The Role of Crystallography-Grade Proteins in Advancing Structure-Based Drug Discovery

KRAS mutations have been a significant focus of cancer research for decades. These mutations affect a member of the RAS family of GTPases, which play a critical role in regulating cell division. The discovery of KRAS mutations dates back to the early 1980s when researchers first identified RAS oncogenes in human cancers. Since then, KRAS mutations have been strongly associated with poor prognosis in several cancers, including pancreatic, lung, and colorectal cancers (Cox et al., 2014; Stephen et al., 2014). Historically, KRAS mutants were labeled “undruggable” due to their challenging molecular properties, including the lack of well-defined binding pockets and their high affinity for GTP/GDP, which made targeting them with small molecules extremely difficult. However, structure-based drug design (SBDD) has transformed this landscape.
 

In the context of KRAS mutations, SBDD enabled the discovery of inhibitors targeting previously undruggable sites by leveraging structural information about the mutant protein's binding pocket. This approach offers significant advantages, including higher precision in drug design, reduced time and cost in lead optimization, and an increased likelihood of success by focusing on well-characterized binding sites. By providing a detailed understanding of the molecular interactions between the target and potential drug candidates, SBDD facilitates the rational design of compounds with improved efficacy and safety profiles.

In 2013, researchers discovered a novel allosteric site on the KRAS G12C mutant, leading to the development of effective inhibitors using x-ray crystallography.
 

Aurora Biolabs has played a critical role in the development of KRAS inhibitors through its expertise in SBDD. Notably, Aurora Biolabs' scientists were instrumental in the production, screening, and co-crystallization of complexes that led to the identification of a KRAS G12D inhibitor (Wang et al., 2022, Mirati Therapeutics). This mutation, KRAS G12D, is the most prevalent among KRAS mutations associated with pancreatic cancer.

The success of the Mirati Therapeutics project highlights Aurora Biolabs' comprehensive capabilities, offering a one-stop solution for drug discovery—from the production of crystallography-grade proteins to assay development, screening, co-crystallization, and data analysis. To learn more, visit our Services page or Contact Us for tailored solutions.

​References
Cox, A. D., et al. (2014). Drugging the undruggable RAS: Mission possible? Nature Reviews Drug Discovery, 13(11), 828-851.
Stephen, A. G., et al. (2014). Dragging Ras Back in the Ring. Cancer Cell 2014
Ostrem, J. M., et al. (2013). K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature, 503(7477), 548-551.
Jonathan M.L. Ostrem, and Kevan M. Shokat, et al. (2016). Targeting KRAS G12C with Covalent Inhibitors. Annual Review of Cancer Biology 6, pp. 49 - 64 (2022)
Kessler, D., et al. (2019). Drugging an undruggable pocket on KRAS. Proceedings of the National Academy of Sciences, 116(32), 15823-15829.
Wang, X., et al. (2022). Discovery of KRAS G12D inhibitors for the treatment of pancreatic cancer. Journal of Medicinal Chemistry, 65(5), 2456-2470.

 

Available Products

Crystallography-grade WT and mutant KRAS proteins and Assay Kits for your drug discovery campaigns:

Conclusion
The development of effective KRAS inhibitors, once deemed impossible, underscores the transformative power of structure-based drug design (SBDD). By leveraging advanced techniques such as X-ray crystallography and molecular modeling, researchers have identified novel binding sites and created inhibitors targeting previously undruggable KRAS mutations. Aurora Biolabs has been at the forefront of these efforts, offering a comprehensive suite of services, from producing crystallography-grade proteins to assay development and co-crystallization. These advancements not only open new avenues for cancer treatment but also highlight the importance of collaborative efforts in drug discovery. For researchers and pharmaceutical companies aiming to accelerate their drug development pipelines, Aurora Biolabs provides a trusted and capable partner in tackling the challenges of precision medicine. Additionally, all products described above are now available at BioHippo, enabling immediate access to high-quality KRAS proteins and assay kits to support your research.