7T0P

JAK2 JH2 IN COMPLEX WITH JAK315

Summary for 7T0P

• Entry DOI: 10.2210/pdb7t0p/pdb
• Descriptor: Tyrosine-protein kinase JAK2, 4'-{[5-amino-3-(4-sulfamoylanilino)-1H-1,2,4-triazole-1-carbonyl]amino}-4-(benzyloxy)[1,1'-biphenyl]-3-carboxylic acid, GLYCEROL, ... (4 entities in total)
• Functional Keywords: pseudokinase domain, inhibitor, complex, transferase, transferase-transferase inhibitor complex, signaling protein, transferase-inhibitor complex, transferase/inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 67625.34

Authors

Ippolito, J.A.,Liosi, M.-E.,Krimmer, S.G.,Schlessinger, J.,Jorgensen, W.L. (deposition date: 2021-11-30, release date: 2022-06-15, Last modification date: 2023-10-18)

Primary citation

Liosi, M.E.,Ippolito, J.A.,Henry, S.P.,Krimmer, S.G.,Newton, A.S.,Cutrona, K.J.,Olivarez, R.A.,Mohanty, J.,Schlessinger, J.,Jorgensen, W.L.
Insights on JAK2 Modulation by Potent, Selective, and Cell-Permeable Pseudokinase-Domain Ligands.
J.Med.Chem., 65:8380-8400, 2022

PubMed Abstract: JAK2 is a non-receptor tyrosine kinase that regulates hematopoiesis through the JAK-STAT pathway. The pseudokinase domain (JH2) is an important regulator of the activity of the kinase domain (JH1). V617F mutation in JH2 has been associated with the pathogenesis of various myeloproliferative neoplasms, but JAK2 JH2 has been poorly explored as a pharmacological target. In light of this, we aimed to develop JAK2 JH2 binders that could selectively target JH2 over JH1 and test their capacity to modulate JAK2 activity in cells. Toward this goal, we optimized a diaminotriazole lead compound into potent, selective, and cell-permeable JH2 binders leveraging computational design, synthesis, binding affinity measurements for the JH1, JH2 WT, and JH2 V617F domains, permeability measurements, crystallography, and cell assays. Optimized diaminotriazoles are capable of inhibiting STAT5 phosphorylation in both WT and V617F JAK2 in cells.

PubMed: 35653642
DOI: 10.1021/acs.jmedchem.2c00283

Experimental method

X-RAY DIFFRACTION (2.04 Å)