RET inhibitors are a class of targeted therapies designed to inhibit the activity of the RET proto-oncogene. Alfa Cytology's innovative solutions are designed to support the development of RET inhibitors for pancreatic cancer by addressing all phases of the drug development process, and providing expertise and resources to facilitate the translation of research results into potential therapeutic agents.
Introduction to RET and Its Signaling Pathway
RET (rearranged during transfection) protein belongs to the transmembrane receptor tyrosine kinase family, and this protein is activated by binding to ligands of the glial cell line-derived neurotrophic factor (GDNF) family. These ligands include GDNF, neurturin, artemin, and persephin. This activation initiates several signaling cascades involved in the regulation of cell growth, differentiation, and survival:
- MAPK/ERK Pathway
- PI3K/AKT Pathway
- JAK/STAT Pathway
- PLCγ Pathway
RET protein can become an oncogenic driver when constitutively activated as a result of rearrangements and point mutations. This has been linked to a variety of hereditary and sporadic cancers, highlighting RET's importance as a therapeutic target.
Fig. 1 Canonical RET signaling. (Regua A T, et al, 2022)
RET Inhibitor for Pancreatic Cancer
Pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer, often exhibits poor prognosis due to late diagnosis and limited therapeutic options. given the aggressiveness of pancreatic cancer, a malignant tumor, and its resistance to conventional therapy, RET inhibitors have shown efficacy in overcoming resistance mechanisms that limit the effectiveness of conventional therapies. By targeting RET pathways, these inhibitors offer a novel approach to curtailing tumor growth and improving patient outcomes.
Mechanism of RET Inhibitor
Inhibition of RET Kinase Activity
RET inhibitors bind to the ATP-binding site of the RET kinase domain, blocking its activation and thereby halting tumor growth and inducing apoptosis in cancer cells.
Disruption of RET Fusion Proteins
RET inhibitors target and neutralize RET fusion proteins, reducing their oncogenic activity and tumor progression.
Suppression of RET-Mediated Signaling Pathways
RET inhibitors interfere with downstream signaling pathways like RAS/MAPK, PI3K/AKT, and JAK/STAT, leading to decreased tumor cell viability and invasiveness.
Our Services
With expertise in preclinical research in pancreatic cancer, Alfa Cytology' is committed to providing optimal solutions for the development of RET inhibitors for pancreatic cancer (PC), with the aim of delivering targeted and innovative therapies against pancreatic cancer at all levels of pathology and supporting the development of targeted therapies.
Molecule Types for RET Inhibitor Development
Alfa Cytology targets the key molecular mechanisms and pathways associated with pancreatic cancer, aiming to provide targeted therapy development services across multiple molecule types to inhibit RET activity and disrupt cancer progression.
Low molecular weight, easily penetrates cells and specifically inhibits the kinase activity of the RET receptor by competing with ATP for binding.
Targets the extracellular structural domain of the RET receptor, thereby inhibiting its activation.
Simultaneously targeting RET and another pathway involved in cancer progression may provide stronger inhibition.
RNAi and ASOs can be designed to specifically downregulate RET expression at the mRNA level, reducing the production of the RET protein.
Antibody-Drug Conjugates (ADCs)
The antibody component targets the RET receptor and delivers the attached cytotoxic agent directly to pancreatic cancer cells.
Our Advantages
Comprehensive In Vivo Models
Developing robust in vivo models, to evaluate the therapeutic potential of RET inhibitors in a physiologically relevant setting.
Expertise in Computational Modeling
Leveraging sophisticated computational tools and molecular docking studies to optimize lead compounds.
State-of-the-Art Screening Platforms
Utilizing cutting-edge screening technologies to accelerate drug discovery and identify high-potential candidates efficiently.
Integrated PK/PD Studies
Conducting integrated pharmacokinetic and pharmacodynamic studies to understand the ADME profiles of RET inhibitors and inform dose optimization.
Alfa Cytology offers a comprehensive suite of preclinical services for the development of RET inhibitors targeting pancreatic cancer. These services encompass high-throughput screening, molecular docking, in vitro and in vivo testing, and PK/PD studies. The structured development process ensures thorough evaluation and optimization of RET inhibitors. In addition, we also provide more targeted therapy development for pancreatic cancer, such as metabolic inhibitor, cancer stem cells inhibitor, tumor-associated macrophage modulator. For inquiries or to learn more about how we can support your research project, please contact us.
Reference
- Regua A T, et al. RET signaling pathway and RET inhibitors in human cancer. Frontiers in Oncology. 2022, 12: 932353.
