8R7X
Kras G12D in complex with compound 4
Summary for 8R7X
| Entry DOI | 10.2210/pdb8r7x/pdb |
| Descriptor | GTPase KRas, PHOSPHOMETHYLPHOSPHONIC ACID GUANYLATE ESTER, MAGNESIUM ION, ... (5 entities in total) |
| Functional Keywords | kras, inhibitor, xray, small molecule, oncoprotein |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 2 |
| Total formula weight | 40128.02 |
| Authors | Kessler, D.,Zak, K.M. (deposition date: 2023-11-27, release date: 2024-10-02, Last modification date: 2025-04-23) |
| Primary citation | Gerstberger, T.,Berger, H.,Buttner, F.H.,Gmachl, M.,Kessler, D.,Koegl, M.,Lucas, S.,Martin, L.J.,Mayer, M.,McConnell, D.B.,Mitzner, S.,Scholz, G.,Treu, M.,Wolkerstorfer, B.,Zahn, S.,Zak, K.M.,Jaeger, P.A.,Ettmayer, P. Chasing Red Herrings: Palladium Metal Salt Impurities Feigning KRAS Activity in Biochemical Assays. J.Med.Chem., 67:11701-11711, 2024 Cited by PubMed Abstract: Identifying promising chemical starting points for small molecule inhibitors of active, GTP-loaded KRAS "on" remains of great importance to clinical oncology and represents a significant challenge in medicinal chemistry. Here, we describe broadly applicable learnings from a KRAS hit finding campaign: While we initially identified KRAS inhibitors in a biochemical high-throughput screen, we later discovered that compound potencies were all but assay artifacts linked to metal salts interfering with KRAS AlphaScreen assay technology. The source of the apparent biochemical KRAS inhibition was ultimately traced to unavoidable palladium impurities from chemical synthesis. This discovery led to the development of a Metal Ion Interference Set (MIIS) for up-front assay development and testing. Profiling of the MIIS across 74 assays revealed a reduced interference liability of label-free biophysical assays and, as a result, provided general estimates for luminescence- and fluorescence-based assay susceptibility to metal salt interference. PubMed: 39009041DOI: 10.1021/acs.jmedchem.3c02381 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.314 Å) |
Structure validation
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