KRAS mutations are well-known to be associated with poor prognosis for various types of cancers, especially in the cases of pancreatic cancer, lung cancer, and colorectal cancer. Furthermore, KRAS mutants were once considered “undruggable” due to their intrinsic properties. This is where structure-based drug design (SBDD) plays an important role. Due to the discovery of a new allosteric site for KRAS G12C mutant in 2013 and the subsequent design of inhibitors with the aid of x-ray crystallography (Ostrem et al., 2013, 2016), KRAS mutants, at least G12C mutant, are now considered druggable, giving hope to researchers and patients alike. Kessler et al. also used a structure-based drug design approach to uncover a non-specific KRAS inhibitor that binds to a pocket between switch I and II on both active and inactive KRAS in 2019 (Kessler et al., 2019).

Scientists at Aurora Biolabs, a company of Structure Based Design, had been instrumental in the screening and co-crystallization of complexes for the identification of a KRAS G12D inhibitor (Wang et al., 2022, Mirati Therapeutics). The G12D mutation is the most common mutation, among KRAS mutations, responsible for pancreatic cancer.

The success of the Mirati Therapeutics project attests to the ability of Aurora Biolabs to provide a ONE-STOP solution from production of crystallography-grade proteins to assay development to screening to co-crystallization and analysis for drug discovery. Visit our Services for more information or Contact Us.

Wang, X. et al. Identification of MRTX1133, a noncovalent, potent, and selective KRAS G12D inhibitor. J. Med. Chem. 65, 3123-3133 (2022).

Kessler, D. et al. Drugging an undruggable pocket on KRAS. Proc. Natl Acad. Sci. USA 116, 15823–15829 (2019).

Ostrem, J. M. & Shokat, K. M. Direct small-molecule inhibitors of KRAS: from structural insights to mechanism-based design. Nat. Rev. Drug Disco. 15, 771–785 (2016).

Ostrem, J. M. et al. K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature 503, 548–551 (2013)