KRASG12C was recently identified to be potentially druggable by allele-specific covalent targeting of Cys-12 in vicinity to an inducible allosteric switch II pocket (S-IIP). Success of this approach requires active cycling of KRASG12C between its active-GTP and inactive-GDP conformations as accessibility of the S-IIP is restricted only to the GDP-bound state. This strategy proved feasible for inhibiting mutant KRAS in vitro; however, it is uncertain whether this approach would translate to in vivo. Here, we describe structure-based design and identification of ARS-1620, a covalent compound with high potency and selectivity for KRASG12C. ARS-1620 achieves rapid and sustained in vivo target occupancy to induce tumor regression. We use ARS-1620 to dissect oncogenic KRAS dependency and demonstrate that monolayer culture formats significantly underestimate KRAS dependency in vivo. This study provides in vivo evidence that mutant KRAS can be selectively targeted and reveals ARS-1620 as representing a new generation of KRASG12C-specific inhibitors with promising therapeutic potential.
Pubmed ID: 29373830 RIS Download
Publication data is provided by the National Library of Medicine ® and PubMed ®. Data is retrieved from PubMed ® on a weekly schedule. For terms and conditions see the National Library of Medicine Terms and Conditions.
This polyclonal targets DYKDDDK
View all literature mentionsThis polyclonal targets alpha-Tubulin
View all literature mentionsThis monoclonal targets Casp3
View all literature mentionsThis monoclonal targets Phospho-S6 Ribosomal Protein (Ser235/236) (D57.2.2E) XP Rabbit mAb
View all literature mentionsThis monoclonal targets Phospho-Akt (Thr308) (C31E5E) Rabbit mAb
View all literature mentionsThis monoclonal targets Phospho-Akt (Ser473)
View all literature mentionsThis monoclonal targets Hsp90aa1
View all literature mentionsThis polyclonal targets Cleaved PARP (Asp214) (Human Specific)
View all literature mentionsThis monoclonal targets Akt (pan) (C67E7) Rabbit mAb
View all literature mentionsThis monoclonal targets p44/42 MAPK (Erk1/2)
View all literature mentionsThis monoclonal targets Phospho-p44/42 MAPK (Erk1/2) (Thr202/Tyr204)
View all literature mentionsThis polyclonal targets KRAS
View all literature mentionsThis monoclonal targets Ras antibody [EPR3255]
View all literature mentionsCell line HCC44 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line HCC1171 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line Lu-99A is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line Lu-65 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line A-375 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line HCT 116 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line NCI-H441 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line A-549 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line SW1573 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line NCI-H1792 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line NCI-H1373 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line NCI-H2030 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line SW1463 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line NCI-H2122 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line NCI-H23 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line Calu-1 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line SW837 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line MIA PaCa-2 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line NCI-H358 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsSoftware for single-cell flow cytometry analysis. Its functions include management, display, manipulation, analysis and publication of the data stream produced by flow and mass cytometers.
View all literature mentionsSoftware for identifying, characterizing, and quantifying proteins in biological samples. Can be used for range of proteomics workflows such as protein and peptide identification, PTM analysis, and isobaric mass tagging for quantification. Supports multiple database search algorithms and multiple dissociation techniques.
View all literature mentionsStatistical analysis software that combines scientific graphing, comprehensive curve fitting (nonlinear regression), understandable statistics, and data organization. Designed for biological research applications in pharmacology, physiology, and other biological fields for data analysis, hypothesis testing, and modeling.
View all literature mentions