Structure (London), 2017-09, Vol.25 (9), p.1442-1448.e3
2017
Details
- Autor(en) / Beteiligte
- Titel
- KRAS G12C Drug Development: Discrimination between Switch II Pocket Configurations Using Hydrogen/Deuterium-Exchange Mass Spectrometry
- Ist Teil von
- Structure (London), 2017-09, Vol.25 (9), p.1442-1448.e3
- Ort / Verlag
- United States: Elsevier Ltd
- Erscheinungsjahr
- 2017
- Link zum Volltext
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- KRAS G12C, the most common RAS mutation found in non-small-cell lung cancer, has been the subject of multiple recent covalent small-molecule inhibitor campaigns including efforts directed at the guanine nucleotide pocket and separate work focused on an inducible pocket adjacent to the switch motifs. Multiple conformations of switch II have been observed, suggesting that switch II pocket (SIIP) binders may be capable of engaging a range of KRAS conformations. Here we report the use of hydrogen/deuterium-exchange mass spectrometry (HDX MS) to discriminate between conformations of switch II induced by two chemical classes of SIIP binders. We investigated the structural basis for differences in HDX MS using X-ray crystallography and discovered a new SIIP configuration in response to binding of a quinazoline chemotype. These results have implications for structure-guided drug design targeting the RAS SIIP. [Display omitted] •HDX mass spectrometry detects differences between classes of RAS SIIP inhibitors•X-ray crystal structures show conformational dynamics upon SIIP inhibitor binding•Quinazoline SIIP inhibitor has similar activity to chloro hydroxy aniline inhibitor Covalent inhibitors are promising for addressing cancers driven by KRAS G12C, the most common KRAS mutation in lung cancer. Lu et al. characterize a quinazoline switch II pocket (SIIP) inhibitor and demonstrate the utility of HDX MS for characterizing SIIP compounds.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0969-2126eISSN: 1878-4186DOI: 10.1016/j.str.2017.07.003Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_8475952
- Format
- –
- Schlagworte
- 60 APPLIED LIFE SCIENCES, Cell Line, covalent inhibitor, Crystallography, X-Ray, Deuterium Exchange Measurement, Drug Design, drug discovery, Enzyme Inhibitors - chemistry, Enzyme Inhibitors - pharmacology, Humans, Mass Spectrometry, Models, Molecular, Molecular Conformation, Mutation, protein dynamics, Proto-Oncogene Proteins p21(ras) - chemistry, Proto-Oncogene Proteins p21(ras) - genetics, Quinazolines - chemistry, Quinazolines - pharmacology, RAS, Structure-Activity Relationship