Chasing Red Herrings: Palladium Metal Salt Impurities Feigning KRAS Activity in Biochemical Assays

被引：0

作者：

Gerstberger, Thomas ^{[1
]}

Berger, Helmut ^{[1
]}

Buettner, Frank H. ^{[2
]}

Gmachl, Michael ^{[1
]}

Kessler, Dirk ^{[1
]}

Koegl, Manfred ^{[1
]}

Lucas, Simon ^{[1
]}

Martin, Laetitia J. ^{[1
]}

Mayer, Moriz ^{[1
]}

McConnell, Darryl B. ^{[1
]}

Mitzner, Sophie ^{[1
]}

Scholz, Guido ^{[1
]}

Treu, Matthias ^{[1
]}

Wolkerstorfer, Bernhard ^{[1
]}

Zahn, Stephan ^{[1
]}

Zak, Krzysztof M. ^{[1
]}

Jaeger, Philipp A. ^{[1
]}

Ettmayer, Peter ^{[1
]}

机构：

[1] Boehringer Ingelheim RCV GmbH & Co KG, A-1121 Vienna, Austria

[2] Boehringer Ingelheim Pharm GmbH & Co KG, D-88397 Biberach, Germany

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2024年 / 67卷 / 14期

关键词：

INHIBITORS; IMMUNOASSAY; KRAS(G12C); STATE;

D O I：

10.1021/acs.jmedchem.3c02381

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：11701 / 11711

页数：11

共 2 条

[1] PALLADIUM(II) COMPLEXES WITH BIS-CARBON-METAL BONDS - LIGAND SYNTHESES, COMPLEXATION, X-RAY-ANALYSIS, AND BIOCHEMICAL-ACTIVITY WITH SUPERCOILED DNA
NEWKOME, GR
KAWATO, T
KOHLI, DK
PUCKETT, WE
OLIVIER, BD
CHIARI, G
FRONCZEK, FR
DEUTSCH, WA
[J]. ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 1981, 181 (MAR): : 154 - ORGN
[2] CHEMISTRY OF HETEROCYCLIC CHEMISTRY SERIES .67. PALLADIUM(II) COMPLEXES WITH TRANS BIS(CARBON-METAL) BONDS - LIGAND SYNTHESES, COMPLEXATION, X-RAY-ANALYSIS, AND BIOCHEMICAL-ACTIVITY WITH SUPERCOILED DNA
NEWKOME, GR
KAWATO, T
KOHLI, DK
PUCKETT, WE
OLIVIER, BD
CHIARI, G
FRONCZEK, FR
DEUTSCH, WA
[J]. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1981, 103 (12) : 3423 - 3429

← 1 →