The RAS proteins (HRAS, NRAS and KRAS) are small membrane-localised G protein-like molecules of 21 kd. They act as an on/off switch linking receptor and non-receptor tyrosine kinase activation to downstream cytoplasmic or nuclear events. Binding of GTP activates the switch, and hydrolysis of the GTP to GDP inactivates the switch.

The RAS proto-oncogenes are the most frequently mutated class of proteins in human cancers. Common mutations compromise the GTP-hydrolysing ability of the proteins causing constitutive activation [4], which leads to increased cell proliferation and decreased apoptosis [5]. Because of their importance in oncogenic transformation these proteins have become the targets of intense drug discovery effort [1].

* Key recommended reading is highlighted with an asterisk

* Chen H, Smaill JB, Liu T, Ding K, Lu X. (2020) Small-Molecule Inhibitors Directly Targeting KRAS as Anticancer Therapeutics. J Med Chem, 63 (23): 14404-14424. [PMID:33225706]

* Dorard C, Vucak G, Baccarini M. (2017) Deciphering the RAS/ERK pathway in vivo. Biochem Soc Trans, 45 (1): 27-36. [PMID:28202657]

* Kattan WE, Hancock JF. (2020) RAS Function in cancer cells: translating membrane biology and biochemistry into new therapeutics. Biochem J, 477 (15): 2893-2919. [PMID:32797215]

* Keeton AB, Salter EA, Piazza GA. (2017) The RAS-Effector Interaction as a Drug Target. Cancer Res, 77 (2): 221-226. [PMID:28062402]

Lu S, Jang H, Muratcioglu S, Gursoy A, Keskin O, Nussinov R, Zhang J. (2016) Ras Conformational Ensembles, Allostery, and Signaling. Chem Rev, 116 (11): 6607-65. [PMID:26815308]

Ostrem JM, Shokat KM. (2016) Direct small-molecule inhibitors of KRAS: from structural insights to mechanism-based design. Nat Rev Drug Discov, 15 (11): 771-785. [PMID:27469033]

* Papke B, Der CJ. (2017) Drugging RAS: Know the enemy. Science, 355 (6330): 1158-1163. [PMID:28302824]

* Quah SY, Tan MS, Teh YH, Stanslas J. (2016) Pharmacological modulation of oncogenic Ras by natural products and their derivatives: Renewed hope in the discovery of novel anti-Ras drugs. Pharmacol Ther, 162: 35-57. [PMID:27016467]

* Simanshu DK, Nissley DV, McCormick F. (2017) RAS Proteins and Their Regulators in Human Disease. Cell, 170 (1): 17-33. [PMID:28666118]

1. 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]

2. 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 KRAS^G12C (AMG 510) for the Treatment of Solid Tumors. J Med Chem, 63 (1): 52-65. [PMID:31820981]

3. 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]

4. Stanley LA. (1995) Molecular aspects of chemical carcinogenesis: the roles of oncogenes and tumour suppressor genes. Toxicology, 96 (3): 173-94. [PMID:7900159]

5. Zhang J, Lodish HF. (2007) Endogenous K-ras signaling in erythroid differentiation. Cell Cycle, 6 (16): 1970-3. [PMID:17721087]