6tpf

Fragment-based discovery of pyrazolopyridones as JAK1 inhibitors with excellent subtype selectivity

spinqualitylabelsall models 6tpf, resolution 2.31Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6tpf is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: NTQ NonStd Res: PTR Activity: Non-specific protein-tyrosine kinase, with EC number 2.7.10.2 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [JAK1_HUMAN] Tyrosine kinase of the non-receptor type, involved in the IFN-alpha/beta/gamma signal pathway. Kinase partner for the interleukin (IL)-2 receptor. Publication Abstract from PubMed Herein, we report the discovery of a series of JAK1-selective kinase inhibitors with high potency and excellent JAK family subtype selectivity. A fragment screening hit 1 with a pyrazolopyridone core and a JAK1 bias was selected as the starting point for our fragment-based lead generation efforts. A two-stage strategy was chosen with the dual aims of improving potency and JAK1 selectivity: Optimization of the lipophilic ribose pocket-targeting substituent was followed by the introduction of a variety of P-loop-targeting functional groups. Combining the best moieties from both stages of the optimization afforded compound 40, which showed excellent potency and selectivity. Metabolism studies in vitro and in vivo together with an in vitro safety evaluation suggest that 40 may be a viable lead compound for the development of highly subtype-selective JAK1 inhibitors. Fragment-Based Discovery of Pyrazolopyridones as JAK1 Inhibitors with Excellent Subtype Selectivity.,Hansen BB, Jepsen TH, Larsen M, Sindet R, Vifian T, Burhardt MN, Larsen J, Seitzberg JG, Carnerup MA, Jerre A, Molck C, Lovato P, Rai S, Nasipireddy VR, Ritzen A J Med Chem. 2020 Jun 8. doi: 10.1021/acs.jmedchem.0c00359. PMID:32462873 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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