Allele-specific inhibitors inactivate mutant KRAS G12C by a trapping mechanism | Zendy

Piro Lito | Zendy; Martha Solomon | Zendy; LianSheng Li | Zendy; Rasmus Hansen | Zendy; Neal Rosen | Zendy

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Allele-specific inhibitors inactivate mutant KRAS G12C by a trapping mechanism

Author(s) -

Piro Lito,

Martha Solomon,

LianSheng Li,

Rasmus Hansen,

Neal Rosen

Publication year - 2016

Publication title -

science

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 12.556

H-Index - 1186

eISSN - 1095-9203

pISSN - 0036-8075

DOI - 10.1126/science.aad6204

Subject(s) - kras , gtpase , guanosine , nucleotide , guanine nucleotide exchange factor , mutant , chemistry , mutation , cancer research , small gtpase , microbiology and biotechnology , biochemistry , tyrosine kinase , mechanism (biology) , biology , signal transduction , gene , philosophy , epistemology

Cancer therapy by entrapment Mutations in theKRAS oncogene occur at high frequency in several of the most lethal human cancers, including lung and pancreatic cancer. Substantial effort has thus been directed toward developing KRAS inhibitors.KRAS encodes an enzyme that binds the nucleotide GTP and hydrolyzes it to GDP. It had been thought that oncogenic mutations disable this hydrolytic activity, locking KRAS in the GTP-bound, active state. Surprisingly, Litoet al. found that a certain KRAS mutant (G12C) retains hydrolytic activity and continues to cycle between its active and inactive states. They describe a compound that inhibits KRAS(G12C) signaling and tumor cell growth by binding to the GDPbound form of KRAS, trapping it in its inactive state.Science , this issue p.604

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