Table 2.
Selected orthosteric phosphatase modulators
| Compound (company/investigator) | Target | IC50 | Stage of development | Comments | Refs. |
|---|---|---|---|---|---|
| Orthosteric competitive inhibitors | |||||
| AKB-9778/razuprotafib (Aerpio Therapeutics) | VE-PTP | 17 pM | Phase II trial in patients with COVID-19 | Monotherapy did not meet the study’s primary endpoint in the phase IIb TIME-2b trial for diabetic retinopathy, but showed positive results in secondary endpoint measures of kidney function and intra-ocular pressure; reverses COVID-19 plasma-induced prothrombotic state in cultured endothelial cells | 28,211,212 |
| Compound 8 (Zhang Laboratory, Indiana University) | TC-PTP | 9 nM | Tool compound | Intracerebroventricular administration has been used to study TC-PTP as a regulator of hypothalamic leptin signalling and arcuate pro-opiomelanocortin neuron response to insulin | 213–215 |
| Compound 13 (Tabernero Laboratory, University of Manchester) |
Mycobacterium tuberculosis PTP B |
3 µM | Tool compound | Decreases bacterial burden in a guinea pig model of tuberculosis infection | 216 |
| L-1 (Zhang Laboratory, Purdue University) | PTPN22 | 1.4 µM | Tool compound | Intraperitoneal or subcutaneous via osmotic pump administration in a DMSO–PBS–cremophor-EL formulation leads to significant impairment of xenografted tumour growth | 14 |
| Compound 28 (Zhang Laboratory, Purdue University) | LMPTP | 2.1 µM | Tool compound | Induces a conformational change in the LMPTP active site to induce its own fit; enhances insulin signalling in HepG2 hepatocytes | 31 |
| Orthosteric uncompetitive inhibitors | |||||
| Compound 6g (Bottini Laboratory, University of California, San Diego and SBPMDI CGC) | LMPTP | 83 nM | Tool compound | Oral administration improves glucose tolerance and increases liver insulin sensitivity in mice fed a high-fat diet | 30 |
| Compound 23 (Bottini Laboratory, University of California, San Diego and SBPMDI CGC) | LMPTP | 800 nM | Tool compound | Oral administration improves glucose tolerance and increases liver insulin sensitivity in mice fed a high-fat diet | 29 |
| Oxidative inhibitors | |||||
| JMS-053 (Lazo (University of Virginia)/Sharlow (University of Virginia)/Wipf (University of Pittsburgh) Laboratories) | PRL1/PRL2/PRL3 | ~30 nM | Tool compound | Intraperitoneal JMS-053 administration to mice bearing HeyA8-MDR ovarian tumours reduces tumour weight without affecting body weight | 217–219 |
| UPD-140 (Ferrari Laboratory, University of Zurich) | CDC25A/CDC25B/CDC25C | Low μM | Tool compound | Reversible inhibition, likely through catalytic Cys residue oxidation; regresses tumours and reduces metastases in zebrafish embryo xenograft models | 220 |
| Irreversible inhibition | |||||
| TC-2153 (Lombroso Laboratory, Yale University) | STEP | 57 nM | Tool compound | Irreversible inhibition, likely through covalent interaction between catalytic Cys472 and TC-2153 sulfur; TC-2153 administration is efficacious in multiple rodent models of cognitive dysfunction | 221–225 |
CDC, cell division cycle; COVID-19, coronavirus disease 2019; IC50, half-maximal inhibitory concentration; LMPTP, low-molecular-weight PTP; PRL, phosphatase of regenerating liver; PTP, protein tyrosine phosphatase; SBPMDI CGC, Sanford Burnham Prebys Medical Discovery Institute Chemical Genomics Center; STEP, striatum-enriched PTP; TC-PTP, T cell PTP; VE-PTP, vascular endothelial PTP.