ABSTRACT
A new series of pyrazolo[1,5-a]pyrimidines exemplified by compound 1, has been identified with moderate activity (IC50=165nM), following GSK256066 rescaffolding. Compound 1 optimization at positions 2, 3, 6 and 7 gave compound 10 with high in vitro activity (IC50=0.7nM). Modeling studies based on the PDB structure 3GWT with compound 5 showed the expected overlay with the carboxamide, the aryl moiety and the sulfone. Cyclisation of the primary amide to the 5 position of the pyrazolo[1,5-a]pyrimidines scaffold afforded compounds 15 and 16 with 200-fold enhancement in activity and cellular potency.
Subject(s)
Phosphodiesterase 4 Inhibitors/pharmacology , Pyrazoles/pharmacology , Pyrimidines/pharmacology , Aminoquinolines/chemistry , Cell Line, Tumor , Cyclic AMP/biosynthesis , Humans , Models, Molecular , Phosphodiesterase 4 Inhibitors/chemical synthesis , Pyrazoles/chemical synthesis , Pyrimidines/chemical synthesis , Structure-Activity Relationship , Sulfones/chemical synthesis , Sulfones/chemistry , Sulfones/pharmacologyABSTRACT
We report the analysis of an in-house fragment screening campaign for the oncology target MEK1. The application of virtual screening (VS) as a primary fragment screening approach, followed by biophysical validation using differential screening fluorimetry (DSF), with resultant binding mode determination by X-ray crystallography (X-ray), is presented as the most time and cost-effective combination of in silico and in vitro methods to identify fragments. We demonstrate the effectiveness of the VS-DSF workflow for the early identification of fragments to both 'jump-start' the drug discovery project and to complement biochemical screening data.
