2. Academic Validation
  3. Receptor-interacting protein kinase 2 (RIPK2) and nucleotide-binding oligomerization domain (NOD) cell signaling inhibitors based on a 3,5-diphenyl-2-aminopyridine scaffold

Receptor-interacting protein kinase 2 (RIPK2) and nucleotide-binding oligomerization domain (NOD) cell signaling inhibitors based on a 3,5-diphenyl-2-aminopyridine scaffold

  • Eur J Med Chem. 2020 Aug 15;200:112417. doi: 10.1016/j.ejmech.2020.112417.
Chalada Suebsuwong 1,  Bing Dai 2,  Daniel M Pinkas 3,  Anantha Lakshmi Duddupudi 4,  Li Li 4,  Joshua C Bufton 3,  Lisa Schlicher 5,  Mads Gyrd-Hansen 5,  Ming Hu 4,  Alex N Bullock 3,  Alexei Degterev 6,  Gregory D Cuny 7
Affiliations

Affiliations

  • 1 Department of Chemistry, University of Houston, Health Building 2, Houston, TX, 77204, USA.
  • 2 Department of Developmental, Molecular & Chemical Biology, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA, 02111, USA.
  • 3 Structural Genomics Consortium, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford, OX3 7DQ, UK.
  • 4 Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Health Building 2, Houston, TX, 77204, USA.
  • 5 Nuffield Department of Medicine, Ludwig Institute for Cancer Research, University of Oxford, Old Road Campus, Roosevelt Drive, OX3 7DQ, UK.
  • 6 Department of Developmental, Molecular & Chemical Biology, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA, 02111, USA. Electronic address: alexei.degterev@tufts.edu.
  • 7 Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Health Building 2, Houston, TX, 77204, USA. Electronic address: gdcuny@central.uh.edu.
PMID: 32505849 DOI: 10.1016/j.ejmech.2020.112417
Abstract

Receptor-interacting protein kinase 2 (RIPK2) is a key mediator of nucleotide-binding oligomerization domain (NOD) cell signaling that has been implicated in various chronic inflammatory conditions. A new class of RIPK2 kinase/NOD signaling inhibitors based on a 3,5-diphenyl-2-aminopyridine scaffold was developed. Several co-crystal structures of RIPK2•inhibitor complexes were analyzed to provide insights into inhibitor selectivity versus the structurally related activin receptor-like kinase 2 (ALK2) demonstrating that the inhibitor sits deeper in the hydrophobic binding pocket of RIPK2 perturbing the orientation of the DFG motif. In addition, the structure-activity relationship study revealed that in addition to anchoring to the hinge and DFG via the 2-aminopyridine and 3-phenylsulfonamide, respectively, appropriate occupancy of the region between the gatekeeper and the αC-helix provided by substituents in the 4- and 5-positions of the 3-phenylsulfonamide were necessary to achieve potent NOD cell signaling inhibition. For example, compound 18t (e.g. CSLP37) displayed potent biochemical RIPK2 kinase inhibition (IC50 = 16 ± 5 nM), >20-fold selectivity versus ALK2 and potent NOD cell signaling inhibition (IC50 = 26 ± 4 nM) in the HEKBlue assay. Finally, in vitro ADME and pharmacokinetic characterization of 18t further supports the prospects of the 3,5-diphenyl-2-aminopyridine scaffold for the generation of in vivo pharmacology probes of RIPK2 kinase and NOD cell signaling functions.

Keywords

Inhibitor; Kinase; NOD; Nucleotide-binding oligomerization domain; RIPK2; Receptor-interacting protein kinase 2.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z