Abstract
Oncogenic mutations in RAS genes result in the elevation of cellular active RAS protein levels and increased signal propagation through downstream pathways that drive tumor cell proliferation and survival. These gain-of-function mutations drive over 30% of all human cancers, presenting promising therapeutic potential for RAS inhibitors. However, many have deemed RAS “undruggable” after nearly 40 years of failed drug discovery campaigns aimed at identifying a RAS inhibitor with clinical activity. Here we review RAS nucleotide cycling and the opportunities that RAS biochemistry presents for developing novel RAS inhibitory compounds. Additionally, compounds that have been identified to inhibit RAS by exploiting various aspects of RAS biology and biochemistry will be covered. Our current understanding of the biochemical properties of RAS, along with reports of direct-binding inhibitors, both provide insight on viable strategies for the discovery of novel clinical candidates with RAS inhibitory activity.
Highlights
RAS mutations are among the most common mutations in cancer, driving aggressive, metastatic malignancies with poor patient prognoses
A number of anti-cancer drugs that block a multitude of signaling nodes, either upstream or downstream of RAS, have been developed and approved for clinical use by the United States Food and Drug Administration (FDA)
Two highly conserved switch I residues, tyrosine-32 and threonine-35, have been reported to coordinate the state of guanosine triphosphate (GTP) binding, while participating in initiation of the GTPase reaction that hydrolyzes GTP back to GDP. Tight interaction of these residues with the phosphates of GTP, along with threonine-35 coordinating the position of the magnesium cofactor in the active site, has been reported to produce the state 2 conformation of GTP-bound RAS [22,23,24,25,26]
Summary
RAS mutations are among the most common mutations in cancer, driving aggressive, metastatic malignancies with poor patient prognoses. The elevation of RAS-GTP levels in RAS mutant tumors causes increased activation of its vast array of downstream effectors, promoting cell signal transduction pathways, and facilitating proliferation and survival [3]. A number of anti-cancer drugs that block a multitude of signaling nodes, either upstream or downstream of RAS, have been developed and approved for clinical use by the United States Food and Drug Administration (FDA). These therapies have limited clinical utility for RAS-driven cancers, and often result in the reoccurrence of highly aggressive cancers that are resistant to chemotherapy or radiation [4]. Inhibitors that directly target RAS and inhibit its ability to activate complex downstream signaling pathways are expected to have strong efficacy and safety advantages over currently available upstream or downstream inhibitors of RAS signaling
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