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KRAS

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Target id: 2824

Nomenclature: KRAS

Family: RAS subfamily

Contents:

Gene and Protein Information Click here for help
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.
Previous and Unofficial Names Click here for help
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 Click here for help
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_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 Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of MRTX849 bound to KRASG12C.
PDB Id:  6UT0
Ligand:  adagrasib
Resolution:  1.94Å
Species:  Human
References:  9
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:  14
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:  11
Image of receptor 3D structure from RCSB PDB
Description:  KRAS G12D in complex with MRTX-1133
PDB Id:  7RPZ
Ligand:  MRTX1133
Resolution:  1.3Å
Species:  Human
References:  28
Image of receptor 3D structure from RCSB PDB
Description:  CRYSTAL STRUCTURE OF KRAS-G12C IN COMPLEX WITH COMPOUND 23 (BI-0474)
PDB Id:  8AFB
Ligand:  BI-0474
Resolution:  1.12Å
Species:  Human
References:  3

Download all structure-activity data for this target as a CSV file go icon to follow link

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
MRTX1133 Small molecule or natural product Ligand has a PDB structure Hs Inhibition 12.7 pKd 28
⤷ pKd 12.7 (Kd 2x10-13 M) [28]
Description: In vitro binding affinity for hKRASG12D by SPR
LUNA18 Peptide Hs Inhibition 10.4 pKd 27
⤷ pKd 10.4 (Kd 4.3x10-11 M) [27]
Description: Binding affinity for KRASG12D
BI-2493 Small molecule or natural product Ligand has a PDB structure Hs Inhibition ~8.0 pKd 15
⤷ pKd ~8.0 (Kd ~1x10-8 M) [15]
Description: Binding affinity for WT hKRAS
RMC-6236 Small molecule or natural product Hs Inhibition 6.4 – 6.9 pKd 12
⤷ pKd 6.9 (Kd 1.31x10-7 M) [12]
Description: Binding affinity of the RMC-6236/CypA binary complex for mutated KRASG12V
pKd 6.8 (Kd 1.54x10-7 M) [12]
Description: Binding affinity of the RMC-6236/CypA binary complex for WT human KRAS
pKd 6.4 (Kd 3.64x10-7 M) [12]
Description: Binding affinity of the RMC-6236/CypA binary complex for mutated KRASG12C
BI-0474 Small molecule or natural product Ligand has a PDB structure Hs Inhibition 8.6 pKi 3
⤷ pKi 8.6 (Ki 2.5x10-9 M) [3]
Description: Inhibition of KRASG12C by mass spectrometry
adagrasib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibition 5.4 pKi 9
⤷ pKi 5.4 (Ki 3.7x10-6 M) [9]
LUNA18 Peptide Hs Inhibition 8.9 pIC50 27
⤷ pIC50 8.9 (IC50 1.4x10-9 M) [27]
Description: Inhibition of AsPC-1 cell (pancreatic cancer cells with KRASG12D mutation) proliferation
ERAS-5024 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 8.4 – 9.1 pIC50 6
⤷ pIC50 9.1 (IC50 8.6x10-10 M) [6]
Description: Measuring inhibition of binding of KRAS G12D to RAF Ras binding domain
pIC50 8.4 (IC50 3.9x10-9 M) [6]
Description: Measuring inhibition of binding of wild type KRAS to RAF Ras binding domain
compound 25 [PMID: 32023060] Small molecule or natural product Hs Inhibition >8.3 pIC50 14
⤷ pIC50 >8.3 (IC50 <5x10-9 M) [14]
Description: Inhibition of KRASG12C in vitro.
lonafarnib Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 8.3 pIC50 18
⤷ pIC50 8.3 (IC50 5.2x10-9 M) [18]
Description: Measuring inhibition of farnesylation of KRAS4B by human farnesyltransferase
divarasib Small molecule or natural product Hs Inhibition >8.0 pIC50 19
⤷ pIC50 >8.0 (IC50 <1x10-8 M) [19]
Description: Inhibition of KRAS G12C of nucleotide exchange in the presence of the SOS1 GTP exchange factor, in a HTRF assay
opnurasib Small molecule or natural product Hs Inhibition 7.8 pIC50 17
⤷ pIC50 7.8 (IC50 1.7x10-8 M) [17]
Description: in vitro inhibition of radio-labelled probe binding to hKRASG12C
fulzerasib Small molecule or natural product Hs Inhibition 7.6 pIC50 31
⤷ pIC50 7.6 (IC50 2.5x10-8 M) [31]
Description: HTRF assay detecting repacement of GDP by GTP on the KRASG12C protein catalyzed by SOS1
ASP2453 Small molecule or natural product Hs Inhibition 7.4 pIC50 22
⤷ pIC50 7.4 (IC50 4x10-8 M) [22]
Description: Measuring inhibition of SOS-induced interaction between KRAS G12C and Raf.
ARS-1620 Small molecule or natural product Primary target of this compound Ligand has a PDB structure Hs Inhibition 6.9 pIC50 11
⤷ pIC50 6.9 (IC50 1.2x10-7 M) [11]
Description: Inhibition of KRAS G12C signalling in vitro.
sotorasib Small molecule or natural product Approved drug Hs Inhibition - - 16
⤷ [16]
Description: Selectively inhibits KRASG12C.
LY3499446 Small molecule or natural product Hs Inhibition - - 30
⤷ [30]
Description: Selective inhibitor of hKRASG12C
Inhibitor Comments
Eli Lilly's Phase 1/2 KRASG12C lead LY3499446 (NCT04165031) [21] was dropped from the company pipeline in 2020 due to toxicity problems.
Allosteric Modulators
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
AZD4625 Small molecule or natural product Ligand has a PDB structure Hs Negative 8.5 pIC50 13
⤷ pIC50 8.5 (IC50 3x10-9 M) [13]
Description: Negative modulation of KRASG12C in vitro
Immuno Process Associations
Immuno Process:  Inflammation
Immuno Process:  Immune regulation
Immuno Process:  Cellular signalling
Immuno Process:  Cytokine production & signalling
Clinically-Relevant Mutations and Pathophysiology Click here for help
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 [4,29], colon cancer [5,24], pancreatic cancer [1,7] and lung cancer [8,26]. The single amino acid substitution replacing glycine at position 12 with cysteine (G12C) is a common oncogenic KRAS mutation, as are other substitutions at Gly12 (G12D) and Glu61 (G61C) [25]. The search for small molecule inhibitors of activated KRAS with anticancer activity is intense [2,10,20,23].

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. Bröker J, Waterson AG, Smethurst C, Kessler D, Böttcher J, Mayer M, Gmaschitz G, Phan J, Little A, Abbott JR et al.. (2022) Fragment Optimization of Reversible Binding to the Switch II Pocket on KRAS Leads to a Potent, In Vivo Active KRASG12C Inhibitor. J Med Chem, 65 (21): 14614-14629. [PMID:36300829]

4. Braun BS, Shannon K. (2008) Targeting Ras in myeloid leukemias. Clin Cancer Res, 14 (8): 2249-52. [PMID:18413813]

5. 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]

6. Cheng H, Li P, Chen P, Irimia A, Bae JH, Brooun A, Fagan P, Lam R, Lin B, Zhang J et al.. (2023) Structure-Based Design and Synthesis of Potent and Selective KRAS G12D Inhibitors. ACS Med Chem Lett, 14 (10): 1351-1357. [PMID:37849557]

7. Collins MA, Pasca di Magliano M. (2013) Kras as a key oncogene and therapeutic target in pancreatic cancer. Front Physiol, 4: 407. [PMID:24478710]

8. 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]

9. 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]

10. 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]

11. 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]

12. Jiang J, Jiang L, Maldonato BJ, Wang Y, Holderfield M, Aronchik I, Winters IP, Salman Z, Blaj C, Menard M et al.. (2024) Translational and Therapeutic Evaluation of RAS-GTP Inhibition by RMC-6236 in RAS-Driven Cancers. Cancer Discov, 14 (6): 994-1017. [PMID:38593348]

13. 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, 65 (9): 6940-6952. [PMID:35471939]

14. 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]

15. Kim D, Herdeis L, Rudolph D, Zhao Y, Böttcher J, Vides A, Ayala-Santos CI, Pourfarjam Y, Cuevas-Navarro A, Xue JY et al.. (2023) Pan-KRAS inhibitor disables oncogenic signalling and tumour growth. Nature, 619 (7968): 160-166. [PMID:37258666]

16. 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]

17. Liu B, Cotesta S, Gerspacher M, Leblanc C, Lorthois ELJ, Machuaer R, Mah R, Mura C, Rigollier P, Schneider N et al.. (2021) Pyrazolyl derivatives useful as anti-cancer agents. Patent number: WO2021120890A1. Assignee: Novartis. Priority date: 20/12/2019. Publication date: 24/06/2021.

18. 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]

19. Malhotra S, Xin J, Do S, Terrett J. (2022) Fused ring compounds. Patent number: US11236068B2. Assignee: Pharmaron, Hoffmann La Foche (originally Genentech). Priority date: 09/11/2018. Publication date: 01/02/2022.

20. Mugarza E, van Maldegem F, Boumelha J, Moore C, Rana S, Llorian Sopena M, East P, Ambler R, Anastasiou P, Romero-Clavijo P et al.. (2022) Therapeutic KRASG12C inhibition drives effective interferon-mediated antitumor immunity in immunogenic lung cancers. Sci Adv, 8 (29): eabm8780. [PMID:35857848]

21. 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]

22. Nakayama A, Nagashima T, Nishizono Y, Kuramoto K, Mori K, Homboh K, Yuri M, Shimazaki M. (2022) Characterisation of a novel KRAS G12C inhibitor ASP2453 that shows potent anti-tumour activity in KRAS G12C-mutated preclinical models. Br J Cancer, 126 (5): 744-753. [PMID:34795410]

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

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

25. 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]

26. 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]

27. Tanada M, Tamiya M, Matsuo A, Chiyoda A, Takano K, Ito T, Irie M, Kotake T, Takeyama R, Kawada H et al.. (2023) Development of Orally Bioavailable Peptides Targeting an Intracellular Protein: From a Hit to a Clinical KRAS Inhibitor. J Am Chem Soc, 145 (30): 16610-16620. [PMID:37463267]

28. Wang X, Allen S, Blake JF, Bowcut V, Briere DM, Calinisan A, Dahlke JR, Fell JB, Fischer JP, Gunn RJ et al.. (2022) Identification of MRTX1133, a Noncovalent, Potent, and Selective KRASG12D Inhibitor. J Med Chem, 65 (4): 3123-3133. [PMID:34889605]

29. 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]

30. Yu S, Li B. (2022) Compound for inhibiting krasg12c mutant protein, preparation method therefor, and use thereof. Patent number: WO2022002018A1. Assignee: Suzhou Wentian Pharmaceutical Technology Co. Priority date: 03/07/2020. Publication date: 06/01/2022.

31. Zhou F, Jiang T, Lin C, Cai L, He W, Lan J. (2021) Substituted heterocyclic fused cyclic compound, preparation method therefor and pharmaceutical use thereof. Patent number: WO2021083167A1. Assignee: GENFLEET THERAPEUTICS (SHANGHAI) INC. Priority date: 30/10/2019. Publication date: 06/05/2021.

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