6TPF

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

Summary for 6TPF

• Entry DOI: 10.2210/pdb6tpf/pdb
• Descriptor: Tyrosine-protein kinase JAK1, (1~{S})-2,2-bis(fluoranyl)-~{N}-[4-(3-methyl-6-oxidanylidene-2,7-dihydropyrazolo[3,4-b]pyridin-4-yl)cyclohexyl]cyclopropane-1-carboxamide (3 entities in total)
• Functional Keywords: janus kinase, inhibitor, complex, proteros biostructures gmbh, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 67937.38

Authors

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.,Rai, S.,Nasipireddy, V.R.,Griessner, A.,Ritzen, A. (deposition date: 2019-12-13, release date: 2020-06-10, Last modification date: 2020-07-22)

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 (2.31 Å)