6TPD

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

Summary for 6TPD

• Entry DOI: 10.2210/pdb6tpd/pdb
• Descriptor: Tyrosine-protein kinase JAK2, 3-methyl-4-phenyl-2,7-dihydropyrazolo[3,4-b]pyridin-6-one (3 entities in total)
• Functional Keywords: inhibitor, complex, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 34181.13

Authors

Hansen, B.B.,Jepsen, T.J.,Larsen, M.,Sindet, R.,Vifian, T.,Burhardt, M.N.,Larsen, J.,Seitzberg, J.G.,Carnerup, M.A.,Jerre, A.,Moelck, C.,Rai, S.,Nasipireddy, V.R.,Ritzen, A. (deposition date: 2019-12-13, release date: 2020-06-10, Last modification date: 2024-01-24)

Primary citation

Hansen, B.B.,Jepsen, T.H.,Larsen, M.,Sindet, R.,Vifian, T.,Burhardt, M.N.,Larsen, J.,Seitzberg, J.G.,Carnerup, M.A.,Jerre, A.,Molck, C.,Lovato, P.,Rai, S.,Nasipireddy, V.R.,Ritzen, A.
Fragment-Based Discovery of Pyrazolopyridones as JAK1 Inhibitors with Excellent Subtype Selectivity.
J.Med.Chem., 63:7008-7032, 2020

PubMed Abstract: 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 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 , which showed excellent potency and selectivity. Metabolism studies and together with an safety evaluation suggest that may be a viable lead compound for the development of highly subtype-selective JAK1 inhibitors.

PubMed: 32462873
DOI: 10.1021/acs.jmedchem.0c00359

Experimental method

X-RAY DIFFRACTION (1.99 Å)