RAS is a membrane localized small GTPase frequently mutated in human cancer. As such, RAS has been a focal target for developing cancer therapeutics since its discovery nearly four decades ago. However, efforts to directly target RAS have been challenging due to the apparent lack of readily discernable deep pockets for binding small molecule inhibitors leading many to consider RAS as undruggable. An important milestone in direct RAS inhibition was achieved recently with the groundbreaking discovery of covalent inhibitors that target the mutant Cys residue in KRAS(G12C). Surprisingly, these G12C-reactive compounds only target mutant RAS in the GDP-bound state thereby locking it in the inactive conformation and blocking its ability to couple with downstream effector pathways. Building on this success, several groups have developed similar compounds that selectively target KRAS(G12C), with AMG510 and MRTX849 the first to advance to clinical trials. Both have shown early promising results. Though the success with these compounds has reignited the possibility of direct pharmacological inhibition of RAS, these covalent inhibitors are limited to treating KRAS(G12C) tumors which account for <15% of all RAS mutants in human tumors. Thus, there remains an unmet need to identify more broadly efficacious RAS inhibitors. Here, we will discuss the current state of RAS(G12C) inhibitors and the potential for inhibiting additional RAS mutants through targeting RAS dimerization which has emerged as an important step in the allosteric regulation of RAS function.
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October 2020
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Centrosomes are microtubule-organizing centres required for the asymmetric division of neural stem cells, which support neurodevelopment, as discussed in a mini-review by Robinson and colleagues (pages 2101–2115) In the cover image, microtubules are shown in yellow and neural stem cells (aPKC) are magenta. Image provided by Dorothy Lerit.
Review Article|
September 01 2020
Inhibition of RAS: proven and potential vulnerabilities
Mariyam Zuberi;
Mariyam Zuberi
1Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, U.S.A.
2Ralph H. Johnson VA Medical Center, Charleston, SC 29401, U.S.A.
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Imran Khan;
Imran Khan
1Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, U.S.A.
2Ralph H. Johnson VA Medical Center, Charleston, SC 29401, U.S.A.
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John P. O'Bryan
1Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, U.S.A.
2Ralph H. Johnson VA Medical Center, Charleston, SC 29401, U.S.A.
Correspondence: John P. O'Bryan (obryanjo@musc.edu)
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Biochem Soc Trans (2020) 48 (5): 1831–1841.
Article history
Received:
July 06 2020
Revision Received:
July 31 2020
Accepted:
August 05 2020
Citation
Mariyam Zuberi, Imran Khan, John P. O'Bryan; Inhibition of RAS: proven and potential vulnerabilities. Biochem Soc Trans 30 October 2020; 48 (5): 1831–1841. doi: https://doi.org/10.1042/BST20190023
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