4WHZ

Design and Synthesis of Highly Potent and Isoform Selective JNK3 Inhibitors: SAR Studies on Aminopyrazole Derivatives

Summary for 4WHZ

• Entry DOI: 10.2210/pdb4whz/pdb
• Descriptor: Mitogen-activated protein kinase 10, 3-(4-{[(2-chlorophenyl)carbamoyl]amino}-1H-pyrazol-1-yl)-N-{1-[(3S)-pyrrolidin-3-yl]-1H-pyrazol-4-yl}benzamide (3 entities in total)
• Functional Keywords: jnk3, jnk2, jnk1, p38, kinase inhibitor, parkinson disease, isoform-selectivity, aminopyrazole, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm : P53779
• Total number of polymer chains: 1
• Total formula weight: 44590.87

Authors

Park, H.,LoGrasso, P. (deposition date: 2014-09-24, release date: 2014-11-26, Last modification date: 2023-12-27)

Primary citation

Zheng, K.,Iqbal, S.,Hernandez, P.,Park, H.,LoGrasso, P.V.,Feng, Y.
Design and Synthesis of Highly Potent and Isoform Selective JNK3 Inhibitors: SAR Studies on Aminopyrazole Derivatives.
J.Med.Chem., 57:10013-10030, 2014

PubMed Abstract: The c-jun N-terminal kinase 3 (JNK3) is expressed primarily in the brain. Numerous reports have shown that inhibition of JNK3 is a promising strategy for treatment of neurodegeneration. The optimization of aminopyrazole-based JNK3 inhibitors with improved potency, isoform selectivity, and pharmacological properties by structure-activity relationship (SAR) studies utilizing biochemical and cell-based assays, and structure-based drug design is reported. These inhibitors had high selectivity over JNK1 and p38α, minimal cytotoxicity, potent inhibition of 6-OHDA-induced mitochondrial membrane potential dissipation and ROS generation, and good drug metabolism and pharmacokinetic (DMPK) properties for iv dosing. 26n was profiled against 464 kinases and was found to be highly selective hitting only seven kinases with >80% inhibition at 10 μM. Moreover, 26n showed good solubility, good brain penetration, and good DMPK properties. Finally, the crystal structure of 26k in complex with JNK3 was solved at 1.8 Å to explore the binding mode of aminopyrazole based JNK3 inhibitors.

PubMed: 25393557
DOI: 10.1021/jm501256y

Experimental method

X-RAY DIFFRACTION (1.79 Å)