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Synfacts 2022; 18(10): 1141
DOI: 10.1055/s-0041-1738592
Innovative Drug Discovery and Development

A β-Lactone for Covalent Inhibition of KRAS G12S

Contributor(s):
Dirk Trauner
,
Klaus-Peter Ruehmann
Zhang Z, Guiley KZ, Shokat KM. University of California, San Francisco, USA
Chemical Acylation of an Acquired Serine Suppresses Oncogenic Signaling of K-Ras(G12S).

Nat. Chem. Biol. 2022;
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Key words

cancer - covalent inhibition - nucleophile-catalyzed aldol lactonization (NCAL)

Significance

K-Ras is an important kinase that regulates many signaling cascades. Its encoding gene, KRAS, is mutated in approximately 25% of human cancers. The covalent inhibitor sotorasib was recently approved by the FDA and shows promise in treatment of KRAS G12C-mutated tumors. Here, Zhang et al. developed a clever approach to covalently target a different KRAS ­mutant, G12S, by implementing an electrophilic ­β-lactone moiety.


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Comment

The racemic β-lactone was synthesized from an aldehyde acid precursor by treatment with Mukaiyama-type pyridinium reagent A, which initiated an intramolecular, nucleophile-catalyzed, aldol lactonization (NCAL). SNAr of lactones B and triflated tetrahydropyridopyrimidine E (US202003191A1) afforded a diastereomeric mixture of inhibitors, G12Si-1. Covalent binding with KRAS G12S was confirmed by X-ray crystallography.


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Publication History

Article published online:
20 September 2022

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