IUPHAR/BPS Guide to Pharmacology CITE
https://doi.org/10.2218/gtopdb/F896/2025.3

3.6.5.2 Small monomeric GTPases in GtoPdb v.2025.3



Elena Faccenda1
  1. University of Edinburgh, UK


Abstract

Small G-proteins, are a family of hydrolase enzymes that can bind and hydrolyze guanosine triphosphate (GTP). They are a type of G-protein found in the cytosol that are homologous to the alpha subunit of heterotrimeric G-proteins, but unlike the alpha subunit of G proteins, a small GTPase can function independently as a hydrolase enzyme to bind to and hydrolyze a guanosine triphosphate (GTP) to form guanosine diphosphate (GDP). The best-known members are the Ras GTPases and hence they are sometimes called Ras subfamily GTPases.

Contents

This is a citation summary for 3.6.5.2 Small monomeric GTPases in the Guide to Pharmacology database (GtoPdb). It exists purely as an adjunct to the database to facilitate the recognition of citations to and from the database by citation analyzers. Readers will almost certainly want to visit the relevant sections of the database which are given here under database links.

GtoPdb is an expert-driven guide to pharmacological targets and the substances that act on them. GtoPdb is a reference work which is most usefully represented as an on-line database. As in any publication this work should be appropriately cited, and the papers it cites should also be recognized. This document provides a citation for the relevant parts of the database, and also provides a reference list for the research cited by those parts. For further details see [11].

Please note that the database version for the citations given in GtoPdb are to the most recent preceding version in which the family or its subfamilies and targets were substantially changed. The links below are to the current version. If you need to consult the cited version, rather than the most recent version, please contact the GtoPdb curators.

Database links

3.6.5.2 Small monomeric GTPases
https://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=896
    RAS subfamily
    https://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=897
    Introduction to RAS subfamily
    https://www.guidetopharmacology.org/GRAC/FamilyIntroductionForward?familyId=897
        Enzymes
                HRAS
                https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2822
                NRAS
                https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2823
                KRAS
                https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2824
                ARF GTPase 6
                https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=3324
    RAB subfamily
    https://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=938
        Enzymes
                RAB27A, member RAS oncogene family
                https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2916
                RAB32, member RAS oncogene family
                https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=3292

References

  1. Alessi DR and Pfeffer SR. (2024) Leucine-Rich Repeat Kinases. Annu Rev Biochem 93: 261-287 [PMID:38621236]
  2. Almoguera C, Shibata D, Forrester K, Martin J, Arnheim N and Perucho M. (1988) Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes. Cell 53: 549-54 [PMID:2453289]
  3. Baines AT, Xu D and Der CJ. (2011) Inhibition of Ras for cancer treatment: the search continues. Future Med Chem 3: 1787-808 [PMID:22004085]
  4. Bauer A, Amegadzie A, Smaligo A, Wigman B, Lanman BA, Mohr C, Emmetiere F, Stellwagen JC, Medina JH and Pettus LH et al.. (2024) Macrocyclic KRAS inhibitors and methods of use Patent number: WO2024107686A1. Assignee: Amgen Inc.. Priority date: 14/11/2023. Publication date: 23/05/2024.
  5. Bezniakow N, Gos M and Obersztyn E. (2014) The RASopathies as an example of RAS/MAPK pathway disturbances - clinical presentation and molecular pathogenesis of selected syndromes. Dev Period Med 18: 285-96 [PMID:25182392]
  6. Blum R, Jacob-Hirsch J, Amariglio N, Rechavi G and Kloog Y. (2005) Ras inhibition in glioblastoma down-regulates hypoxia-inducible factor-1alpha, causing glycolysis shutdown and cell death. Cancer Res 65: 999-1006 [PMID:15705901]
  7. Bos JL. (1989) ras oncogenes in human cancer: a review. Cancer Res 49: 4682-9 [PMID:2547513]
  8. Bröker J, Waterson AG, Smethurst C, Kessler D, Böttcher J, Mayer M, Gmaschitz G, Phan J, Little A and 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: 14614-14629 [PMID:36300829]
  9. Braun BS and Shannon K. (2008) Targeting Ras in myeloid leukemias. Clin Cancer Res 14: 2249-52 [PMID:18413813]
  10. Brzezinska AA, Johnson JL, Munafo DB, Crozat K, Beutler B, Kiosses WB, Ellis BA and Catz SD. (2008) The Rab27a effectors JFC1/Slp1 and Munc13-4 regulate exocytosis of neutrophil granules. Traffic 9: 2151-64 [PMID:18939952]
  11. Buneman P, Christie G, Davies JA, Dimitrellou R, Harding SD, Pawson AJ, Sharman JL and Wu Y. (2020) Why data citation isn't working, and what to do about it Database 2020 [PMID:32367113]
  12. Burmer GC and Loeb LA. (1989) Mutations in the KRAS2 oncogene during progressive stages of human colon carcinoma. Proc Natl Acad Sci USA 86: 2403-7 [PMID:2648401]
  13. Catz SD. (2014) The role of Rab27a in the regulation of neutrophil function. Cell Microbiol 16: 1301-10 [PMID:24964030]
  14. Cheng H, Li P, Chen P, Irimia A, Bae JH, Brooun A, Fagan P, Lam R, Lin B and Zhang J et al.. (2023) Structure-Based Design and Synthesis of Potent and Selective KRAS G12D Inhibitors. ACS Med Chem Lett 14: 1351-1357 [PMID:37849557]
  15. Collins MA and Pasca di Magliano M. (2013) Kras as a key oncogene and therapeutic target in pancreatic cancer. Front Physiol 4: 407 [PMID:24478710]
  16. Cooper WA, Lam DC, O'Toole SA and Minna JD. (2013) Molecular biology of lung cancer. J Thorac Dis 5 Suppl 5: S479-90 [PMID:24163741]
  17. Ebi H, Faber AC, Engelman JA and Yano S. (2014) Not just gRASping at flaws: finding vulnerabilities to develop novel therapies for treating KRAS mutant cancers. Cancer Sci 105: 499-505 [PMID:24612015]
  18. El Otmani H, Daghi M, Tahiri Jouti N and Lesage S. (2023) An overview of the worldwide distribution of LRRK2 mutations in Parkinson's disease. Neurodegener Dis Manag 13: 335-350 [PMID:38305913]
  19. Fell JB, Fischer JP, Baer BR, Blake JF, Bouhana K, Briere DM, Brown KD, Burgess LE, Burns AC and 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]
  20. Goitre L, Trapani E, Trabalzini L and Retta SF. (2014) The Ras superfamily of small GTPases: the unlocked secrets. Methods Mol Biol 1120: 1-18 [PMID:24470015]
  21. Hansen R, Peters U, Babbar A, Chen Y, Feng J, Janes MR, Li LS, Ren P, Liu Y and Zarrinkar PP. (2018) The reactivity-driven biochemical mechanism of covalent KRASG12C inhibitors. Nat Struct Mol Biol 25: 454-462 [PMID:29760531]
  22. Hop PJ, Lai D, Keagle PJ, Baron DM, Kenna BJ, Kooyman M, Shankaracharya, Halter C, Straniero L and Asselta R et al.. (2024) Systematic rare variant analyses identify RAB32 as a susceptibility gene for familial Parkinson's disease. Nat Genet 56: 1371-1376 [PMID:38858457]
  23. Janes MR, Zhang J, Li LS, Hansen R, Peters U, Guo X, Chen Y, Babbar A, Firdaus SJ and Darjania L et al.. (2018) Targeting KRAS Mutant Cancers with a Covalent G12C-Specific Inhibitor. Cell 172: 578-589.e17 [PMID:29373830]
  24. Jiang J, Jiang L, Maldonato BJ, Wang Y, Holderfield M, Aronchik I, Winters IP, Salman Z, Blaj C and Menard M et al.. (2024) Translational and Therapeutic Evaluation of RAS-GTP Inhibition by RMC-6236 in RAS-Driven Cancers. Cancer Discov 14: 994-1017 [PMID:38593348]
  25. Johnson JL, Monfregola J, Napolitano G, Kiosses WB and Catz SD. (2012) Vesicular trafficking through cortical actin during exocytosis is regulated by the Rab27a effector JFC1/Slp1 and the RhoA-GTPase-activating protein Gem-interacting protein. Mol Biol Cell 23: 1902-16 [PMID:22438581]
  26. Johnson JL, Ramadass M, He J, Brown SJ, Zhang J, Abgaryan L, Biris N, Gavathiotis E, Rosen H and Catz SD. (2016) Identification of Neutrophil Exocytosis Inhibitors (Nexinhibs), Small Molecule Inhibitors of Neutrophil Exocytosis and Inflammation: DRUGGABILITY OF THE SMALL GTPase Rab27a. J Biol Chem 291: 25965-25982 [PMID:27702998]
  27. Kettle JG, Bagal SK, Bickerton S, Bodnarchuk MS, Boyd S, Breed J, Carbajo RJ, Cassar DJ, Chakraborty A and Cosulich S et al.. (2022) Discovery of AZD4625, a Covalent Allosteric Inhibitor of the Mutant GTPase KRASG12C. J Med Chem 65: 6940-6952 [PMID:35471939]
  28. Kettle JG, Bagal SK, Bickerton S, Bodnarchuk MS, Breed J, Carbajo RJ, Cassar DJ, Chakraborty A, Cosulich S and Cumming I et al.. (2020) Structure-Based Design and Pharmacokinetic Optimization of Covalent Allosteric Inhibitors of the Mutant GTPase KRASG12C. J Med Chem 63: 4468-4483 [PMID:32023060]
  29. Kim D, Herdeis L, Rudolph D, Zhao Y, Böttcher J, Vides A, Ayala-Santos CI, Pourfarjam Y, Cuevas-Navarro A and Xue JY et al.. (2023) Pan-KRAS inhibitor disables oncogenic signalling and tumour growth. Nature 619: 160-166 [PMID:37258666]
  30. Komori T and Kuwahara T. (2023) An Update on the Interplay between LRRK2, Rab GTPases and Parkinson's Disease. Biomolecules 13 [PMID:38002327]
  31. Lanman BA, Allen JR, Allen JG, Amegadzie AK, Ashton KS, Booker SK, Chen JJ, Chen N, Frohn MJ and Goodman G et al.. (2020) Discovery of a Covalent Inhibitor of KRASG12C (AMG 510) for the Treatment of Solid Tumors. J Med Chem 63: 52-65 [PMID:31820981]
  32. Lanman BA, Wurz RP, Verma R, Osgood T, Gaida K, Mohn D, Chen YC, Diaz G and Saiki AY et al.. ND01 - AMG 410: An H/NRAS-sparing pan-KRAS inhibitor with dual GTP(on)/GDP(off)-state activity for the treatment of diverse KRAS-mutant tumors https://www.abstractsonline.com/pp8/#!/20273/presentation/7352. Accessed on 20/08/2025.
  33. Li Q, Xie K, Lin B and Gong Y. (2025) TBC1D24 promotes the progression of the breast cancer cells via ARF6/PLD axis under hypoxia. Sci Prog 108: 368504251367649 [PMID:40790967]
  34. Liu B, Cotesta S, Gerspacher M, Leblanc C, Lorthois ELJ, Machuaer R, Mah R, Mura C, Rigollier P and 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.
  35. Liu M, Bryant MS, Chen J, Lee S, Yaremko B, Lipari P, Malkowski M, Ferrari E, Nielsen L and 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: 4947-56 [PMID:9810004]
  36. Malhotra S, Xin J, Do S and 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.
  37. Mugarza E, van Maldegem F, Boumelha J, Moore C, Rana S, Llorian Sopena M, East P, Ambler R, Anastasiou P and Romero-Clavijo P et al.. (2022) Therapeutic KRASG12C inhibition drives effective interferon-mediated antitumor immunity in immunogenic lung cancers. Sci Adv 8: eabm8780 [PMID:35857848]
  38. Nagasaka M, Li Y, Sukari A, Ou SI, Al-Hallak MN and Azmi AS. (2020) KRAS G12C Game of Thrones, which direct KRAS inhibitor will claim the iron throne? Cancer Treat Rev 84: 101974 [PMID:32014824]
  39. Nakayama A, Nagashima T, Nishizono Y, Kuramoto K, Mori K, Homboh K, Yuri M and 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: 744-753 [PMID:34795410]
  40. Navarro E, Efthymiou AG, Parks M, Riboldi GM, Vialle RA, Udine E, Muller BZ, Humphrey J, Allan A and Argyrou CC et al.. (2024) LRRK2 G2019S variant is associated with transcriptional changes in Parkinson's disease human myeloid cells under proinflammatory environment. bioRxiv [PMID:38854101]
  41. O'Bryan JP. (2019) Pharmacological targeting of RAS: Recent success with direct inhibitors. Pharmacol Res 139: 503-511 [PMID:30366101]
  42. Ostrem JM, Peters U, Sos ML, Wells JA and Shokat KM. (2013) K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature 503: 548-51 [PMID:24256730]
  43. Rasool S, Rasool V, Naqvi T, Ganai BA and Shah BA. (2014) Genetic unraveling of colorectal cancer. Tumour Biol 35: 5067-82 [PMID:24573608]
  44. Rotblat B, Ehrlich M, Haklai R and Kloog Y. (2008) The Ras inhibitor farnesylthiosalicylic acid (Salirasib) disrupts the spatiotemporal localization of active Ras: a potential treatment for cancer. Meth Enzymol 439: 467-89 [PMID:18374183]
  45. Shi Z, Weng J, Niu H, Yang H, Liu R, Weng Y, Zhu Q, Zhang Y, Tao L and Wang Z et al.. (2023) D-1553: A novel KRASG12C inhibitor with potent and selective cellular and in vivo antitumor activity. Cancer Sci 114: 2951-2960 [PMID:37158138]
  46. Spiegel J, Cromm PM, Zimmermann G, Grossmann TN and Waldmann H. (2014) Small-molecule modulation of Ras signaling. Nat Chem Biol 10: 613-22 [PMID:24929527]
  47. Stanley LA. (1995) Molecular aspects of chemical carcinogenesis: the roles of oncogenes and tumour suppressor genes. Toxicology 96: 173-94 [PMID:7900159]
  48. Tam IY, Chung LP, Suen WS, Wang E, Wong MC, Ho KK, Lam WK, Chiu SW, Girard L and 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: 1647-53 [PMID:16533793]
  49. Tanada M, Tamiya M, Matsuo A, Chiyoda A, Takano K, Ito T, Irie M, Kotake T, Takeyama R and 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: 16610-16620 [PMID:37463267]
  50. Wang X, Allen S, Blake JF, Bowcut V, Briere DM, Calinisan A, Dahlke JR, Fell JB, Fischer JP and Gunn RJ et al.. (2022) Identification of MRTX1133, a Noncovalent, Potent, and Selective KRASG12D Inhibitor. J Med Chem 65: 3123-3133 [PMID:34889605]
  51. Wennerberg K, Rossman KL and Der CJ. (2005) The Ras superfamily at a glance. J Cell Sci 118: 843-6 [PMID:15731001]
  52. Xu H, Chen D, Lu J, Zhong L, Wang L and Ge J. (2025) ARF6 Promotes AML Progression via Activation of PI3K/AKT/mTOR Signaling. Cancer Med 14: e70872 [PMID:40275490]
  53. Yang Y, Qing L, You C, Li Q, Xu W and Dong Z. (2025) Methuosis key gene ARF6 as a diagnostic, prognostic and immunotherapeutic marker for prostate cancer: based on a comprehensive pan-cancer multi-omics analysis. Discov Oncol 16: 882 [PMID:40410613]
  54. Yoo JH, Shi DS, Grossmann AH, Sorensen LK, Tong Z, Mleynek TM, Rogers A, Zhu W, Richards JR and Winter JM et al.. (2016) ARF6 Is an Actionable Node that Orchestrates Oncogenic GNAQ Signaling in Uveal Melanoma. Cancer Cell 29: 889-904 [PMID:27265506]
  55. Yoshida N, Doisaki S and Kojima S. (2012) Current management of juvenile myelomonocytic leukemia and the impact of RAS mutations. Paediatr Drugs 14: 157-63 [PMID:22480363]
  56. Yu S and 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.
  57. Zhang C, Liu Y, Yuan X, Yang X, Yang B, Huang Y, Wang F, He Z and Li Y. (2025) Identification and validation of ARF6 for a potential prognostic biomarker of acute myeloid leukemia. Cancer Cell Int 25: 218 [PMID:40542378]
  58. Zhang J and Lodish HF. (2007) Endogenous K-ras signaling in erythroid differentiation. Cell Cycle 6: 1970-3 [PMID:17721087]
  59. Zhao HG, Cruz-Rodriguez N, Johnson KC, Pomicter AD, Bates B, Bateman B, Haferlach T, Gu T, Ahmann J and Yan D et al.. (2025) The small GTPase ARF6 regulates sphingolipid homeostasis and supports proliferation in acute myeloid leukemia. Haematologica [PMID:40637748]
  60. Zhou F, Jiang T, Lin C, Cai L, He W and 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.