8R7X

Kras G12D in complex with compound 4

8R7X の概要

• エントリーDOI: 10.2210/pdb8r7x/pdb
• 分子名称: GTPase KRas, PHOSPHOMETHYLPHOSPHONIC ACID GUANYLATE ESTER, MAGNESIUM ION, ... (5 entities in total)
• 機能のキーワード: kras, inhibitor, xray, small molecule, oncoprotein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 40128.02

構造登録者

Kessler, D.,Zak, K.M. (登録日: 2023-11-27, 公開日: 2024-10-02, 最終更新日: 2025-04-23)

主引用文献

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

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: 39009041
DOI: 10.1021/acs.jmedchem.3c02381

実験手法

X-RAY DIFFRACTION (1.314 Å)