Ensemble Docking-based Virtual Screening Yields Novel Spirocyclic JAK1 Inhibitors

Small molecule inhibition of Janus kinases (JAKs) has been demonstrated as a viable strategy for the treatment of various inflammatory conditions and continues to emerge in cancer-related indications. In this study, a large supplier database was screened to identify novel chemistry starting points for JAK1. The docking-based screening was followed up by testing ten hit compounds experimentally, out of which five have displayed single-digit micromolar and submicromolar IC values on JAK1. Thus, the study was concluded with the discovery of five novel JAK inhibitors from a tiny screening deck with a remarkable hitrate of 50%. The results have highlighted spirocyclic pyrrolopyrimidines with submicromolar JAK1 IC values and a preference for JAK1 over JAK2 as potential starting points in developing a novel class of JAK1 inhibitors.