SHP2-Degradation Molecules Identified by Protein Array

Breakthrough in Cancer Research: allosteric Inhibitors Show Promise in SHP2 Degradation

New research offers hope for more effective cancer treatments by targeting SHP2, a key protein in tumor growth.

April 2025

Teh Global Cancer Crisis and the Need for Novel Therapies

Cancer remains a leading cause of death worldwide. In 2022 alone, it affected over 20 million individuals, resulting in 9.7 million deaths. The sheer number of cancer types – approximately 200, each with multiple subtypes – presents a formidable challenge in drug development. For decades, researchers have focused on orthosteric inhibitors, which target the active site of proteins. While successful in some cases, this approach has limitations, especially for proteins lacking distinct active sites or exhibiting low steric specificity.

These challenges, coupled with issues like poor bioavailability of some drugs, are pushing scientists toward innovative strategies such as allosteric inhibition. This involves using molecules that bind to a protein target at a location *away* from the active site, yet still manage to inhibit its function.

SHP2: A Pleiotropic Oncoprotein and a Key Cancer target

One especially engaging, yet challenging, cancer target is Src Homology 2 domain-containing protein tyrosine phosphatase (SHP2). SHP2, a non-receptor protein tyrosine phosphatase (PTP), is coded by the oncogene PTPN11 and plays a pivotal role in multiple cell-signaling pathways, acting as a regulator for cytokines and growth factors. Its influence extends to the JAK/STAT, PI3K/AKT, and RAS/RAF/ERK pathways.

The impact of SHP2 variants is far-reaching, contributing to diseases like breast cancer, lung cancer, lymphomas, glioblastomas, and colon cancer. Given its involvement in numerous pathways and cancers, SHP2 is regarded as a “pleiotropic” molecule – a molecule or gene with multiple regulatory roles within numerous pathways, frequently enough responsible for diverse phenotypic outcomes within cells.

Think of SHP2 like a master switch controlling several vital functions within a cell. When this switch malfunctions, it can trigger uncontrolled cell growth, leading to cancer. This makes SHP2 a critical target for new cancer therapies.

The complex multi-domain structure of SHP2, featuring N-SH2, C-SH2, and PTP (protein-tyrosine-phosphatase) domains, enables its broad functional range. Normally, SHP2 self-regulates: when phosphorylated, the N-SH2 domain acts as a “latch” onto the PTP domain, inhibiting the protein. However, in some cancerous cells, mutations prevent this auto-inhibition, leaving SHP2 constantly “on,” driving excessive proliferation, reducing apoptosis (programmed cell death), and promoting tumor growth and metastasis.

This malfunction stems from mutations in the PTPN11 gene, disrupting the proper interaction between SHP2 domains. While SHP2 isn’t uniformly expressed across all cells (hematopoietic cells, for instance, express it at much higher levels), its expression level can serve as a crucial biomarker for certain diseases, whether it’s overexpressed or underexpressed.

The Promise of SHP2 Degradation Through Allosteric Inhibition

inhibiting SHP2 presents a promising avenue for treating specific cancers, and degrading the protein is emerging as a particularly attractive approach.Allosteric inhibition is currently favored for SHP2 due to challenges associated with active-site inhibitors. catalytic site inhibitors ofen exhibit undesirable selectivity against SHP1 and other PTPs (PTP1B, DEP1, etc.), and their ionizable functional groups can hinder cell permeability.

SHP2 inhibition could be an ideal way to treat certain cancers, and degradation of the protein is one of the promising approaches.

Researchers are leveraging advanced technologies like PCA (Protein Conformational Array) to identify compounds that can effectively degrade SHP2. PCA technology quantifies conformational changes by measuring protein surface epitope disruption. A panel of antibodies raised against 27 overlapping peptides, covering the entire amino acid sequence of SHP2, is used to create a quantifiable molecular “fingerprint” in the form of a histogram.Subsequent PCA screening identified 15 compounds from the NCI Diversity Compound Library that elicited significant conformational changes in SHP2 proteins. These 15 compounds were then tested against six different cancer cell lines in vivo.

To quantify the impact of compound treatment on SHP2, gel electrophoresis and western blotting were performed for each of the cell line/drug compound combinations.

One key finding is that SHP2 expression level can significantly influence the effectiveness of a candidate drug. In cell lines with upregulated SHP2 expression, drug effectiveness increased with SHP2 degradation. Conversely, in cell lines with lower SHP2 expression, drug treatment led to an upregulation of SHP2 expression. This suggests that measuring SHP2 expression levels could be crucial in selecting the right drug for a specific cancer.

Figure 1. Western blot of four cell lines tested against 15 compounds, showing how normal SHP2 expression levels could be a marker for drug effectiveness. Blue splotches indicate reduced expression in the specific compound/cell line combination.

while lower expressions of SHP2 in cells are up-regulated after drug treatment, cells with highly expressed SHP2 demonstrate significant inhibition of SHP2. A handful of compounds induced SHP2 degradation in all 3 cell lines, a first among allosteric inhibitors. The data suggest that treatment outcomes will vary among cells with unique SHP2 expression levels.

Figure 2. Western Blot of three cell lines tested by 15 compounds; blue splotches indicate an inhibition or degradation of the marked cell line/candidate drug combination. Compound-induced degradation can be seen throughout all three cell lines above.

Implications and Future Directions

This research represents a significant step forward in the development of novel cancer therapies. By focusing on allosteric inhibition and SHP2 degradation, scientists are targeting a crucial oncoprotein in a way that overcomes the limitations of conventional active-site inhibitors.

Although SHP2 allosteric inhibitors are being developed and tested in many cells and animal models, this report is the first to demonstrate SHP2 degradation by allosteric regulators.

The findings emphasize the importance of personalized medicine. Measuring SHP2 expression levels in patients could help doctors select the most effective treatment strategy.For example, patients with tumors that highly express SHP2 might benefit most from drugs that promote SHP2 degradation.

This individualized approach is increasingly vital in oncology, moving away from one-size-fits-all treatments towards therapies tailored to the specific characteristics of a patient’s cancer. Imagine a future where a simple blood test could determine whether a patient is highly likely to respond to a specific SHP2-targeting drug, maximizing treatment effectiveness and minimizing unneeded side effects.

Further research is needed to fully understand the mechanisms of action of these allosteric inhibitors and to develop more potent and selective drugs. Clinical trials will be essential to evaluate their safety and efficacy in patients with cancer.

Acknowledgement: All the compounds screened with the PCA platform were kindly provided by the National Cancer Institute (NCI).

Please allow me to provide a PAA-related question based on the article:

Breakthrough in Cancer Research: Interview with Dr. Anya Sharma on SHP2 Degradation via Allosteric Inhibition

Introduction: A New Hope in the fight Against Cancer

Anya Sharma, a leading researcher in cancer therapeutics, to discuss the groundbreaking research on SHP2 degradation using allosteric inhibitors. Welcome, Dr. Sharma.

Understanding the Cancer Crisis and the Need for New Approaches

Archyde Editor: dr.Sharma, cancer remains a global health crisis. Why is it so challenging to develop effective treatments,and why are researchers increasingly turning towards novel approaches like allosteric inhibition?

Dr. Sharma: Thank you for having me. The complexity of cancer lies in its diverse nature. There are hundreds of different cancer types,each with its own set of genetic mutations and drivers. Orthosteric inhibitors, which target the active site of proteins, have had some success, but thay face limitations, particularly with proteins that lack a clearly defined active site or when selectivity is an issue. Allosteric inhibition offers an innovative strategy by targeting a site distinct from the active site, possibly achieving better selectivity and efficacy. Additionally, many active site inhibitors exhibited poor bioavailability, making the allosteric approach an attractive one.

SHP2: Exploring a Critical Cancer Target

Archyde Editor: Could you elaborate on the role of SHP2 in cancer, and why itS such a compelling target for therapy?

Dr. Sharma: SHP2, encoded by the PTPN11 gene, is a pleiotropic protein tyrosine phosphatase. Think of it as a master regulator in multiple cell-signaling pathways, including JAK/STAT, PI3K/AKT, and RAS/RAF/ERK.It’s like a switch that, when malfunctioning due to mutations, can drive uncontrolled cell growth, reduce apoptosis, and promote tumor growth. The impact that SHP2 variants have on multiple types of cancer and tumors, making it a critical target.

Allosteric Inhibition and SHP2 Degradation: A Promising Strategy

Archyde Editor: Your research focuses on SHP2 degradation through allosteric inhibition. Can you explain the advantages of this approach compared to traditional methods?

Dr. Sharma: Absolutely.Active-site inhibitors, in some cases, have lacked specificity, potentially affecting other vital proteins. The method of allosteric inhibitors on the SHP2 protein degradation is novel. Targeting SHP2 degradation offers the potential of more specific action. By using compounds that induce conformational changes in the protein, we can effectively “tag” SHP2 for degradation within the cell, effectively getting rid of it.Results also show that having SHP2 expression will dictate the success the candidate drug will have. This allows for a more notable impact on cancer cells with SHP2 overexpression, where the rogue SHP2 is most actively contributing to cancer growth.

Key Findings and Implications for Personalized Medicine

Archyde Editor: your work shows it can be a significant marker for the success and effectiveness of a drug. What are the current implications of this for patient treatment and clinical practice?

Dr. Sharma: “Yes, we found that SHP2 expression levels can suggest the type of treatment a patient may respond to. In cell lines where we saw high SHP2 expression were correlated to drug effectiveness. Conversely, tumors with lower SHP2 expression can actually upregulate expression and become more resistant to the drug. It’s a very vital indicator. Personalized medicine should use SHP2 expression levels to determine a treatment strategy specific to each patient. If we understand the patient’s tumor’s expression and the type of SHP2 tumor they have, will determine the best chances of success or treatment.

Future directions and The Road Ahead

Archyde Editor: What are the next steps in this research, and what are your hopes for the future of cancer treatment based on your findings?

Dr. Sharma: We’re now focusing on further research of the current compounds and what the mechanics are. Through many different platforms, we want to understand them more. Clinical trials will be important in evaluating the safety and efficacy in patients.

Archyde editor: Dr. Sharma, thank you for shedding light on such critical research. It’s a very exciting time in cancer therapy,and we hope these latest developments will offer new options for those facing cancer with their treatment.

Call For Reader Comments and Questions

Archyde Editor: What are your thoughts on the potential of SHP2-targeting therapies? Are you optimistic about the future of personalized medicine in cancer treatment? Share your comments and questions below!