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KRAS Inhibitor Development for Pancreatic Cancer
The development of KRAS inhibitors represents a promising avenue for the treatment of pancreatic cancer. Alfa Cytology's innovative solutions are designed to support the development of KRAS inhibitors for pancreatic cancer by addressing all phases of the drug development process, providing expertise and resources to facilitate the translation of research results into potential therapeutic agents.
Introduction to KRAS and Its Signaling Pathway
KRAS (Kirsten rat sarcoma virus), belongs to the Ras family of small GTPases, is a gene that provides instructions for making a protein called K-Ras, a part of the RAS/MAPK pathway. K-Ras plays a pivotal role in transmitting extracellular signals from cell surface receptors to the nucleus, influencing various cellular processes such as proliferation, differentiation, and survival. Mutations in KRAS, particularly single nucleotide substitutions, can lead to activating mutations. The resulting transforming proteins are associated with a variety of malignancies, including lung adenocarcinoma, mucinous adenoma, pancreatic ductal carcinoma, and colorectal cancer.
Fig. 1 Targeted agents for blocking KRAS signaling in pancreatic ductal adenocarcinoma. (Zhang J, et al, 2023)
KRAS Mutation Position and Mutant KRAS
KRAS mutations are a hallmark of pancreatic cancers, occurring in over 90% of cases. The majority of these mutations are found at specific positions within the KRAS gene, predominantly in codon 12. The most common mutations in the G12 position are G12D (36–45% of all mutations), G12V (28–39%), G12R (12–21%), and G12C (0–4%).
Fig. 2 KRAS mutation position and mutant KRAS allele in patients with pancreatic ductal adenocarcinoma. (de Jesus VHF, et al, 2023)
KRAS Inhibitor Development for Pancreatic Cancer
KRAS inhibitors are a class of targeted therapeutic agents those aim to block the downstream signaling pathways activated by KRAS mutations, thereby hindering tumor growth and progression. Studies have shown that the following KRAS inhibitors can effectively inhibit the mutated KRAS protein, leading to pancreatic tumor regression in preclinical models.
| KRAS Inhibitor | Target | Phase |
|---|---|---|
| Sotorasib (AMG 510) | KRAS G12C | |
| Adagrasib (MRTX849) | KRAS G12C | |
| MRTX1133 | KRAS G12D | |
| GDC-6036 | KRAS G12C | |
| ARS-1620 | KRAS G12C | |
| LY3499446 | KRAS G12C | |
| JAB-21822 | KRAS G12C | |
| D-1553 | KRAS G12C |
Our Services
With expertise in preclinical research in pancreatic cancer, Alfa Cytology offers optimal solutions for the development of KRAS inhibitors against pancreatic cancer (PC). We aim to support the development of targeted therapies by providing innovative solutions and expertise in KRAS mutation analysis, compound screening and inhibitor validation.
One-Stop Solutions for KRAS Inhibitor Development
In response to the latest advances in KRAS inhibitor research, Alfa Cytology currently offers the following specific service offerings. We will continue to roll out more relevant services, so please contact us for details.
KRAS Mutation Subtype-Specific Inhibitor Screening
Screening and optimizing inhibitors tailored to specific KRAS mutation subtypes (e.g., G12D, G12V, G12C) using high-throughput screening and structure-activity relationship analysis.
Allosteric KRAS Inhibitor Development
Identifying and optimizing allosteric inhibitors that target non-active site regions of the KRAS protein through advanced molecular modeling and structure-based drug design.
Co-targeting Strategies with KRAS Inhibitors
Exploring synergistic drug combinations with KRAS inhibitors to overcome resistance and enhance therapeutic efficacy through the combination of high-throughput screening and mechanistic studies.
Direct KRAS Inhibitors Development
We are exploring small molecules that directly bind to the KRAS protein, preventing its interaction with downstream effectors. This approach aims to block the oncogenic signaling at its source.
KRAS-Driven Pathway Inhibitors Development
KRAS mutations activate multiple downstream pathways, and we targeted key nodes in these pathways, such as RAF, MEK, and ERK, to assess the ability of inhibitors targeting these kinases to inhibit KRAS-driven tumor growth.
Biomarker-Driven Preclinical Validation
Identifying and validating biomarkers to predict response to KRAS inhibitors, using proteomic, transcriptomic, and metabolomic approaches in patient-derived xenografts and organoids.
Why Choose Us?
Tailored Solutions
Advanced Technology
Professional Expertise
Collaborative Approach
Leveraging extensive experience and cutting-edge technologies, Alfa Cytology collaborates with academic institutions, pharmaceutical companies, and biotech firms to facilitate the progression of potential therapeutic agents from discovery to preclinical validation. The goal is to enhance the understanding and application of KRAS inhibitors in treating pancreatic cancer, addressing a critical need in oncology research. In addition, we also provide more targeted therapy development for pancreatic cancer, such as immune checkpoint, cancer growth, cytokine and chemokine pathway, protein kinase. For more details about our services, please don't hesitate to contact us.
References
- Zhang J, et al. Targeting KRAS for the potential treatment of pancreatic ductal adenocarcinoma: Recent advancements provide hope. Oncology Reports. 2023, 50(5):1-16.
- de Jesus VHF, et al. Targeting KRAS in Pancreatic Ductal Adenocarcinoma: The Long Road to Cure. Cancers (Basel). 2023, 15(20):5015.
