Discovery of potent and selective pyrazolopyrimidine janus kinase 2 inhibitors.

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Hanan EJ, van Abbema A, Barrett K, Blair WS, Blaney J, Chang C, Eigenbrot C, Flynn S, Gibbons P, Hurley CA, Kenny JR, Kulagowski J, Lee L, Magnuson SR, Morris C, Murray J, Pastor RM, Rawson T, Siu M, Ultsch M, Zhou A, Sampath D, Lyssikatos JP

Discovery of potent and selective pyrazolopyrimidine janus kinase 2 inhibitors.

J Med Chem. 2012 Nov 26;55(22):10090-107. doi: 10.1021/jm3012239. Epub 2012 Oct 24.

PubMed ID

23061660 [ View in PubMed

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Abstract

The discovery of somatic Jak2 mutations in patients with chronic myeloproliferative neoplasms has led to significant interest in discovering selective Jak2 inhibitors for use in treating these disorders. A high-throughput screening effort identified the pyrazolo[1,5-a]pyrimidine scaffold as a potent inhibitor of Jak2. Optimization of lead compounds 7a-b and 8 in this chemical series for activity against Jak2, selectivity against other Jak family kinases, and good in vivo pharmacokinetic properties led to the discovery of 7j. In a SET2 xenograft model that is dependent on Jak2 for growth, 7j demonstrated a time-dependent knock-down of pSTAT5, a downstream target of Jak2.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Ruxolitinib	Tyrosine-protein kinase JAK2	IC 50 (nM)	6.85	N/A	N/A	Details
Ruxolitinib	Tyrosine-protein kinase JAK2	Ki (nM)	0.24	N/A	N/A	Details