2. Academic Validation
  3. Identification of quinazoline based inhibitors of IRAK4 for the treatment of inflammation

Identification of quinazoline based inhibitors of IRAK4 for the treatment of inflammation

  • Bioorg Med Chem Lett. 2017 Jun 15;27(12):2721-2726. doi: 10.1016/j.bmcl.2017.04.050.
Graham F Smith 1,  Michael D Altman 2,  Brian Andresen 2,  James Baker 2,  Jason D Brubaker 3,  Hongmin Chen 2,  Yiping Chen 2,  Matthew Childers 2,  Anthony Donofrio 2,  Heidi Ferguson 2,  Christian Fischer 2,  Thierry O Fischmann 2,  Craig Gibeau 2,  Alexander Hicks 4,  Sue Jin 2,  Sam Kattar 2,  Melanie A Kleinschek 5,  Erica Leccese 2,  Charles Lesburg 2,  Chaomin Li 2,  Jongwon Lim 6,  Duan Liu 2,  John K F Maclean 7,  Faruk Mansoor 2,  Lilly Y Moy 2,  Erin F Mulrooney 2,  Antoaneta S Necheva 2,  Jeremy Presland 2,  Larissa Rakhilina 2,  Ruojing Yang 2,  Luis Torres 2,  Jie Zhang-Hoover 2,  Alan Northrup 2
Affiliations

Affiliations

  • 1 AstraZeneca, 35 Gatehouse Drive, Waltham, MA 02451, United States. Electronic address: Graham.smith@astrazeneca.com.
  • 2 Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, United States.
  • 3 Blueprint Medicines, 38 Sidney St Suite 200, Cambridge, MA 02139, United States.
  • 4 Oncorus, 50 Hampshire St. Suite 401, Cambridge, MA 02139, United States.
  • 5 Theravance Biopharma US, Inc., 901 Gateway Boulevard, South San Francisco, CA 94080, United States.
  • 6 Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, United States. Electronic address: jongwon_lim@merck.com.
  • 7 Redx Pharma, Block 33, Mereside, Alderley Park, Macclesfield SK10 4TG, United Kingdom.
PMID: 28501511 DOI: 10.1016/j.bmcl.2017.04.050
Abstract

Interleukin-1 receptor associated kinase 4 (IRAK4) has been implicated in IL-1R and TLR based signaling. Therefore selective inhibition of the kinase activity of this protein represents an attractive target for the treatment of inflammatory diseases. Medicinal chemistry optimization of high throughput screening (HTS) hits with the help of structure based drug design led to the identification of orally-bioavailable quinazoline based IRAK4 inhibitors with excellent pharmacokinetic profile and kinase selectivity. These highly selective IRAK4 compounds show activity in vivo via oral dosing in a TLR7 driven model of inflammation.

Keywords

IRAK4; Inflammatory disease; Kinase inhibitor; Quinazoline; Serine-threonine kinase.

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