Src homology 2 domain-containing phosphatase 2 (SHP2) is a non-receptor protein tyrosine phosphatase belonging to the protein tyrosine phosphatase (PTP) family. Studies have shown that dysregulation of SHP2 is associated with abnormal cell proliferation, differentiation, adhesion migration, and apoptosis. Moreover, inhibition of SHP2 can effectively overcome drug resistance after chemotherapy and other treatment. Therefore, SHP2 is a potential target for cancer therapy. However, due to low cell permeability and poor bioavailability, the effectiveness of traditional inhibitors targeting phospho-catalytic sites of protein tyrosine is generally not ideal. In recent years, researchers have developed allosteric inhibitors with significant inhibition of SHP2, and clinical trials in solid tumors have made much progress.
Current progress
SHP2 inhibitors have experienced the development process from catalytic site inhibitors to allosteric site inhibitors, and then to SHP2 degradants. Currently, no drug targeting SHP2 has been approved for the market, but several SHP2 small molecule inhibitors have been approved for clinical use. The most advanced is phase II clinical TNO-155, which is also the first SHP2 inhibitor to enter the clinical stage.
1. Inhibitors targeting SHP2 catalytic site
Early attempts at small molecule SHP2 inhibitors focused on the development of active site inhibitors. Although several catalytic SHP2 inhibitors have been identified, their apparent lack of desired pharmacokinetic properties and non-specific binding to other PTPs have made it difficult to develop inhibitors targeting the SHP2 catalytic sites. Moreover, the highly conserved amino acid sequences of many PTPs and the positive charge properties of the active site of the PTP domain make it hard to find small molecule inhibitors with high affinity and sufficient cell permeability. In addition, the high structural homology between SHP2 and SHP1 makes it difficult to develop selective catalytic inhibitors of SHP2. Representative SHP2 catalytic site inhibitors, such as 11a-1 (IC50 = 0.2 μm) and CNBDA (IC50 = 5 μm), are 7 and 25 times more active against SHP2 than SHP1, respectively (Figure 1).
2. Inhibitors targeting SHP2 allosteric site
Studies have shown that small molecule inhibitors of SHP2 interact not only with phosphotyrosine binding pockets but also with nearby peripheral sites specific to some PTPs. Researchers have attempted to develop small molecule inhibitors targeting the allosteric sites of SHP2 to overcome the inherent limitations associated with catalytic sites.
In 2016, Novartis reported that SHP099, the first allosteric inhibitor of SHP2, binds simultaneously to the interface of SHP2’s N-SH2, C-SH2, and PTP domains and stabilizes SHP2’s self-inhibiting conformation. Allosteric SHP2 inhibitors such as IACS-13909 (IC50 = 15.7 nm) have been found to be specific to SHP2 and have no inhibitory effect on SHP1. TNO155 (IC50 = 0.011 μm) and LY6 (IC50 = 9.8 μm) also showed high selectivity for SHP2. In addition, several allosteric SHP2 inhibitors, including SHP099, TNO155, and RMC-4630, are being studied in combination with other inhibitors. Currently, allosteric SHP2 inhibitors including BBP-398, JAB-3068, TNO155, and RMC-4630 are in phase I/II clinical trials for the treatment of various types of metastatic solid tumors.
However, a key limitation of these drugs is that they do not effectively inhibit SHP2 mutants, which becomes the focus of subsequent research.
3. SHP2 PROTACs
Proteolysis-targeting chimera PROTAC is a novel therapeutic strategy that degrades disease-related proteins. PROTAC molecules hijack E3 ligase to form a ternary complex with POI, inducing proteasome ubiquitination and subsequent degradation of POI. It boasts a advantage that it can effectively inhibit POI at low doses, and rapidly degrade and clear POI, providing an effective strategy with high safety, resistance, and broad application prospect. Since SHP2 inhibitors are not effective against SHP2 mutants, targeted degradation of SHP2 via PROTAC is an alternative strategy for SHP2-mediated cancer therapy and provides a highly effective way to inhibit SHP2 activity.
Some of the most efficient SHP2 PROTACs found to date include D26, ZB-S-29 (DC50 = 6.02nm), SP4, and R1-3C (Figure 2).
4. Inhibitors targeting SHP2 protein-protein interaction
Recently, Bobone et al., University of Rome, reported a novel strategy for targeted therapy of SHP2 that uses the peptide molecule OP (GLN-F2Pmp-IDLDW) to target protein-protein interactions (PPI) between SHP2 and its substrates or binding partners, rather than inhibiting its catalytic activity. It was found that OP had a low nanomolar affinity and high specificity for the N-SH2 domain of SHP2, and also showed good resistance to degradation. The publication of this result suggests that inhibiting the interaction of SHP2 with other proteins is also a promising alternative for targeting SHP2 therapy.
How does BOC Sciences devote to SHP2 inhibitor development?
BOC Sciences has directed sincere efforts toward the R&D of small-molecule inhibitors (inhibitors, agonists, and modulators), which greatly free researchers from material outsourcing and selection workload. Most of the inhibitors are supplied ranging from milligram to kilogram scales and arrived with an analytic report. With the broad joint efforts from material supply to clinical research and trials, we believe that SHP2 inhibitors will become promising anticancer drugs for the benefit of more patients.
Related Products:
| Name | CAS | Description |
| PROTAC | Proteolysis targeting chimeras (PROTACs) are small molecule drugs that are mixed with two different functional ligands, one of which binds to a protein of interest (POI) and the other is used to recruit an E3 ligase. | |
| Inhibitor | BOC Sciences has directed sincere efforts toward providing customers with high quality small-molecule inhibitors (inhibitors, agonists and modulators) with optimal prices. | |
| SHP2 Inhibitor | SHP2 provide novel targets for the treatment of human disease. Small molecule SHP2 inhibitors might have important therapeutic applications for Noonan syndrome patients. | |
| TNO-155 | 1801765-04-7 | TNO-155 is an inhibitor of protein tyrosine phosphatase (PTP) non-receptor type 11 (SHP2), with potential antineoplastic activity. |
| SHP099 | 1801747-42-1 | SHP099 is a potent, selective, orally bioavailable, and efficacious SHP2 inhibitor (IC50 value 0.071 μM) that stabilizes SHP2 in an auto-inhibited conformation. |
| IACS-13909 | 2160546-07-4 | IACS-13909 is a specific and potent allosteric inhibitor of SHP2 that suppresses signaling through the MAPK pathway. |