6HMX

RIP2 Kinase Catalytic Domain complex with N(4,5dimethyl1Hpyrazol3yl)7methoxy6(2methylpropane2sulfonyl)quinolin4amine

Summary for 6HMX

• Entry DOI: 10.2210/pdb6hmx/pdb
• Descriptor: Receptor-interacting serine/threonine-protein kinase 2, 6-~{tert}-butylsulfonyl-~{N}-(3,4-dimethyl-1~{H}-pyrazol-5-yl)-7-methoxy-quinolin-4-amine (3 entities in total)
• Functional Keywords: kinase, kinase inhibitor, complex, structure based drug discovery, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 72142.92

Authors

Convery, M.A.,Haile, P.A. (deposition date: 2018-09-13, release date: 2018-11-07, Last modification date: 2024-05-15)

Primary citation

Haile, P.A.,Casillas, L.N.,Bury, M.J.,Mehlmann, J.F.,Singhaus Jr., R.,Charnley, A.K.,Hughes, T.V.,DeMartino, M.P.,Wang, G.Z.,Romano, J.J.,Dong, X.,Plotnikov, N.V.,Lakdawala, A.S.,Convery, M.A.,Votta, B.J.,Lipshutz, D.B.,Desai, B.M.,Swift, B.,Capriotti, C.A.,Berger, S.B.,Mahajan, M.K.,Reilly, M.A.,Rivera, E.J.,Sun, H.H.,Nagilla, R.,LePage, C.,Ouellette, M.T.,Totoritis, R.D.,Donovan, B.T.,Brown, B.S.,Chaudhary, K.W.,Gough, P.J.,Bertin, J.,Marquis, R.W.
Identification of Quinoline-Based RIP2 Kinase Inhibitors with an Improved Therapeutic Index to the hERG Ion Channel.
ACS Med Chem Lett, 9:1039-1044, 2018

PubMed Abstract: RIP2 kinase was recently identified as a therapeutic target for a variety of autoimmune diseases. We have reported previously a selective 4-aminoquinoline-based RIP2 inhibitor and demonstrated its effectiveness in blocking downstream NOD2 signaling in cellular models, rodent in vivo models, and human ex vivo disease models. While this tool compound was valuable in validating the biological pathway, it suffered from activity at the hERG ion channel and a poor PK/PD profile thereby limiting progression of this analog. Herein, we detail our efforts to improve both this off-target liability as well as the PK/PD profile of this series of inhibitors through modulation of lipophilicity and strengthening hinge binding ability. These efforts have led to inhibitor , which possesses high binding affinity for the ATP pocket of RIP2 (IC = 1 nM) and inhibition of downstream cytokine production in human whole blood (IC = 10 nM) with reduced hERG activity (14 μM).

PubMed: 30344914
DOI: 10.1021/acsmedchemlett.8b00344

Experimental method

X-RAY DIFFRACTION (2.53 Å)