Structure, signaling and the drug discovery of the Ras oncogene protein

Mutations in Ras GTPase are among the most common genetic alterations in human cancers. Despite extensive research investigating Ras proteins, their functions still remain a challenge over a long period of time. The currently available data suggests that solving the outstanding issues regarding Ras could lead to development of effective drugs that could have a significant impact on cancer treatment. Developing a better understanding of their biochemical properties or modes of action, along with improvements in their pharmacologic profiles, clinical design and scheduling will enable the development of more effective therapies.

• Publication year

  2017

• Venue

  BMB Reports

• Publication date

  2017-07-01

• Fields of study

  Biology, Medicine, Chemistry

• Identifiers
  DOI 10.5483/BMBRep.2017.50.7.062PMID 28571593PMCID 5584742
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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  2002cited by this paper
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  1997cited by this paper
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