1404437-70-2Relevant academic research and scientific papers
Biochemical, cellular and structural characterization of novel and selective ERK3 inhibitors
Gr?dler, Ulrich,Busch, Michael,Leuthner, Birgitta,Raba, Michael,Burgdorf, Lars,Lehmann, Martin,Linde, Nina,Esdar, Christina
supporting information, (2020/09/18)
Triazolo[4,5-d]pyrimidin-5-amines were identified from kinase selectivity screening as novel ERK3 inhibitors with sub-100 nanomolar potencies in a biochemical assay using MK5 as substrate and with an attractive kinase selectivity profile. ERK3 crystal structures clarified the inhibitor binding mode in the ATP pocket with impact on A-loop, GC-loop and αC-helix conformations suggesting a potential structural link towards MK5 interaction via the FHIEDE motif. The inhibitors also showed sub-100 nM potencies in a cellular ERK3 NanoBRET assay and with excellent correlation to the biochemical IC50s. This novel series provides valuable tool compounds to further investigate the biological function and activation mechanism of ERK3.
A potent and selective quinoxalinone-based STK33 inhibitor does not show synthetic lethality in KRAS-dependent cells
We?wer, Michel,Spoonamore, James,Wei, Jingqiang,Guichard, Boris,Ross, Nathan T.,Masson, Kristina,Silkworth, Whitney,Dandapani, Sivaraman,Palmer, Michelle,Scherer, Christina A.,Stern, Andrew M.,Schreiber, Stuart L.,Munoz, Benito
supporting information, p. 1034 - 1038 (2013/02/22)
The KRAS oncogene is found in up to 30% of all human tumors. In 2009, RNAi experiments revealed that lowering mRNA levels of a transcript encoding the serine/threonine kinase STK33 was selectively toxic to KRAS-dependent cancer cell lines, suggesting that small-molecule inhibitors of STK33 might selectively target KRAS-dependent cancers. To test this hypothesis, we initiated a high-throughput screen using compounds in the Molecular Libraries Small Molecule Repository (MLSMR). Several hits were identified, and one of these, a quinoxalinone derivative, was optimized. Extensive SAR studies were performed and led to the chemical probe ML281 that showed low nanomolar inhibition of purified recombinant STK33 and a distinct selectivity profile as compared to other STK33 inhibitors that were reported in the course of these studies. Even at the highest concentration tested (10 μM), ML281 had no effect on the viability of KRAS-dependent cancer cells. These results are consistent with other recent reports using small-molecule STK33 inhibitors. Small molecules having different chemical structures and kinase-selectivity profiles are needed to fully understand the role of STK33 in KRAS-dependent cancers. In this regard, ML281 is a valuable addition to small-molecule probes of STK33.
