K-Ras Isoform A (G12C mutant; human, recombinant)

K-Ras is a small GTPase and member of the RAS family of GTPases with roles in apoptosis, as well as cell proliferation, survival, and migration.^1,2 K-Ras is composed of a guanine nucleotide binding domain containing an active site, an effector binding domain, and an isoform-specific C-terminal hypervariable region, which varies by four amino acids between isoforms A and B.^1,3 The active site cycles between GDP-bound inactive and GTP-bound active states and is regulated by its associations with GTPase-activating proteins (GAPs) or guanine nucleotide exchange factors (GEFs).^3,4 K-Ras is ubiquitously expressed and is tethered to the intracellular side of cell membranes via farnesyl and palmitoyl lipidation.^1,5 The glycine-to-cysteine substitution at position 12 mutant K-Ras (K-Ras^G12C) is constitutively active and found in pancreatic, colon, and lung cancers.^6,2 Inhibition of K-Ras^G12C with a cysteine-targeted inhibitor ARS1620 (Item No. 27915) reduces tumor volume in K-Ras^G12C-expressing, but not K-Ras^G12V-expressing, MiaPaCa-2 pancreatic cancer mouse xenograft models.⁷ Tumor levels of K-Ras^G12C are increased in patients with lung adenocarcinoma who reported to be former or current smokers.⁸ Cayman's K-Ras Isoform A (G12C mutant; human, recombinant) consists of 185 amino acids and has a calculated molecular weight of 23 kDa. By SDS-PAGE, the apparent molecular mass of the protein is 25-26 kDa due to glycosylation.

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1. Nussinov, R., Tsai, C.-J., Chakrabarti, M., et al. A new view of Ras isoforms in cancers. Cancer Res. 76(1), 18-23 (2016).

2. Padavano, J., Henkhaus, R.S., Chen, J., et al. Mutant K^-RAS promotes invasion and metastasis in pancreatic cancer through GTPase signaling pathways. Cancer Growth Metastasis 8 (Suppl 1), 95-113 (2015).

3. Hillig, R.C., Sautier, B., Schroeder, J., et al. Discovery of potent SOS1 inhibitors that block RAS activation via disruption of the RAS-SOS1 interaction. Proc. Natl. Acad. Sci. USA 116(7), 2551-2560 (2019).

4. Sermon, B.A., Eccleston, J.F., Skinner, R.H., et al. Mechanism of inhibition by arachidonic acid of the catalytic activity of ras GTPase-activating proteins. The Journal of Biological Chemisty 271(3), 1566-1572 (1996).

5. Salim, A.A., Tan, L., Huang, X.-C., et al. Oligomycins as inhibitors of K-Ras plasma membrane localisation. Org. Biomol. Chem. 14(2), 711-715 (2016).

6. Hallin, J., Engstrom, L.D., Hargis, L., et al. The KRASG12C inhibitor MRTX849 provides insight toward therapeutic susceptibility of KRAS-mutant cancers in mouse models and patients. Cancer Discov. 10(1), 54-71 (2020).

7. Janes, M.R., Zhang, J., Li, L.-S., et al. Targeting KRAS mutant cancer cells with a covalent G12C-specific inhibitor. Cell 172(3), 578-589 (2018).

8. Dogan, S., Shen, R., Ang, D.C., et al. Molecular epidemiology of EGFR and KRAS mutations in 3,026 lung adenocarcinomas: Higher susceptibility of women to smoking-related KRAS-mutant cancers. Clin. Cancer Res. 18(22), 6169-6177 (2012).