SERP
Comments:
Compound 44 exhibits impressive potency and selectivity as an inhibitor of PERK, making it a valuable tool for elucidating PERK’s role in cellular signaling. Notably, Compound 44 offers chemical diversity and greater selectivity compared to previously known PERK inhibitors like GSK2606414 and GSK2656157. Its design is supported by CADD methods, with the X-ray crystal structure of PERK in complex with Compound 44 (PDB accession code: 4X7N), ensuring an optimized fit within the PERK active site. This careful optimization contributes to its potency and specificity, as demonstrated in kinase selectivity profiling when against a panel of 387 kinases.
In cellular models, Compound 44 has shown potent PERK inhibition (in vitro IC50 = 6 nM) with over 1,000-fold selectivity against GCN2, and no observable GCN2-related effects in cellular assays. While the compound’s pharmacokinetic properties in rats were moderate, its pharmacokinetics in mice were significantly improved. However, one significant limitation is the lack of data regarding Compound 44’s efficacy in disease models. Although it’s in vitro potency and selectivity make it a strong candidate for PERK-related studies, more data on pharmacokinetics, toxicity, and therapeutic efficacy in animal models are necessary to fully assess its suitability for in vivo applications.
(last updated:
21 Oct 2024 )
