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Targeting mutant KRAS for anticancer therapeutics: a review of novel small molecule modulators

Yuanxiang Wang1, Christine E Kaiser, Brendan Frett

  • 1Department of Pharmacoloy and Toxicology, College of Pharmacy, The University of Arizona , Tucson, Arizona 85721, United States.

Journal of Medicinal Chemistry
|April 10, 2013
PubMed

Insights

This review explores high-throughput screening assays for discovering small molecules targeting KRAS-mutant cancers. These methods aim to inhibit aberrant RAS signaling, a key driver in many cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • RAS proteins regulate cell growth; aberrant signaling drives ~30% of cancers.
  • KRAS mutations lead to constitutive activity, making it a prime cancer target.
  • Targeting mutant KRAS involves synthetic lethality, blocking interactions, inhibiting effectors, or disrupting post-translational processing.

Purpose of the Study:

  • To review high-throughput screening (HTS) assays for identifying novel small-molecule inhibitors of mutant KRAS.
  • To highlight strategies for targeting KRAS-driven cancers, including direct and indirect approaches.
  • To discuss the potential of targeting PLK1 as an alternative strategy in KRAS-mutant cancers.

Main Methods:

  • Review of literature on high-throughput screening assays.
  • Analysis of different therapeutic strategies against KRAS signaling.
  • Examination of novel targets like PLK1 in the context of KRAS mutations.

Main Results:

  • Various HTS assays are employed to discover compounds targeting mutant KRAS.
  • Multiple approaches exist to inhibit aberrant RAS signaling pathways.
  • Targeting PLK1 shows promise in KRAS-mutant cancer cells.

Conclusions:

  • HTS assays are crucial for identifying new therapeutic agents for KRAS-mutant cancers.
  • A multi-pronged approach, including targeting novel pathways, is necessary for effective cancer treatment.
  • Further research into these screening methods and targets can lead to effective therapies.

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