2. Academic Validation
  3. Discovery of potent and selective pyrazolopyrimidine janus kinase 2 inhibitors

Discovery of potent and selective pyrazolopyrimidine janus kinase 2 inhibitors

  • J Med Chem. 2012 Nov 26;55(22):10090-107. doi: 10.1021/jm3012239.
Emily J Hanan 1,  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,  Joseph P Lyssikatos
Affiliations

Affiliation

  • 1 Department of Discovery Chemistry, Genentech, Inc. 1 DNA Way, South San Francisco, California 94080, USA.
PMID: 23061660 DOI: 10.1021/jm3012239
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.

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