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- Emily J Hanan, Anne van Abbema, Kathy Barrett, Wade S Blair, Jeff Blaney, Christine Chang, Charles Eigenbrot, Sean Flynn, Paul Gibbons, Christopher A Hurley, Jane R Kenny, Janusz Kulagowski, Leslie Lee, Steven R Magnuson, Claire Morris, Jeremy Murray, Richard M Pastor, Tom Rawson, Michael Siu, Mark Ultsch, Aihe Zhou, Deepak Sampath, and Joseph P Lyssikatos.
- Department of Discovery Chemistry, Genentech, Inc. 1 DNA Way, South San Francisco, California 94080, USA.
- J. Med. Chem. 2012 Nov 26; 55 (22): 10090-107.
AbstractThe 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.
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