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ACS Chem Biol. 2019 Apr 19;14(4):587-593. doi: 10.1021/acschembio.8b00722. Epub 2019 Mar 11.

Discovery and Structural Characterization of ATP-Site Ligands for the Wild-Type and V617F Mutant JAK2 Pseudokinase Domain.

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Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School and Department of Cancer Biology , Dana-Farber Cancer Institute , Boston , Massachusetts 02115 , United States.
Chemical Biology and Therapeutics , Novartis Institutes for BioMedical Research , 4056 Basel , Switzerland.
Oncology Research , Novartis Institutes for BioMedical Research , 4056 Basel , Switzerland.
Global Discovery Chemistry , Novartis Institutes for BioMedical Research , 4056 Basel , Switzerland.


The oncogenic V617F mutation lies in the pseudokinase domain of JAK2, marking it as a potential target for development of compounds that might inhibit the pathogenic activity of the mutant protein. We used differential scanning fluorimetry to identify compounds that bind the JAK2 pseudokinase domain. Crystal structures of five candidate compounds with the wild-type domain reveal their modes of binding. Exploration of analogs of screening hit BI-D1870 led to the identification of compound 2, a 123 nM ligand for the pseudokinase domain. Interestingly, crystal structures of the V617F domain in complex with two unrelated compounds reveal a conformation that is characteristic of the wild-type domain, rather than that previously observed for the V617F mutant. These structures suggest that certain ATP-site ligands can modulate the V617F allosteric site, thereby providing a mechanistic rationale for targeting the pseudokinase domain and a structural foundation for development of more potent and pseudokinase-selective compounds.


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