The Identification and Pharmacological Characterization of 6-(tert-Butylsulfonyl)-N-(5-fluoro-1H-indazol-3-yl)quinolin-4-amine (GSK583), a Highly Potent and Selective Inhibitor of RIP2 Kinase

Haile, Pamela A.; Votta, Bartholomew J.; Marquis, Robert W.; Bury, Michael J.; Mehlmann, John F.; Singhaus, Robert R.; Charnley, Adam K.; Lakdawala, Ami S.; Convery, M.A.; Lipshutz, David B.; Desai, Biva M.; Swift, Brandon; Capriotti, Carol A.; Berger, Scott B.; Mahajan, Mukesh; Reilly, Michael; Rivera, Elizabeth J.; Sun, Helen H.; Nagilla, Rakesh; Beal, Allison M.; Finger, Joshua N.; Cook, Michael N.; King, Bryan W.; Ouellette, Michael T.; Totoritis, Rachel D.; Pierdomenico, Maria; Negroni, Anna; Stronati, Laura; Cucchiara, Salvatore; Ziółkowski, Bartłomiej; Vossenkämper, Anna; MacDonald, Thomas T.; Gough, Peter J.; Bertin, John; Casillas, Linda

doi:10.1021/acs.jmedchem.6b00211

Cited by 107 publications

(132 citation statements)

References 57 publications

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“…This is further revealed by the molecular docking of CSLP37 (R 1 = F) and CSLP43 (R 1 = OMe), which demonstrates that the larger R 1 groups of these molecules more optimally fill the deep pocket (Figs E and F, and EV2F). Notably, examining available crystal data, we observed that all previously reported inhibitors that potently antagonize NOD2 signaling, including GSK583, ponatinib, and the recently reported compound 7f (Canning et al , ; Nachbur et al , ; Najjar et al , ; Haile et al , ; He et al , ), all occupy the deep pocket (Fig G).…”

Section: Resultsmentioning

confidence: 65%

“…Previous reports showed that tyrosine‐kinase inhibitors such as ponatinib, gefitinib, and the RIPK2‐selective kinase inhibitors GSK583 and WEHI‐345 inhibit cellular responses to the NOD2 agonist MDP (or L18‐MDP) by antagonizing RIPK2 function (Tigno‐Aranjuez et al , ; Canning et al , ; Nachbur et al , ; Haile et al , ). In concordance, ponatinib and GSK583 inhibited the degradation of IκBα and NF‐κB‐mediated production of the chemokine CXCL8 in a dose‐dependent manner in U2OS/NOD2 cells stimulated with L18‐MDP (Fig A–C).…”

Section: Resultsmentioning

confidence: 99%

“…Ponatinib displays highly promiscuous inhibitory activity (Fauster et al , ; Najjar et al , ), and clinical development of GSK583 was halted (Haile et al , ), raising a need for new classes of RIPK2 inhibitors. We have developed a new chemical series of RIPK2 inhibitors, termed CSLP.…”

Section: Resultsmentioning

confidence: 99%

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Small molecule inhibitors reveal an indispensable scaffolding role of RIPK 2 in NOD 2 signaling

et al. 2018

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RIPK2 mediates inflammatory signaling by the bacteria‐sensing receptors NOD1 and NOD2. Kinase inhibitors targeting RIPK2 are a proposed strategy to ameliorate NOD‐mediated pathologies. Here, we reveal that RIPK2 kinase activity is dispensable for NOD2 inflammatory signaling and show that RIPK2 inhibitors function instead by antagonizing XIAP‐binding and XIAP‐mediated ubiquitination of RIPK2. We map the XIAP binding site on RIPK2 to the loop between β2 and β3 of the N‐lobe of the kinase, which is in close proximity to the ATP‐binding pocket. Through characterization of a new series of ATP pocket‐binding RIPK2 inhibitors, we identify the molecular features that determine their inhibition of both the RIPK2‐XIAP interaction, and of cellular and in vivo NOD2 signaling. Our study exemplifies how targeting of the ATP‐binding pocket in RIPK2 can be exploited to interfere with the RIPK2‐XIAP interaction for modulation of NOD signaling.

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Section: Resultsmentioning

confidence: 65%

Section: Resultsmentioning

confidence: 99%

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Small molecule inhibitors reveal an indispensable scaffolding role of RIPK 2 in NOD 2 signaling

et al. 2018

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“…Finally, substituents at the 6- and 7-position of the quinoline are directed toward the surface of the protein. Changes in the aniline head group and on the quinoline core are known to affect kinase potency and selectivity profiles in other, structurally-related inhibitor series [33] , as these parts of the ligand project into a pocket lined with varied functionality or having a range of conformational plasticity [30b] .…”

Section: Discussionmentioning

confidence: 99%

Identification and Optimization of 4‐Anilinoquinolines as Inhibitors of Cyclin G Associated Kinase

et al. 2017

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4-Anilinoquinolines were identified as potent and narrow-spectrum inhibitors of the cyclin G associated kinase (GAK), an important regulator of viral and bacterial entry into host cells. Optimization of the 4-anilino group and the 6,7-quinoline substituents produced GAK inhibitors with nanomolar activity, over 50 000-fold selectivity relative to other members of the numb-associated kinase (NAK) subfamily, and a compound (6,7-dimethoxy-N-(3,4,5-trimethoxyphenyl)quinolin-4-amine; 49) with a narrow-spectrum kinome profile. These compounds may be useful tools to explore the therapeutic potential of GAK in prevention of a broad range of infectious and systemic diseases.

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“…This conformation is stabilized allosterically by dimerization or by interaction with another protein. Interestingly, all the recently published RIP2K structures, with or without inhibitor bound, show that phosphorylated RIP2K crystallises as a side-by-side dimer, highlighting the possibility that dimerization plays a role in kinase activation [4, 13, 35, 37–40]. The symmetrical RIP2K homodimer is antiparallel with the N-Lobe of one monomer interacting with the C-Lobe of the other and the two active sites facing in opposite directions [38, 39].…”

Section: Introductionmentioning

confidence: 99%

Structures of the inactive and active states of RIP2 kinase inform on the mechanism of activation

Pellegrini¹,

Signor²,

Singh³

et al. 2017

PLoS ONE

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Innate immune receptors NOD1 and NOD2 are activated by bacterial peptidoglycans leading to recruitment of adaptor kinase RIP2, which, upon phosphorylation and ubiquitination, becomes a scaffold for downstream effectors. The kinase domain (RIP2K) is a pharmaceutical target for inflammatory diseases caused by aberrant NOD2-RIP2 signalling. Although structures of active RIP2K in complex with inhibitors have been reported, the mechanism of RIP2K activation remains to be elucidated. Here we analyse RIP2K activation by combining crystal structures of the active and inactive states with mass spectrometric characterization of their phosphorylation profiles. The active state has Helix αC inwardly displaced and the phosphorylated Activation Segment (AS) disordered, whilst in the inactive state Helix αC is outwardly displaced and packed against the helical, non-phosphorylated AS. Biophysical measurements show that the active state is a stable dimer whilst the inactive kinase is in a monomer-dimer equilibrium, consistent with the observed structural differences at the dimer interface. We conclude that RIP2 kinase auto-phosphorylation is intimately coupled to dimerization, similar to the case of BRAF. Our results will help drug design efforts targeting RIP2 as a potential treatment for NOD2-RIP2 related inflammatory diseases.

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The Identification and Pharmacological Characterization of 6-(tert-Butylsulfonyl)-N-(5-fluoro-1H-indazol-3-yl)quinolin-4-amine (GSK583), a Highly Potent and Selective Inhibitor of RIP2 Kinase

Cited by 107 publications

References 57 publications

Small molecule inhibitors reveal an indispensable scaffolding role of RIPK 2 in NOD 2 signaling

Small molecule inhibitors reveal an indispensable scaffolding role of RIPK 2 in NOD 2 signaling

Identification and Optimization of 4‐Anilinoquinolines as Inhibitors of Cyclin G Associated Kinase

Structures of the inactive and active states of RIP2 kinase inform on the mechanism of activation

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