SHP2 inhibitors are a novel class of therapeutic agents that target the SHP2 protein, a key regulator in cellular signaling pathways. By controlling SHP2 activity, these molecules show promise for treating diseases characterized by uncontrolled cell growth and abnormal development. This represents a targeted approach in medicine, addressing underlying molecular causes of illness.
Understanding SHP2
SHP2, or Src homology 2 domain-containing phosphatase 2, is a protein tyrosine phosphatase. It functions as a molecular switch, influencing pathways that regulate cell growth, differentiation, and survival. SHP2 contains two SH2 domains (N-SH2 and C-SH2), a protein tyrosine phosphatase (PTP) domain, and a C-terminal tail.
SHP2 plays a positive role in activating the RAS/MAPK signaling pathway, fundamental for cell proliferation, differentiation, and survival. Under normal conditions, SHP2 is kept in an inactive state through an internal interaction where its N-SH2 domain blocks the catalytic PTP domain. When activated by signals from receptor tyrosine kinases, SHP2 undergoes a change in shape, exposing its active site and enabling it to regulate proteins in the RAS/MAPK pathway.
This involves dephosphorylating specific tyrosine residues, which facilitates the conversion of inactive RAS (GDP-bound) to active RAS (GTP-bound), initiating signaling. Dysregulation or specific gain-of-function mutations in the gene encoding SHP2, PTPN11, can lead to continuous activation of the RAS/MAPK pathway. This uncontrolled signaling contributes to the development and progression of various diseases, including certain cancers and developmental disorders. For instance, germline PTPN11 mutations are a common cause of Noonan Syndrome, while somatic mutations are found in juvenile myelomonocytic leukemia and other malignancies.
How SHP2 Inhibitors Function
SHP2 inhibitors are small molecules engineered to block the activity of the SHP2 protein. These inhibitors work by binding to specific sites on the SHP2 enzyme, preventing its activation or catalytic function. This disruption then interferes with the aberrant signaling pathways driven by overactive SHP2, potentially halting disease progression.
Most current SHP2 inhibitors are allosteric inhibitors, meaning they bind to a site on the enzyme distinct from the active catalytic site. This allosteric binding stabilizes SHP2 in its autoinhibited, closed conformation, simultaneously blocking its catalytic activity and its ability to act as a scaffold for other signaling proteins. For example, SHP099, an early-generation allosteric inhibitor, binds to a specific pocket, stabilizing the inactive state.
By stabilizing this inactive state, allosteric inhibitors prevent the conformational change that exposes SHP2’s catalytic site. This mechanism differs from active-site inhibitors, which directly block the enzyme’s catalytic region. Allosteric inhibitors offer better selectivity and improved drug properties, reducing unintended effects on other proteins.
Therapeutic Applications of SHP2 Inhibitors
SHP2 inhibitors are being investigated for their therapeutic potential across a range of diseases, particularly in oncology, where dysregulated SHP2 activity contributes to tumor growth. Their primary role is in cancers driven by mutations in the RAS/MAPK pathway, such as non-small cell lung cancer, melanoma, and colorectal cancer. In these cancers, SHP2 inhibition can help overcome resistance to other targeted therapies by dampening the hyperactive signaling cascade that promotes tumor proliferation.
These inhibitors are particularly relevant in cancers with specific mutations like KRASG12C, KRASG12D, NF1 loss of function, and BRAF Class 3 mutations, all of which rely on SHP2 for sustained RAS/MAPK activation. For instance, SHP2 inhibition can resensitize tumors to existing MAPK pathway inhibitors, offering a strategy to improve treatment outcomes when initial therapies lose effectiveness. This combination approach leverages that SHP2 is a central node in the RAS pathway, making its inhibition effective even if other components of the pathway are mutated.
Beyond cancer, SHP2 inhibitors show promise in treating rare developmental disorders known as RASopathies, including Noonan Syndrome and Neurofibromatosis Type 1. Noonan Syndrome, often caused by gain-of-function PTPN11 mutations, leads to developmental abnormalities and increased cancer risk due to hyperactivated RAS/MAPK signaling. Inhibiting SHP2 could normalize these pathways, potentially addressing symptoms like hypertrophic cardiomyopathy, growth retardation, and cognitive impairment. Similarly, in Neurofibromatosis Type 1, which involves mutations in the NF1 gene affecting RAS signaling, SHP2 inhibitors could offer a way to manage tumor development and other associated complications.
Current Progress and Clinical Landscape
Several SHP2 inhibitors have advanced into clinical trials, demonstrating the growing interest in this class of drugs. Key compounds include TNO155, RMC-4630, PF-07282489 (formerly ARRY-558), and BBP-398. These agents are primarily in Phase 1 or Phase 2 clinical trials, evaluating their safety, tolerability, and preliminary anti-tumor activity.
TNO155, one of the first SHP2 inhibitors to enter clinical development, is currently in Phase 1 and Phase 2 trials for various metastatic solid tumors, including non-small cell lung cancer with KRAS mutations. RMC-4630 has also shown anti-tumor activity in initial Phase 1 trials for tumors with diverse RAS pathway mutations, such as KRASG12C, KRASG12D, and BRAF Class 3. Both TNO155 and RMC-4630 are being investigated as single agents and in combination with other targeted therapies, like MEK inhibitors or KRAS inhibitors, to enhance efficacy and overcome resistance mechanisms.
PF-07282489, an allosteric SHP2 inhibitor, is designed to overcome bypass signaling that leads to resistance in various oncogene-addicted solid tumors. BBP-398 (formerly IACS-15509) is another SHP2 inhibitor undergoing Phase 1 and Phase 1B studies for advanced solid tumors, including non-small cell lung cancer with KRAS mutations, often in combination with immunotherapies like nivolumab. While no SHP2 inhibitor has yet received market approval, ongoing research and clinical progress highlight a promising outlook for these targeted therapies.