Insulin and Lectin are two hormones which play crucial roles in energy storage and peripheral energy uptake. Resistance to these hormones is a hallmark for both Type 2 Diabetes Mellitus (T2DM) and obesity1. Nearly 220 million people are living with diabetes and WHO projected the death due to diabetes would double between 2005 and 20302. The global epidemic nature of T2DM and obesity demand the need for new therapeutic approaches. PTP1B stands out in the PTP family as a negative regulator of insulin signal transduction pathway through its ability to dephosphorylate and inactivate the insulin receptor3. PTP1B also negatively regulates the leptin signalling pathway by dephosphorylating JAK2 (a phosphorylated tyrosine kinase) in the hypothalamus. Leptin is a key hormone directly associated with obesity that regulates food intake and energy expenditure4,11.
Fig.1: PTP1B dephosphorylates the insulin receptor during its biosynthesis in the endoplasmic reticulum (ER)4
Natural products like prenylated xanthones, flavonoids, bromophenols, phenolic acids, cumarins, terpenes, steroids were isolated and tested to have potent PTP1B inhibition of 1.6-30.0 µmol/L5. These natural products have opened the gate to many small molecule inhibitors for PTP1B. However, carboxylates and phosphonates with nanomolar inhibition have failed to progress to the clinic due to poor membrane penetration6.
Many studies have postulated that existing anti-diabetic drugs belonging to the thiazolidinediones (TZDs) family, commonly known as glitazones (rosiglitazone7, pioglitazones etc.), could inhibit PTP1B8. Early competitive PTP1B inhibitors based on Vanadium compounds (vanadates and pentavanadates) have significant therapeutic values in human but they are not specific8,11. Series of benzofurans, benzothiophenes and phosphonates have been synthesised and patented as potential PTP1B inhibitors6,8. Unfortunately, none of them has made Phase II clinical trials9. Ertiprotafab from Wyeth, the first PTP1B inhibitor, was halted in Phase II due to data inconsistencies10.
Selectivity6,11 and bioavailability12 are the main challenges in developing potent PTP inhibitors. The PTP1B catalytic site shares structural motifs of other enzymes of PTP family and is highly charged. Consequently, highly charged inhibitors with very strong PTP1B inhibition lack biovailability11. Achieving selectivity against TC-PTP13 is the most challenging task for medicinal chemists. Many clinical trials, patent applications and drugs validation experiments proves that PTP1B has emerged as a novel target for the management, treatment of T2DM. However, the journey in the search for selective PTP1B inhibitors has been facing many pitfalls.
Interestingly, current phase II trial on Trodusquemine14 and PTP1B antisense oligonucleotides (IONIS-GCGRRX) by Ionis pharmaceuticals15 could be an alternate therapeutic option for T2DM and obesity. At least one of the clinical candidates in Phase II studies will receive green signal from FDA in few years’ time
Blog by Srinivasan Natarajan
- D.Popov, Biochemical and Biophysical Research Communications, 2011, 410, 377-381
- WHO diabetes fact sheet available from
- S.Koren and I.G Fantus., Best Practice & research Clinical Endocrinology & Metabolism, 2007, 21(4), 621-640
- J.Montalibet and B.P.Kennedy., Drug Discovery Today: Therapeutic Stragies, 2005, 2, 129-135.
- C.S JIANG, L.LIANG and Y GUO, Acta Pharmacologica Sinica (2012) 33: 1217–1245
- H.Cho Vitamins and Harmones, V 91, chapter 17, 2013, Elsevier Inc.,
- The antidiabetic drug rosiglitazone was withdrawn from European market since 2010 due to the increased risk of heart attack
- Review by A.K Tamarkar and A.K. Rai, Expert Opin. Ther. Patents, 2014, 24(10), 1-15.
- Review by M.L.Tremblay et al., Crit.Rev.Biochem.Mol.Biol., 2013, 48(5), 430-445
- DV. Erbe et al. Molecular Pharmacology, 67(1), 69-77.
- S.Koren, I.G. Fantus, Best Practice & Research Clinical Endocrinology & Metabolism, 214, 621-640.
Tonks N.K et al., Nature Chemical Biology, 2014, 10, 558-568
- H.Oh et al., Molecules, 2015, 20, 11173-11183
- T.Tcell PTP (TC-PTP) which linked to the development of several inflammatory disorder including type 1diabetes, Crohn disease and rheumatoid arthritis (J.Am.Chem.Soc.,2009, 131(36), 13072-79)
- K.A. Lantz et al. Obesity, 2010, 18(8), 1516-1523.
- Phase II for IONIS-GCGRRX completed in January 2017. See the company website http://www.ionispharma.com/pipeline/
also see https://www.ncbi.nlm.nih.gov/pubmed/25197025 for anti -sense oligos for PTP1B