Abstract
Directly inhibiting oncogenic RAS proteins has proven to be an arduous task, as after more than thirty years of intensive investigation, no clinically relevant therapies exist. Recently, two classes of selective small molecule inhibitors that target a cysteine-containing RAS mutant have been developed, representing the first directed approaches to specifically inhibit an oncogenic KRAS mutant. In this mini-review, we first assess the development and targeting strategies associated with novel cysteine-directed RAS inhibitors. Next, we describe the variable oncogenic potency of the KRAS G12C mutant when compared to other KRAS G12 mutants. Lastly, we evaluate how the redox properties of KRAS G12C may play a role in differential signaling and tumorigenic potency of the oncogene, the efficacy of small molecules targeting this specific RAS mutant and further development of directed oncogenic RAS inhibitors.
Keywords: KRAS G12C, RAS inhibition, cysteine-directed inhibitors, RAS oxidation, tethering.
Mini-Reviews in Medicinal Chemistry
Title:Getting a Handle on RAS-targeted Therapies: Cysteine Directed Inhibitors
Volume: 16 Issue: 5
Author(s): Minh V. Huynh and Sharon L. Campbell
Affiliation:
Keywords: KRAS G12C, RAS inhibition, cysteine-directed inhibitors, RAS oxidation, tethering.
Abstract: Directly inhibiting oncogenic RAS proteins has proven to be an arduous task, as after more than thirty years of intensive investigation, no clinically relevant therapies exist. Recently, two classes of selective small molecule inhibitors that target a cysteine-containing RAS mutant have been developed, representing the first directed approaches to specifically inhibit an oncogenic KRAS mutant. In this mini-review, we first assess the development and targeting strategies associated with novel cysteine-directed RAS inhibitors. Next, we describe the variable oncogenic potency of the KRAS G12C mutant when compared to other KRAS G12 mutants. Lastly, we evaluate how the redox properties of KRAS G12C may play a role in differential signaling and tumorigenic potency of the oncogene, the efficacy of small molecules targeting this specific RAS mutant and further development of directed oncogenic RAS inhibitors.
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Cite this article as:
Huynh V. Minh and Campbell L. Sharon, Getting a Handle on RAS-targeted Therapies: Cysteine Directed Inhibitors, Mini-Reviews in Medicinal Chemistry 2016; 16 (5) . https://dx.doi.org/10.2174/1389557515666151001154352
DOI https://dx.doi.org/10.2174/1389557515666151001154352 |
Print ISSN 1389-5575 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5607 |
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