5K4J

Crystal Structure of CDK2 in complex with compound 22

Summary for 5K4J

• Entry DOI: 10.2210/pdb5k4j/pdb
• Related: 5K4I
• Descriptor: Cyclin-dependent kinase 2, 1-[(1~{S})-1-(4-chloranyl-3-fluoranyl-phenyl)-2-oxidanyl-ethyl]-4-[2-[(2-methylpyrazol-3-yl)amino]pyrimidin-4-yl]pyridin-2-one (3 entities in total)
• Functional Keywords: protein kinase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm, cytoskeleton, microtubule organizing center, centrosome: P24941
• Total number of polymer chains: 1
• Total formula weight: 34488.43

Authors

Yin, J.,Wang, W. (deposition date: 2016-05-20, release date: 2016-07-06, Last modification date: 2024-03-06)

Primary citation

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.
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.
J.Med.Chem., 59:5650-5660, 2016

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.

PubMed: 27227380
DOI: 10.1021/acs.jmedchem.6b00389

Experimental method

X-RAY DIFFRACTION (1.6 Å)