Table 3.
Selected allosteric phosphatase modulators
| Compound (company/investigator) | Target | IC50 | Stage of development | Comments | Refs. |
|---|---|---|---|---|---|
| SHP099 and TNO155 (Novartis) | SHP2 | 71 and 11 nM | Phase I and I/II clinical trials (TNO155) | ‘Molecular glue’ compounds; stabilize auto-inhibited state of SHP2 by binding to the pocket created by the closed conformation of the enzyme | 20–22 |
| RMC-4550 and RMC-4630 (Revolution Medicines) | SHP2 | 583 pM and NR | Phase I and I/II clinical trials (RMC-4630) | Preliminary trial results demonstrate disease control in five of seven patients with KRASG12C non-small-cell lung cancer | 23 |
| IACS-13909 and BBP-398/IACS-15509 (Navire Pharma, Inc. and University of Texas MD Anderson Cancer Center) | SHP2 | 15.7 nM and NR | Phase I clinical trial (BBP-398/IACS-15509) | 24 | |
| DPM-1001 (DepYmed) | PTP1B | 100 nM | Preclinical | Binds to PTP1B C terminus as a complex with chelated copper; oral DPM-1001 administration to mice fed a high-fat diet leads to weight loss and improves glucose tolerance and insulin sensitivity | 19 |
| Chelerythrine (Tonks Laboratory, Cold Spring Harbor Laboratory) | PTP1B | 5 µM | Tool compound | Stabilizes reversible PTP1B oxidation; enhances insulin signalling in 293T cells and leptin signalling in hepatic stellate cells; intraperitoneal chelerythrine administration to mice fed a high-fat diet leads to weight loss and improves glucose tolerance and insulin sensitivity | 210 |
| MSI-1436/trodusquemine (characterized by Tonks (Cold Spring Harbor Laboratory) and Peti (Brown University) Laboratories) | PTP1B | 600 nM | Discontinued | Intraperitoneal MSI-1436 administration inhibits tumour growth and metastasis in mouse models of breast cancer; phase I trial was terminated | 88 |
| GSK2830371 (GlaxoSmithKline) | WIP1 | 6 nM | Preclinical | Enhances phosphorylation of WIP1 substrates in multiple cancer cell lines and inhibits growth of xenografted DOHH2 B cell lymphoma tumours in mice when administered orally | 27 |
| Compound 1 (Bennett Laboratory, Yale University) | MKP5 | 3.9 µM | Tool compound | Enhances p38α and JNK phosphorylation in C2C12 myoblasts and inhibits transforming growth factor β1 signalling | 25 |
| MLS000544460 (Zhao (University of Colorado)/Ford (University of Colorado)/Marugan (NIH NCATS) Laboratories) | EYA2 | 4.1 µM | Tool compound | Inhibits migration of MCF10A breast cancer cells overexpressing wild-type but not catalytically dead EYA2 | 226 |
| NCGC00249987 (Zhao (University of Colorado)/Ford (University of Colorado)/Marugan (NIH NCATS) Laboratories) | EYA2 | 3.0 µM | Tool compound | Suppresses migration, invadopodia formation and invasion of EYA2-overexpressing Calu-6 lung cancer cells | 26 |
| SHP2 PROTACs (Wang (University of Michigan)/Liu (Zhengzhou University)/Zhou (University of Chinese Academy of Sciences) Laboratories) | SHP2 | NR | Tool compounds | SHP099-based SHP-D26; SHP099-based SP4; TNO155-based 11 (ZB-S-29) | 227–229 |
EYA2, eyes absent 2; IC50, half-maximal inhibitory concentration; MKP5, MAP kinase phosphatase 5; NCATS, National Center for Advancing Translational Sciences; PTP, protein tyrosine phosphatase; SHP2, SH2 domain-containing PTP 2; WIP1, wild-type p53-induced phosphatase 1.