5K4I

Discovery of (S)-1-(1-(4-Chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (GDC-0994), an Extracellular Signal-Regulated Kinase 1/2 (ERK1/2) Inhibitor in Early Clinical Development.

Blake, J.F., Burkard, M., Chan, J., Chen, H., Chou, K.J., Diaz, D., Dudley, D.A., Gaudino, J.J., Gould, S.E., Grina, J., Hunsaker, T., Liu, L., Martinson, M., Moreno, D., Mueller, L., Orr, C., Pacheco, P., Qin, A., Rasor, K., Ren, L., Robarge, K., Shahidi-Latham, S., Stults, J., Sullivan, F., Wang, W., Yin, J., Zhou, A., Belvin, M., Merchant, M., Moffat, J., Schwarz, J.B.

(2016) J Med Chem 59: 5650-5660

• PubMed: 27227380 Search on PubMed
• DOI: https://doi.org/10.1021/acs.jmedchem.6b00389
• Primary Citation of Related Structures:  
  5K4I, 5K4J


• PubMed Abstract: 
  

  The extracellular signal-regulated kinases ERK1/2 represent an essential node within the RAS/RAF/MEK/ERK signaling cascade that is commonly activated by oncogenic mutations in BRAF or RAS or by upstream oncogenic signaling. While targeting upstream nodes with RAF and MEK inhibitors has proven effective clinically, resistance frequently develops through reactivation of the pathway. Simultaneous targeting of multiple nodes in the pathway, such as MEK and ERK, offers the prospect of enhanced efficacy as well as reduced potential for acquired resistance. Described herein is the discovery and characterization of GDC-0994 (22), an orally bioavailable small molecule inhibitor selective for ERK kinase activity.

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Organizational Affiliation: 

Array BioPharma Inc. , 3200 Walnut Street, Boulder, Colorado 80301, United States.