6hmx | pdb_00006hmx
RIP2 Kinase Catalytic Domain complex with N(4,5dimethyl1Hpyrazol3yl)7methoxy6(2methylpropane2sulfonyl)quinolin4amine
Structural highlights
Function[RIPK2_HUMAN] Serine/threonine/tyrosine kinase that plays an essential role in modulation of innate and adaptive immune responses. Upon stimulation by bacterial peptidoglycans, NOD1 and NOD2 are activated, oligomerize and recruit RIPK2 through CARD-CARD domains. Once recruited, RIPK2 autophosphorylates and undergoes 'Lys-63'-linked polyubiquitination by E3 ubiquitin ligases BIRC2 and BIRC3. The polyubiquitinated protein mediates the recruitment of MAP3K7/TAK1 to IKBKG/NEMO and induces 'Lys-63'-linked polyubiquitination of IKBKG/NEMO and subsequent activation of IKBKB/IKKB. In turn, NF-kappa-B is released from NF-kappa-B inhibitors and translocates into the nucleus where it activates the transcription of hundreds of genes involved in immune response, growth control, or protection against apoptosis. Plays also a role during engagement of the T-cell receptor (TCR) in promoting BCL10 phosphorylation and subsequent NF-kappa-B activation.[1] [2] [3] [4] Publication Abstract from PubMedRIP2 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 GSK583 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 7, which possesses high binding affinity for the ATP pocket of RIP2 (IC50 = 1 nM) and inhibition of downstream cytokine production in human whole blood (IC50 = 10 nM) with reduced hERG activity (14 muM). Identification of Quinoline-Based RIP2 Kinase Inhibitors with an Improved Therapeutic Index to the hERG Ion Channel.,Haile PA, Casillas LN, Bury MJ, Mehlmann JF, Singhaus R Jr, Charnley AK, Hughes TV, DeMartino MP, Wang GZ, Romano JJ, Dong X, Plotnikov NV, Lakdawala AS, Convery MA, Votta BJ, Lipshutz DB, Desai BM, Swift B, Capriotti CA, Berger SB, Mahajan MK, Reilly MA, Rivera EJ, Sun HH, Nagilla R, LePage C, Ouellette MT, Totoritis RD, Donovan BT, Brown BS, Chaudhary KW, Gough PJ, Bertin J, Marquis RW ACS Med Chem Lett. 2018 Sep 26;9(10):1039-1044. doi:, 10.1021/acsmedchemlett.8b00344. eCollection 2018 Oct 11. PMID:30344914[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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