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

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KRAS

Target id: 2824

Nomenclature: KRAS

Family: RAS subfamily

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
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)
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
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:  9
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of MRTX849 bound to KRASG12C.
PDB Id:  6UT0
Ligand:  MRTX849
Resolution:  1.94Å
Species:  Human
References:  7
Image of receptor 3D structure from RCSB PDB
Description:  KRasG12C ligand complex
PDB Id:  6T5B
Ligand:  compound 25 [PMID: 32023060]
Resolution:  1.37Å
Species:  Human
References:  10

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
MRTX849 Hs Inhibition 5.4 pKi 7
⤷ pKi 5.4 (Ki 3.7x10-6 M) [7]
compound 25 [PMID: 32023060] Hs Inhibition >8.3 pIC50 10
⤷ pIC50 >8.3 (IC50 <5x10-9 M) [10]
Description: Inhibition of KRASG12C in vitro.
lonafarnib Hs Inhibition 8.3 pIC50 12
⤷ pIC50 8.3 (IC50 5.2x10-9 M) [12]
Description: Measuring inhibition of farnesylation of KRAS4B by human farnesyltransferase
ARS-1620 Hs Inhibition 6.9 pIC50 9
⤷ pIC50 6.9 (IC50 1.2x10-7 M) [9]
Description: Inhibition of KRAS G12C signalling in vitro.
AMG510 Hs Inhibition - - 11
⤷ [11]
Description: Selectively inhibits KRASG12C.
Inhibitor Comments
Eli Lilly's Phase 1/2 KRASG12C lead LY3499446 (NCT04165031) [13] was dropped from the company pipeline in 2020 due to toxicity problems.
Immuno Process Associations
Immuno Process:  Inflammation
GO Annotations:  Associated to 1 GO processes
GO:0002223 stimulatory C-type lectin receptor signaling pathway TAS
Immuno Process:  Immune regulation
GO Annotations:  Associated to 1 GO processes
GO:0002223 stimulatory C-type lectin receptor signaling pathway TAS
Immuno Process:  Cellular signalling
GO Annotations:  Associated to 1 GO processes
GO:0002223 stimulatory C-type lectin receptor signaling pathway TAS
Immuno Process:  Cytokine production & signalling
GO Annotations:  Associated to 1 GO processes, IEA only
click arrow to show/hide IEA associations
GO:0019221 cytokine-mediated signaling pathway IEA
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 [3,18], colon cancer [4,15], pancreatic cancer [1,5] and lung cancer [6,17]. 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) [16]. The search for small molecule inhibitors of activated KRAS with anticancer activity is intense [2,8,14].

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. 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, 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]

11. 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]

12. 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]

13. 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]

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

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

16. 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]

17. 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]

18. 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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