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Gene and Protein Information ![]() |
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Species | TM | AA | Chromosomal Location | Gene Symbol | Gene Name | Reference |
Human | - | 189 | 12p12.1 | KRAS | KRAS proto-oncogene, GTPase | |
Mouse | - | 189 | 6 77.37 cM | Kras | Kirsten rat sarcoma viral oncogene homolog | |
Rat | - | 189 | 4q44 | Kras | KRAS proto-oncogene, GTPase | |
Gene and Protein Information Comments | ||||||
Human KRAS has two isoforms. The prediminant isoform (b) is the 188 amino acid protein (NP_004976), isoform a is 189 amino acids long. |
Database Links ![]() |
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Alphafold | P01116 (Hs), P32883 (Mm), P08644 (Rn) |
ChEMBL Target | CHEMBL2189121 (Hs) |
Ensembl Gene | ENSG00000133703 (Hs), ENSMUSG00000030265 (Mm), ENSRNOG00000009338 (Rn) |
Entrez Gene | 3845 (Hs), 16653 (Mm), 24525 (Rn) |
Human Protein Atlas | ENSG00000133703 (Hs) |
KEGG Gene | hsa:3845 (Hs), mmu:16653 (Mm), rno:24525 (Rn) |
OMIM | 190070 (Hs) |
Pharos | P01116 (Hs) |
RefSeq Nucleotide | NM_033360 (Hs), NM_004985 (Hs), NM_021284 (Mm), NM_031515 (Rn) |
RefSeq Protein | NP_203524 (Hs), NP_004976 (Hs), NP_067259 (Mm), NP_113703 (Rn) |
UniProtKB | P01116 (Hs), P32883 (Mm), P08644 (Rn) |
Wikipedia | KRAS (Hs) |
Selected 3D Structures ![]() |
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Download all structure-activity data for this target as a CSV file
Inhibitors | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Key to terms and symbols | View all chemical structures | Click column headers to sort | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Eli Lilly's Phase 1/2 KRASG12C lead LY3499446 (NCT04165031) [14] was dropped from the company pipeline in 2020 due to toxicity problems. |
Allosteric Modulators | |||||||||||||||||||||||||||||||||||||||||||||||||||
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Immuno Process Associations | ||||||||||||
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Clinically-Relevant Mutations and Pathophysiology ![]() |
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General Comments |
Somatic activating mutations in KRAS are extensively found in leukemias [3,21], colon cancer [4,17], pancreatic cancer [1,5] and lung cancer [6,19]. The single amino acid substitution replacing glycine at position 12 with cysteine is a common oncogenic KRAS mutation, as are substitutions at Gly12 (G12C) and Glu61 (G61C) [18]. The search for small molecule inhibitors of activated KRAS with anticancer activity is intense [2,8,16]. |
1. Almoguera C, Shibata D, Forrester K, Martin J, Arnheim N, Perucho M. (1988) Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes. Cell, 53 (4): 549-54. [PMID:2453289]
2. Baines AT, Xu D, Der CJ. (2011) Inhibition of Ras for cancer treatment: the search continues. Future Med Chem, 3 (14): 1787-808. [PMID:22004085]
3. Braun BS, Shannon K. (2008) Targeting Ras in myeloid leukemias. Clin Cancer Res, 14 (8): 2249-52. [PMID:18413813]
4. Burmer GC, Loeb LA. (1989) Mutations in the KRAS2 oncogene during progressive stages of human colon carcinoma. Proc Natl Acad Sci USA, 86 (7): 2403-7. [PMID:2648401]
5. Collins MA, Pasca di Magliano M. (2013) Kras as a key oncogene and therapeutic target in pancreatic cancer. Front Physiol, 4: 407. [PMID:24478710]
6. Cooper WA, Lam DC, O'Toole SA, Minna JD. (2013) Molecular biology of lung cancer. J Thorac Dis, 5 Suppl 5: S479-90. [PMID:24163741]
7. Fell JB, Fischer JP, Baer BR, Blake JF, Bouhana K, Briere DM, Brown KD, Burgess LE, Burns AC, Burkard MR et al.. (2020) Identification of the Clinical Development Candidate MRTX849, a Covalent KRASG12C Inhibitor for the Treatment of Cancer. J Med Chem,. [PMID:32250617]
8. Hansen R, Peters U, Babbar A, Chen Y, Feng J, Janes MR, Li LS, Ren P, Liu Y, Zarrinkar PP. (2018) The reactivity-driven biochemical mechanism of covalent KRASG12C inhibitors. Nat Struct Mol Biol, 25 (6): 454-462. [PMID:29760531]
9. Janes MR, Zhang J, Li LS, Hansen R, Peters U, Guo X, Chen Y, Babbar A, Firdaus SJ, Darjania L et al.. (2018) Targeting KRAS Mutant Cancers with a Covalent G12C-Specific Inhibitor. Cell, 172 (3): 578-589.e17. [PMID:29373830]
10. Kettle JG, Bagal SK, Bickerton S, Bodnarchuk MS, Boyd S, Breed J, Carbajo RJ, Cassar DJ, Chakraborty A, Cosulich S et al.. (2022) Discovery of AZD4625, a Covalent Allosteric Inhibitor of the Mutant GTPase KRASG12C. J Med Chem, [Epub ahead of print]. DOI: 10.1021/acs.jmedchem.2c00369 [PMID:35471939]
11. Kettle JG, Bagal SK, Bickerton S, Bodnarchuk MS, Breed J, Carbajo RJ, Cassar DJ, Chakraborty A, Cosulich S, Cumming I et al.. (2020) Structure-Based Design and Pharmacokinetic Optimization of Covalent Allosteric Inhibitors of the Mutant GTPase KRASG12C. J Med Chem, 63 (9): 4468-4483. [PMID:32023060]
12. Lanman BA, Allen JR, Allen JG, Amegadzie AK, Ashton KS, Booker SK, Chen JJ, Chen N, Frohn MJ, Goodman G et al.. (2020) Discovery of a Covalent Inhibitor of KRASG12C (AMG 510) for the Treatment of Solid Tumors. J Med Chem, 63 (1): 52-65. [PMID:31820981]
13. Liu M, Bryant MS, Chen J, Lee S, Yaremko B, Lipari P, Malkowski M, Ferrari E, Nielsen L, Prioli N et al.. (1998) Antitumor activity of SCH 66336, an orally bioavailable tricyclic inhibitor of farnesyl protein transferase, in human tumor xenograft models and wap-ras transgenic mice. Cancer Res, 58 (21): 4947-56. [PMID:9810004]
14. Nagasaka M, Li Y, Sukari A, Ou SI, Al-Hallak MN, Azmi AS. (2020) KRAS G12C Game of Thrones, which direct KRAS inhibitor will claim the iron throne?. Cancer Treat Rev, 84: 101974. [PMID:32014824]
15. Nakayama A, Nagashima T, Nishizono Y, Kuramoto K, Mori K, Homboh K, Yuri M, Shimazaki M. (2021) Characterisation of a novel KRAS G12C inhibitor ASP2453 that shows potent anti-tumour activity in KRAS G12C-mutated preclinical models. Br J Cancer, [Epub ahead of print]. DOI: 10.1038/s41416-021-01629-x [PMID:34795410]
16. O'Bryan JP. (2019) Pharmacological targeting of RAS: Recent success with direct inhibitors. Pharmacol Res, 139: 503-511. [PMID:30366101]
17. Rasool S, Rasool V, Naqvi T, Ganai BA, Shah BA. (2014) Genetic unraveling of colorectal cancer. Tumour Biol, 35 (6): 5067-82. [PMID:24573608]
18. Spiegel J, Cromm PM, Zimmermann G, Grossmann TN, Waldmann H. (2014) Small-molecule modulation of Ras signaling. Nat Chem Biol, 10 (8): 613-22. [PMID:24929527]
19. Tam IY, Chung LP, Suen WS, Wang E, Wong MC, Ho KK, Lam WK, Chiu SW, Girard L, Minna JD et al.. (2006) Distinct epidermal growth factor receptor and KRAS mutation patterns in non-small cell lung cancer patients with different tobacco exposure and clinicopathologic features. Clin Cancer Res, 12 (5): 1647-53. [PMID:16533793]
20. Wang X, Allen S, Blake JF, Bowcut V, Briere DM, Calinisan A, Dahlke JR, Fell JB, Fischer JP, Gunn RJ et al.. (2021) Identification of MRTX1133, a Noncovalent, Potent, and Selective KRASG12D Inhibitor. J Med Chem, [Epub ahead of print]. DOI: 10.1021/acs.jmedchem.1c01688 [PMID:34889605]
21. Yoshida N, Doisaki S, Kojima S. (2012) Current management of juvenile myelomonocytic leukemia and the impact of RAS mutations. Paediatr Drugs, 14 (3): 157-63. [PMID:22480363]