoplasmic reticulum. Cell Death Differ. 2006, 13 (8), 1409–1418. 10.1038/sj.cdd.4401960. [DOI] [PubMed] [Google Scholar]
  21. Karbowski M.; Norris K. L.; Cleland M. M.; Jeong S.-Y.; Youle R. J. Role of Bax and Bak in mitochondrial morphogenesis. Nature 2006, 443 (7112), 658–662. 10.1038/nature05111. [DOI] [PubMed] [Google Scholar]
  22. Danial N. N.; Walensky L. D.; Zhang C.-Y.; Choi C. S.; Fisher J. K.; Molina A. J. A.; Datta S. R.; Pitter K. L.; Bird G. H.; Wikstrom J. D.; Deeney J. T.; Robertson K.; Morash J.; Kulkarni A.; Neschen S.; Kim S.; Greenberg M. E.; Corkey B. E.; Shirihai O. S.; Shulman G. I.; Lowell B. B.; Korsmeyer S. J. Dual role of proapoptotic BAD in insulin secretion and beta cell survival. Nat. Med. 2008, 14 (2), 144–153. 10.1038/nm1717. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Szlyk B.; Braun C. R.; Ljubicic S.; Patton E.; Bird G. H.; Osundiji M. A.; Matschinsky F. M.; Walensky L. D.; Danial N. N. A phospho-BAD BH3 helix activates glucokinase by a mechanism distinct from that of allosteric activators. Nat. Struct. Mol. Biol. 2014, 21 (1), 36–42. 10.1038/nsmb.2717. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Ljubicic S.; Polak K.; Fu A.; Wiwczar J.; Szlyk B.; Chang Y.; Alvarez-Perez J. C.; Bird G. H.; Walensky L. D.; Garcia-Ocaña A.; Danial N. N. Phospho-BAD BH3Mimicry Protects β Cells and Restores Functional β Cell Mass in Diabetes. Cell Rep. 2015, 10 (4), 497–504. 10.1016/j.celrep.2014.12.056. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Toulis K. A.; Nirantharakumar K.; Pourzitaki C.; Barnett A. H.; Tahrani A. A. Glucokinase Activators for Type 2 Diabetes: Challenges and Future Developments. Drugs 2020, 80 (5), 467–475. 10.1007/s40265-020-01278-z. [DOI] [PubMed] [Google Scholar]
  26. Zhang C.-L.; Liu S.; Liu X.-C.; Gao J.-M.; Wang S.-L. Discovery of novel inhibitors of anti-apoptotic Bcl-2 proteins derived from Bim BH3 domain. Chin. Chem. Lett. 2017, 28 (7), 1523–1527. 10.1016/j.cclet.2017.03.010. [DOI] [Google Scholar]
  27. Lu X.; Wu L.; Liu X.; Wang S.; Zhang C. BH3 mimetics derived from Bim-BH3 domain core region show PTP1B inhibitory activity. Bioorg. Med. Chem. Lett. 2019, 29 (2), 244–247. 10.1016/j.bmcl.2018.11.047. [DOI] [PubMed] [Google Scholar]
  28. Zhang Z.-Y.; Lee S.-Y. PTP1B inhibitors as potential therapeutics in the treatment of Type diabetes and obesity. Expert Opin. Invest. Drugs 2003, 12 (2), 223–233. 10.1517/13543784.12.2.223. [DOI] [PubMed] [Google Scholar]
  29. Zhang S.; Zhang Z.-Y. PTP1B as a drug target: recent developments in PTP1B inhibitor discovery. Drug Discovery Today 2007, 12 (9), 373–381. 10.1016/j.drudis.2007.03.011. [DOI] [PubMed] [Google Scholar]
  30. Dadke S.; Kusari J.; Chernoff J. Down-regulation of Insulin Signaling by Protein-tyrosine Phosphatase 1B Is Mediated by an N-terminal Binding Region. J. Biol. Chem. 2000, 275 (31), 23642–23647. 10.1074/jbc.M001063200. [DOI] [PubMed] [Google Scholar]
  31. Wälchli S.; Curchod M.-L.; Gobert R. P.; Arkinstall S.; van Huijsduijnen R. H. Identification of Tyrosine Phosphatases That Dephosphorylate the Insulin Receptor: A BRUTE FORCE APPROACH BASED ON “SUBSTRATE-TRAPPING” MUTANTS. J. Biol. Chem. 2000, 275 (13), 9792–9796. 10.1074/jbc.275.13.9792. [DOI] [PubMed] [Google Scholar]
  32. Goldstein B. J.; Bittner-Kowalczyk A.; White M. F.; Harbeck M. Tyrosine Dephosphorylation and Deactivation of Insulin Receptor Substrate-1 by Protein-tyrosine Phosphatase 1B: POSSIBLE FACILITATION BY THE FORMATION OF A TERNARY COMPLEX WITH THE GRB2 ADAPTOR PROTEIN. J. Biol. Chem. 2000, 275 (6), 4283–4289. 10.1074/jbc.275.6.4283. [DOI] [PubMed] [Google Scholar]
  33. Kenner K. A.; Anyanwu E.; Olefsky J. M.; Kusari J. Protein-tyrosine Phosphatase 1B Is a Negative Regulator of Insulin- and Insulin-like Growth Factor-I-stimulated Signaling. J. Biol. Chem. 1996, 271 (33), 19810–19816. 10.1074/jbc.271.33.19810. [DOI] [PubMed] [Google Scholar]
  34. Klaman L. D.; Boss O.; Peroni O. D.; Kim J. K.; Martino J. L.; Zabolotny J. M.; Moghal N.; Lubkin M.; Kim Y.-B.; Sharpe A. H.; Stricker-Krongrad A.; Shulman G. I.; Neel B. G.; Kahn B. B. Increased Energy Expenditure, Decreased Adiposity, and Tissue-Specific Insulin Sensitivity in Protein-Tyrosine Phosphatase 1B-Deficient Mice. Mol. Cell. Biol. 2000, 20 (15), 5479–5489. 10.1128/MCB.20.15.5479-5489.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Elchebly M.; Payette P.; Michaliszyn E.; Cromlish W.; Collins S.; Loy A. L.; Normandin D.; Cheng A.; Himms-Hagen J.; Chan C.-C.; Ramachandran C.; Gresser M. J.; Tremblay M. L.; Kennedy B. P. Increased Insulin Sensitivity and Obesity Resistance in Mice Lacking the Protein Tyrosine Phosphatase-1B Gene. Science 1999, 283 (5407), 1544–1548. 10.1126/science.283.5407.1544. [DOI] [PubMed] [Google Scholar]
  36. Mok A.; Cao H.; Zinman B.; Hanley A. J. G.; Harris S. B.; Kennedy B. P.; Hegele R. A Single Nucleotide Polymorphism in Protein Tyrosine Phosphatase PTP-1B Is Associated with Protection from Diabetes or Impaired Glucose Tolerance in Oji-Cree. J. Clin. Endocrinol. Metab. 2002, 87 (2), 724–727. 10.1210/jcem.87.2.8253. [DOI] [PubMed] [Google Scholar]
  37. Echwald S. M.; Bach H.; Vestergaard H.; Richelsen B.; Kristensen K.; Drivsholm T.; Borch-Johnsen K.; Hansen T.; Pedersen O. A P387L Variant in Protein Tyrosine Phosphatase- 1B (PTP-1B) Is Associated With Type 2 Diabetes and Impaired Serine Phosphorylation of PTP-1B In Vitro. Diabetes 2002, 51 (1), 1–6. 10.2337/diabetes.51.1.1. [DOI] [PubMed] [Google Scholar]
  38. Easty D.; Gallagher W.; Bennett D. Protein Tyrosine Phosphatases, New Targets for Cancer Therapy. Curr. Cancer Drug Targets 2006, 6 (6), 519–532. 10.2174/156800906778194603. [DOI] [PubMed] [Google Scholar]
  39. Tonks N. K.; Muthuswamy S. K. A Brake Becomes an Accelerator: PTP1B—A New Therapeutic Target for Breast Cancer. Cancer Cell 2007, 11 (3), 214–216. 10.1016/j.ccr.2007.02.022. [DOI] [PubMed] [Google Scholar]
  40. Banh R. S.; Iorio C.; Marcotte R.; Xu Y.; Cojocari D.; Rahman A. A.; Pawling J.; Zhang W.; Sinha A.; Rose C. M.; Isasa M.; Zhang S.; Wu R.; Virtanen C.; Hitomi T.; Habu T.; Sidhu S. S.; Koizumi A.; Wilkins S. E.; Kislinger T.; Gygi S. P.; Schofield C. J.; Dennis J. W.; Wouters B. G.; Neel B. G. PTP1B controls non-mitochondrial oxygen consumption by regulating RNF213 to promote tumour survival during hypoxia. Nat. Cell Biol. 2016, 18 (7), 803–813. 10.1038/ncb3376. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Julien S. G.; Dubé N.; Read M.; Penney J.; Paquet M.; Han Y.; Kennedy B. P.; Muller W. J.; Tremblay M. L. Protein tyrosine phosphatase 1B deficiency or inhibition delays ErbB2-induced mammary tumorigenesis and protects from lung metastasis. Nat. Genet. 2007, 39 (3), 338–346. 10.1038/ng1963. [DOI] [PubMed] [Google Scholar]
  42. Combs A. P. Recent Advances in the Discovery of Competitive Protein Tyrosine Phosphatase 1B Inhibitors for the Treatment of Diabetes, Obesity, and Cancer. J. Med. Chem. 2010, 53 (6), 2333–2344. 10.1021/jm901090b. [DOI] [PubMed] [Google Scholar]
  43. Bentires-Alj M.; Neel B. G. Protein-Tyrosine Phosphatase 1B Is Required for HER2/Neu–Induced Breast Cancer. Cancer Res. 2007, 67 (6), 2420–2424. 10.1158/0008-5472.CAN-06-4610. [DOI] [PubMed] [Google Scholar]
  44. Krishnan N.; Koveal D.; Miller D. H.; Xue B.; Akshinthala S. D.; Kragelj J.; Jensen M. R.; Gauss C.-M.; Page R.; Blackledge M.; Muthuswamy S. K.; Peti W.; Tonks N. K. Targeting the disordered C terminus of PTP1B with an allosteric inhibitor. Nat. Chem. Biol. 2014, 10 (7), 558–566. 10.1038/nchembio.1528. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Xu Q.; Wu N.; Li X.; Guo C.; Li C.; Jiang B.; Wang H.; Shi D. Inhibition of PTP1B blocks pancreatic cancer progression by targeting the PKM2/AMPK/mTOC1 pathway. Cell Death Dis. 2019, 10 (12), 874. 10.1038/s41419-019-2073-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Mody N.; Agouni A.; McIlroy G. D.; Platt B.; Delibegovic M. Susceptibility to diet-induced obesity and glucose intolerance in the APPSWE/PSEN1A246E mouse model of Alzheimer’s disease is associated with increased brain levels of protein tyrosine phosphatase 1B (PTP1B) and retinol-binding protein 4 (RBP4), and basal phosphorylation of S6 ribosomal protein. Diabetologia 2011, 54 (8), 2143–2151. 10.1007/s00125-011-2160-2. [DOI] [PubMed] [Google Scholar]
  47. Vieira M. N. N.; Lyra e Silva N. M.; Ferreira S. T.; De Felice F. G. Protein Tyrosine Phosphatase 1B (PTP1B): A Potential Target for Alzheimer’s Therapy?. Front. Aging Neurosci. 2017, 9, 7. 10.3389/fnagi.2017.00007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Figueiredo H.; Figueroa A. L. C.; Garcia A.; Fernandezruiz R.; Broca C.; Wojtusciszyn A.; Malpique R.; Gasa R.; Gomis R. Targeting pancreatic islet PTP1B improves islet graft revascularization and transplant outcomes. Sci. Transl. Med. 2019, 11 (497), eaar6294. 10.1126/scitranslmed.aar6294. [DOI] [PubMed] [Google Scholar]
  49. Maggiora G.; Vogt M.; Stumpfe D.; Bajorath J. Molecular Similarity in Medicinal Chemistry. J. Med. Chem. 2014, 57 (8), 3186–3204. 10.1021/jm401411z. [DOI] [PubMed] [Google Scholar]
  50. Petrone P. M.; Simms B.; Nigsch F.; Lounkine E.; Kutchukian P.; Cornett A.; Deng Z.; Davies J. W.; Jenkins J. L.; Glick M. Rethinking Molecular Similarity: Comparing Compounds on the Basis of Biological Activity. ACS Chem. Biol. 2012, 7 (8), 1399–1409. 10.1021/cb3001028. [DOI] [PubMed] [Google Scholar]
  51. Bech E. M.; Pedersen S. L.; Jensen K. J. Chemical Strategies for Half-Life Extension of Biopharmaceuticals: Lipidation and Its Alternatives. ACS Med. Chem. Lett. 2018, 9 (7), 577–580. 10.1021/acsmedchemlett.8b00226. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Zhang L.; Bulaj G. Converting Peptides into Drug Leads by Lipidation. Curr. Med. Chem. 2012, 19 (11), 1602–1618. 10.2174/092986712799945003. [DOI] [PubMed] [Google Scholar]
  53. Menacho-Melgar R.; Decker J. S.; Hennigan J. N.; Lynch M. D. A review of lipidation in the development of advanced protein and peptide therapeutics. J. Controlled Release 2019, 295, 1–12. 10.1016/j.jconrel.2018.12.032. [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

ml1c00174_si_001.pdf (1.2MB, pdf)

Articles from ACS Medicinal Chemistry Letters are provided here courtesy of American Chemical Society

RESOURCES