6ES0

Crystal structure of the kinase domain of human RIPK2 in complex with the activation loop targeting inhibitor CS-R35

Summary for 6ES0

• Entry DOI: 10.2210/pdb6es0/pdb
• Descriptor: Receptor-interacting serine/threonine-protein kinase 2, 2-[2-fluoranyl-4-[[2-fluoranyl-4-[2-(methylcarbamoyl)pyridin-4-yl]oxy-phenyl]carbamoylamino]phenyl]sulfanylethanoic acid (3 entities in total)
• Functional Keywords: kinase inhibitor, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 73748.63

Authors

Pinkas, D.M.,Bufton, J.C.,Suebsuwong, C.,Ray, S.S.,Dai, B.,Newman, J.A.,Burgess-Brown, N.A.,von Delft, F.,Arrowsmith, C.H.,Edwards, A.M.,Bountra, C.,Degterev, A.,Cuny, G.D.,Bullock, A.N. (deposition date: 2017-10-19, release date: 2018-02-21, Last modification date: 2024-01-17)

Primary citation

Suebsuwong, C.,Pinkas, D.M.,Ray, S.S.,Bufton, J.C.,Dai, B.,Bullock, A.N.,Degterev, A.,Cuny, G.D.
Activation loop targeting strategy for design of receptor-interacting protein kinase 2 (RIPK2) inhibitors.
Bioorg. Med. Chem. Lett., 28:577-583, 2018

PubMed Abstract: Development of selective kinase inhibitors remains a challenge due to considerable amino acid sequence similarity among family members particularly in the ATP binding site. Targeting the activation loop might offer improved inhibitor selectivity since this region of kinases is less conserved. However, the strategy presents difficulties due to activation loop flexibility. Herein, we report the design of receptor-interacting protein kinase 2 (RIPK2) inhibitors based on pan-kinase inhibitor regorafenib that aim to engage basic activation loop residues Lys169 or Arg171. We report development of CSR35 that displayed >10-fold selective inhibition of RIPK2 versus VEGFR2, the target of regorafenib. A co-crystal structure of CSR35 with RIPK2 revealed a resolved activation loop with an ionic interaction between the carboxylic acid installed in the inhibitor and the side-chain of Lys169. Our data provides principle feasibility of developing activation loop targeting type II inhibitors as a complementary strategy for achieving improved selectivity.

PubMed: 29409752
DOI: 10.1016/j.bmcl.2018.01.044

Experimental method

X-RAY DIFFRACTION (2.38 Å)