| Autor: |
Liosi ME; Department of Chemistry, Yale University, New Haven, Connecticut 06520-8107, United States., Ippolito JA; Department of Chemistry, Yale University, New Haven, Connecticut 06520-8107, United States., Henry SP; Department of Chemistry, Yale University, New Haven, Connecticut 06520-8107, United States., Krimmer SG; Department of Chemistry, Yale University, New Haven, Connecticut 06520-8107, United States.; Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520-8066, United States., Newton AS; Department of Chemistry, Yale University, New Haven, Connecticut 06520-8107, United States., Cutrona KJ; Department of Chemistry, Yale University, New Haven, Connecticut 06520-8107, United States., Olivarez RA; Department of Chemistry, Yale University, New Haven, Connecticut 06520-8107, United States., Mohanty J; Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520-8066, United States., Schlessinger J; Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520-8066, United States., Jorgensen WL; Department of Chemistry, Yale University, New Haven, Connecticut 06520-8107, United States. |
| Abstrakt: |
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. |
