KRAS | RAS subfamily | IUPHAR/MMV Guide to MALARIA PHARMACOLOGY

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KRAS

Target id: 2824

Nomenclature: KRAS

Family: RAS subfamily

Annotation status:  image of a grey circle Awaiting annotation/under development. Please contact us if you can help with annotation.  » Email us

Contents:

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 188 12p12.1 KRAS KRAS proto-oncogene, GTPase
Mouse - 188 6 G2 Kras Kirsten rat sarcoma viral oncogene homolog
Rat - 188 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.
Previous and Unofficial Names
KRAS2 | v-Ki-ras2 | v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog | Kirsten rat sarcoma viral oncogene homolog | Kirsten rat sarcoma viral oncogene | KRAS proto-oncogene, GTPase | KRAS proto-oncogene
Database Links
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)
RefSeq Nucleotide NM_004985 (Hs), NM_033360 (Hs), NM_021284 (Mm), NM_031515 (Rn)
RefSeq Protein NP_004976 (Hs), NP_203524 (Hs), NP_067259 (Mm), NP_113703 (Rn)
UniProtKB P01116 (Hs), P32883 (Mm), P08644 (Rn)
Wikipedia KRAS (Hs)
Selected 3D Structures
Image of receptor 3D structure from RCSB PDB
Description:  Crystal Structure of small molecule ARS-1620 covalently bound to K-Ras G12C.
PDB Id:  5V9U
Ligand:  ARS-1620
Resolution:  1.38Å
Species:  Human
References:  8

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
Ligand Sp. Action Value Parameter Reference
lonafarnib Hs Inhibition 8.3 pIC50 9
⤷ pIC50 8.3 (IC50 5.2x10-9 M) [9]
Description: Measuring inhibition of farnesylation of KRAS4B by human farnesyltransferase
ARS-1620 Hs Inhibition 6.9 pIC50 8
⤷ pIC50 6.9 (IC50 1.2x10-7 M) [8]
Description: Inhibition of KRAS G12C signalling in vitro.
Clinically-Relevant Mutations and Pathophysiology
Disease:  Acute myeloid leukemia
Synonyms: Acute myelogenous leukemia
Disease Ontology: DOID:9119
OMIM: 601626
Orphanet: ORPHA519
Disease:  Bladder cancer
Disease Ontology: DOID:11054
OMIM: 109800
Disease:  Breast cancer
Disease Ontology: DOID:1612
OMIM: 114480
Disease:  Cardiofaciocutaneous syndrome 2; CFC2
Synonyms: Cardiofaciocutaneous syndrome [Orphanet: ORPHA1340]
OMIM: 615278
Orphanet: ORPHA1340
Disease:  Familial pancreatic carcinoma
Synonyms: Pancreatic cancer [OMIM: 260350]
Pancreatic carcinoma [Disease Ontology: DOID:4905]
Disease Ontology: DOID:4905
OMIM: 260350
Orphanet: ORPHA1333
Disease:  Gastric cancer, hereditary diffuse; HDGC
OMIM: 137215
Disease:  Juvenile myelomonocytic leukemia; JMML
Disease Ontology: DOID:0050458
OMIM: 607785
Orphanet: ORPHA86834
Disease:  Lung cancer
Disease Ontology: DOID:1324
OMIM: 211980
Disease:  Noonan syndrome 3; NS3
Synonyms: Noonan syndrome [Orphanet: ORPHA648] [Disease Ontology: DOID:3490]
Disease Ontology: DOID:3490
OMIM: 609942
Orphanet: ORPHA648
Disease:  Schimmelpenning-Feuerstein-Mims syndrome; SFM
Synonyms: Linear nevus sebaceus syndrome [Orphanet: ORPHA2612]
OMIM: 163200
Orphanet: ORPHA2612
General Comments
Somatic activating mutations in KRAS are extensively found in leukemias [3,14], colon cancer [4,11], pancreatic cancer [1,5] and lung cancer [6,13]. The single amino acid substitution replacing glycine at position 12 with cysteine is a common oncogenic KRAS mutation, as are substitutions at Gly12 and Glu61 [12]. The search for small molecule inhibitors of activated KRAS with anticancer activity is intense [2,7,10].

References

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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. U.S.A., 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. 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]

8. 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]

9. 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]

10. O'Bryan JP. (2019) Pharmacological targeting of RAS: Recent success with direct inhibitors. Pharmacol. Res., 139: 503-511. [PMID:30366101]

11. Rasool S, Rasool V, Naqvi T, Ganai BA, Shah BA. (2014) Genetic unraveling of colorectal cancer. Tumour Biol., 35 (6): 5067-82. [PMID:24573608]

12. 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]

13. 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]

14. 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]

Contributors

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