Indoloxytriazines as binding molecules for the JAK2 JH2 pseudokinase domain and its V617F variant.

Autor: Newton AS; Department of Chemistry, Yale University, New Haven, Connecticut 06520-8107., Liosi ME; Department of Chemistry, Yale University, New Haven, Connecticut 06520-8107., Henry SP; Department of Chemistry, Yale University, New Haven, Connecticut 06520-8107., Deiana L; Department of Chemistry, Yale University, New Haven, Connecticut 06520-8107., Faver JC; Department of Chemistry, Yale University, New Haven, Connecticut 06520-8107., Krimmer SG; Department of Chemistry, Yale University, New Haven, Connecticut 06520-8107.; Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520-8066., Puleo DE; Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520-8066., Schlessinger J; Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520-8066., Jorgensen WL; Department of Chemistry, Yale University, New Haven, Connecticut 06520-8107.
Jazyk: angličtina
Zdroj: Tetrahedron letters [Tetrahedron Lett] 2021 Aug 03; Vol. 77. Date of Electronic Publication: 2021 Jul 02.
DOI: 10.1016/j.tetlet.2021.153248
Abstrakt: Small molecules that selectively bind to the pseudokinase JH2 domain over the JH1 kinase domain of JAK2 kinase are sought. Virtual screening led to the purchase of 17 compounds among which 9 were found to bind to V617F JAK2 JH2 with affinities of 40 - 300 μM in a fluorogenic assay. Ten analogues were then purchased yielding 9 additional active compounds. Aminoanilinyltriazine 22 was particularly notable as it shows no detectable binding to JAK2 JH1, and it has a 65-μM dissociation constant K d with V617F JAK2 JH2. A crystal structure for 22 in complex with wild-type JAK2 JH2 was obtained to elucidate the binding mode. Additional de novo design led to the synthesis of 19 analogues of 22 with the most potent being 33n with K d values of 2-3 μM for WT and V617F JAK2 JH2, and with 16-fold selectivity relative to binding with WT JAK2 JH1.
Competing Interests: Declaration of competing Interest The authors declare no competing interests.
Databáze: MEDLINE
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