Discovery of selective and orally available spiro-3-piperidyl ATP-competitive MK2 inhibitors

Kaptein, Allard; Oubrie, Arthur; Zwart, Edwin de; Hoogenboom, Niels; Wit, Joeri de; Kar, Bas van de; Hoek, Maaike van; Vogel, G; Kimpe, Vera de; Schultz‐Fademrecht, Carsten; Borsboom, Judith; Zeeland, M. van; Versteegh, Judith; Kazemier, Bert; Roos, Jeroen de; Wijnands, Frank; Dulos, John; Jaeger, Martin; Leandro-Garcia, Paula; Barf, Tjeerd

doi:10.1016/j.bmcl.2011.04.016

Cited by 19 publications

(11 citation statements)

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“…Replacement of the methylenedioxophenyl moiety of 51 with aryl (variously substituted phenyl moieties) and heteroaryl (naphthyl, quinolyl, pyridyl, and pyrimidyl) substituents was tolerated and resulted in compounds with nanomolar affinity. 66 This suggested that the aromatic portion accommodated within the front region of the ATP binding site was not of crucial importance in determining affinity toward MK2. Cellular activity of these compounds was in the micromolar range in most cases, and seemed to be correlated with lipophilicity values higher than 1 (expressed as calculated logP).…”

Section: Crystallization Studiesmentioning

confidence: 99%

“…The basicity of the unsubstituted 4-piperidine, that was introduced to ameliorate the solubility profile of these compounds, was suspected to be in part responsible of the lack of permeability and oral bioavailability. 66 The most simple attempt made to reduce p K a values of these compounds was to change the substitution pattern of the piperazine ring, by moving the basic nitrogen toward the electron-deficient pyrrole ring, resulting in a net electron-withdrawing balance. Accordingly with this hypothesis, 4- and 3-piperidyl analogues showed a difference of more than 0.4 log unit in their clogP.…”

Section: Crystallization Studiesmentioning

confidence: 99%

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Targeting Mitogen-Activated Protein Kinase-Activated Protein Kinase 2 (MAPKAPK2, MK2): Medicinal Chemistry Efforts To Lead Small Molecule Inhibitors to Clinical Trials

2015

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The p38/MAPK-activated kinase 2 (MK2) pathway is involved in a series of pathological conditions (inflammation diseases and metastasis) and in the resistance mechanism to antitumor agents. None of the p38 inhibitors entered advanced clinical trials because of their unwanted systemic side effects. For this reason, MK2 was identified as an alternative target to block the pathway, but avoiding the side effects of p38 inhibition. However, ATP-competitive MK2 inhibitors suffered from low solubility, poor cell permeability, and scarce kinase selectivity. Fortunately, non-ATP-competitive inhibitors of MK2 have been already discovered that allowed circumventing the selectivity issue. These compounds showed the additional advantage to be effective at lower concentrations in comparison to the ATP-competitive inhibitors. Therefore, although the significant difficulties encountered during the development of these inhibitors, MK2 is still considered as an attractive target to treat inflammation and related diseases, to prevent tumor metastasis, and to increase tumor sensitivity to chemotherapeutics.

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Section: Crystallization Studiesmentioning

confidence: 99%

Section: Crystallization Studiesmentioning

confidence: 99%

Targeting Mitogen-Activated Protein Kinase-Activated Protein Kinase 2 (MAPKAPK2, MK2): Medicinal Chemistry Efforts To Lead Small Molecule Inhibitors to Clinical Trials

2015

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“…In other words, for the majority of successful drugs, the cellular EC 50 values are no more than 2.5-fold higher than the biochemical binding or inhibition K i / IC 50 values. However, cellular efficacy data for MK2 inhibitors in disease-relevant assays are limited in the public domain, and BE calculated from these published values are far below the 0.4 threshold (Anderson et al, 2009;Mourey et al, 2010;Kaptein et al, 2011;Oubrie et al, 2012).…”

Section: The Therapeutic Potential Of Targeting Mk2mentioning

confidence: 99%

Mitogen-Activated Protein Kinase–Activated Protein Kinase 2 in Neuroinflammation, Heat Shock Protein 27 Phosphorylation, and Cell Cycle: Role and Targeting

2013

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Mitogen-activated protein kinase (MAPK)-activated protein kinase 2 (MAPKAPK-2 or MK2) is a downstream substrate of the p38 MAPK responsible for the signaling events influencing inflammation, cell division and differentiation, apoptosis, and cell motility in response to a wide range of extracellular stimuli. After the failure of p38 MAPK inhibitors in clinical trials, MK2 was unveiled as a potential target to regulate inflammatory cytokines' mRNA stability and translation. Recent work suggests that this mechanism may underlie the pathophysiology of brain disorders associated with inflammation. In addition, MK2 is a prominent kinase that phosphorylates heat shock protein 27 (Hsp27), an intensively investigated biomarker of cancer progression. This phosphorylation decreases the chaperone properties of Hsp27, making MK2 an endogenous inhibitor of Hsp27. MK2 is also one of the major players in the signal transduction pathways activated in response to DNA damage. Experimental evidence highlights the role of MK2 in G 2 /M and the mitotic spindle checkpoints, two mechanisms by which MK2 contributes to the maintenance of genomic stability. Thus, MK2 is considered a good molecular target to increase, in combination with chemotherapeutic agents, the sensitivity of treatment, especially in p53-mutated tumors. This review looks at the functions of MK2 in inflammation, Hsp27 regulation, and cell cycle checkpoint control with a focus on brain pathologies. Analysis of MK2 signaling in various disease models and a summary of the data on MK2 inhibitors suggest novel indications for MK2 inhibitors in addition to their mainstream use against peripheral inflammatory disorders.

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“…administration in an LPS rat model of inflammation [63]. The (S)-isomer of compound 2.18b is even more selective vs. other kinases than 2.18a, is orally bioavailable, and has a better PK profile, although its chiral nature could hinder its development [64]. Introduction of a benzamide substituent and replacement of the pyrimidine ring with a pyridine, as in compound 2.19 ( Figure 2.3), provides an extremely potent subfamily of in vitro and in vivo active MK2 inhibitors [65].…”

Section: Hsp27mentioning

confidence: 97%

Targeting the Protein Quality Control (PQC) Machinery

Seneci

2015

Chemical Modulators of Protein Misfolding and Neurodegenerative Disease

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Discovery of selective and orally available spiro-3-piperidyl ATP-competitive MK2 inhibitors

Cited by 19 publications

References 11 publications

Targeting Mitogen-Activated Protein Kinase-Activated Protein Kinase 2 (MAPKAPK2, MK2): Medicinal Chemistry Efforts To Lead Small Molecule Inhibitors to Clinical Trials

Targeting Mitogen-Activated Protein Kinase-Activated Protein Kinase 2 (MAPKAPK2, MK2): Medicinal Chemistry Efforts To Lead Small Molecule Inhibitors to Clinical Trials

Mitogen-Activated Protein Kinase–Activated Protein Kinase 2 in Neuroinflammation, Heat Shock Protein 27 Phosphorylation, and Cell Cycle: Role and Targeting

Targeting the Protein Quality Control (PQC) Machinery

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