FIGURE 1 from Discovery of KRB-456, a KRAS G12D Switch-I/II Allosteric Pocket Binder That Inhibits the Growth of Pancreatic Cancer Patient-derived Tumors
Year: 2023
Type: other
Abstract: Alpha screen and GST pulldown assays identify disruptors of the binding of mt KRAS G12D to the RBD of RAF1. A, Alpha screen was used in a one-compound (10 µmol/L)-one well 384-well plate format to identify KRAS G12D/RBD binding disruptors from a natural product-inspired 560 synthetic compound library. The compounds were ranked from highest to lowest based on % inhibition of the KRAS G12D/RBD binding. B, The top ranked 56 hits (10% of the 560-compound library) from the alpha screen were selected for confirmation by a GST pulldown assay, and six of these were found to inhibit the binding of KRAS G12D to GST-RBD potently (77% to 100%) whereas the remaining 50 compounds weakly inhibited the interaction (0% to 31%).
Authors: Aslamuzzaman Kazi, Alok Ranjan, Vasantha Kumar M.V., Bogos Agianian, Martin Garcia Chavez, Vignesh Vudatha, Rui Wang, Rajanikanth Vangipurapu, Liwei Chen, Perry Kennedy, Karthikeyan Subramanian, Jonathan C.K. Quirke, Francisca Beato, Patrick W. Underwood, Jason B. Fleming, Jose Trevino, Paul J. Hergenrother, Evripidis Gavathiotis, Said M. Sebti
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
OpenAlex ID: W4390347691