Download MendeleyDiscovery of Edecesertib (GS-5718): A Potent, Selective Inhibitor of IRAK4.
Ammann, S.E., Cottell, J.J., Wright, N.E., Warr, M.R., Snyder, C.A., Bacon, E.M., Brizgys, G., Chin, E., Chou, C., Conway, A., Dick, R.A., Ferrao, R.D., Garrison, K.L., Hammond, A., Lansdon, E.B., Link, J.O., Mukherjee, P.K., Murray, B.P., Mwangi, J., Ndukwe, M.S., Park, G.Y., Serone, A.P., Suekawa-Pirrone, K., Yang, Z.Y., Zipfel, S.M., Taylor, J.G.(2025) J Med Chem
- PubMed: 40375634
- DOI: https://doi.org/10.1021/acs.jmedchem.5c00463
- Primary Citation of Related Structures:
9NA2, 9NA3, 9NA4, 9NA5, 9NA6 - PubMed Abstract:
Interleukin-1 receptor-associated kinase 4 (IRAK4) activity mediates pro-inflammatory signaling and cytokine production downstream of toll-like and interleukin-1 receptors (TLR, IL-1R). Selective IRAK4 inhibitors have generated interest as potential treatments for inflammatory diseases. Herein, we report the discovery of GS-5718 (edecesertib), a potent, selective, orally bioavailable IRAK4 inhibitor. Key to this endeavor were efforts undertaken to improve the chemical series' profile after a significant hERG liability was encountered for an early compound. GS-5718 was safe and well-tolerated in IND-enabling preclinical animal toxicity studies, demonstrated efficacy in a mouse NZB lupus model, and additionally demonstrated human pharmacokinetic properties suitable for once-daily administration. Edecesertib is currently under clinical evaluation for the treatment of lupus.
Organizational Affiliation:
Gilead Sciences Inc., 333 Lakeside Drive, Foster City, California 94404, United States.
