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Review
. 2022 Mar 28;23(7):3706.
doi: 10.3390/ijms23073706.

Small-Molecule RAS Inhibitors as Anticancer Agents: Discovery, Development, and Mechanistic Studies

Shaila A Shetu  1 , Debasish Bandyopadhyay  1   2
Affiliations
Review

Small-Molecule RAS Inhibitors as Anticancer Agents: Discovery, Development, and Mechanistic Studies

Shaila A Shetu et al. Int J Mol Sci. .

Abstract

Mutations of RAS oncogenes are responsible for about 30% of all human cancer types, including pancreatic, lung, and colorectal cancers. While KRAS1 is a pseudogene, mutation of KRAS2 (commonly known as KRAS oncogene) is directly or indirectly associated with human cancers. Among the RAS family, KRAS is the most abundant oncogene related to uncontrolled cellular proliferation to generate solid tumors in many types of cancer such as pancreatic carcinoma (over 80%), colon carcinoma (40-50%), lung carcinoma (30-50%), and other types of cancer. Once described as 'undruggable', RAS proteins have become 'druggable', at least to a certain extent, due to the continuous efforts made during the past four decades. In this account, we discuss the chemistry and biology (wherever available) of the small-molecule inhibitors (synthetic, semi-synthetic, and natural) of KRAS proteins that were published in the past decades. Commercial drugs, as well as investigational molecules from preliminary stages to clinical trials, are categorized and discussed in this study. In summary, this study presents an in-depth discussion of RAS proteins, classifies the RAS superfamily, and describes the molecular mechanism of small-molecule RAS inhibitors.

Keywords: HRAS; KRAS; NRAS; RAS subfamily; cell signaling; colon cancer; heterocycles; lung cancer; mechanism of action; pancreatic cancer; small-molecule inhibitors.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Classification of the RAS superfamily [6,11].
Figure 2
Figure 2
Frequency of KRAS, HRAS, and NRAS in different types of cancer [2,50,59,60].
Figure 3
Figure 3
Heterocyclic natural product RAS inhibitors.
Figure 4
Figure 4
Carbocyclic natural product RAS inhibitors.
Figure 5
Figure 5
Acyclic natural product RAS inhibitor Chaetomellic acid A.
See this image and copyright information in PMC

References

    1. Karnoub A.E., Weinberg R.A. Ras oncogenes: Split personalities. Nat. Rev. Mol. Cell Biol. 2008;9:517–531. doi: 10.1038/nrm2438. - DOI - PMC - PubMed
    1. Cox A.D., Der C.J. Ras history: The saga continues. Small GTPases. 2010;1:2–27. doi: 10.4161/sgtp.1.1.12178. - DOI - PMC - PubMed
    1. Jemal A., Siegel R., Ward E., Hao Y., Xu J., Thun M.J. Cancer statistics. CA Cancer J. Clin. 2009;59:225–249. doi: 10.3322/caac.20006. - DOI - PubMed
    1. Liu P., Wang Y., Li X. Targeting the untargetable KRAS in cancer therapy. Acta Pharm. Sin. B. 2019;9:871–879. doi: 10.1016/j.apsb.2019.03.002. - DOI - PMC - PubMed
    1. Simanshu D.K., Nissley D.V., McCormick F. RAS Proteins and Their Regulators in Human Disease. Cell. 2017;170:17–33. doi: 10.1016/j.cell.2017.06.009. - DOI - PMC - PubMed

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