Dataset Information

CC-99677, a novel, oral, selective covalent MK2 inhibitor, sustainably reduces pro-inflammatory cytokine production.

ABSTRACT:

Background

Mitogen-activated protein kinase (MAPK)-activated protein kinase-2 (MK2) is activated downstream of p38 MAPK and regulates stability of mRNAs encoding inflammatory cytokines. CC-99677 is a novel, irreversible, covalent MK2 inhibitor under development for the treatment of ankylosing spondylitis (AS) and other inflammatory diseases. As part of a phase I clinical trial to assess safety and tolerability, we evaluated target engagement, pharmacokinetics, and pharmacodynamics of CC-99677.

Methods

The MK2 inhibitor CC-99677 was evaluated for its effect on cytokine expression in vitro in peripheral blood mononuclear cells (PBMCs) from healthy donors and patients with a definitive AS diagnosis. A novel in vitro model was developed to compare the potential for tachyphylaxis of CC-99677 and p38 inhibitors in THP-1 cells. The effect of CC-99677 on tristetraprolin (TTP) and cytokine mRNA was assessed in stimulated human monocyte-derived macrophages. In a first-in-human study, thirty-seven healthy volunteers were randomly assigned to daily oral doses of CC-99677 or placebo, and blood was collected at pre-specified time points before and after dosing. CC-99677 concentrations were assessed in the plasma, and CC-99677 binding to MK2 was evaluated in PBMCs. Ex vivo stimulation of the whole blood was conducted from participants in the first-in-human study to assess the pharmacodynamic effects.

Results

In vitro, CC-99677 inhibited tumor necrosis factor (TNF), interleukin (IL)-6, and IL-17 protein production in samples of monocytes and macrophages from AS patients and healthy volunteers via an mRNA-destabilization mechanism. In the in vitro model of tachyphylaxis, CC-99677 showed a differentiated pattern of sustained TNF protein inhibition compared with p38 inhibitors. CC-99677 reduced TTP phosphorylation and accelerated the decay of inflammatory cytokine mRNA in lipopolysaccharide-stimulated macrophages. Administration of CC-99677 to healthy volunteers was safe and well-tolerated, with linear pharmacokinetics and sustained reduction of ex vivo whole blood TNF, IL-6, and chemokine synthesis.

Conclusions

CC-99677 inhibition of MK2 is a promising approach for the treatment of inflammatory diseases and may overcome the limitations of p38 MAPK inhibition.

Trial registration

ClinicalTrials.gov NCT03554993 .

SUBMITTER: Gaur R

PROVIDER: S-EPMC9386913 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Publications

CC-99677, a novel, oral, selective covalent MK2 inhibitor, sustainably reduces pro-inflammatory cytokine production.

Gaur Rajula R Mensah Kofi A KA Stricker Jason J Adams Mary M Parton Anastasia A Cedzik Dorota D Connarn Jamie J Thomas Michael M Horan Gerald G Schafer Peter P Mair Stuart S Palmisano Maria M Ramírez-Valle Francisco F

Arthritis research & therapy 20220818 1

<h4>Background</h4>Mitogen-activated protein kinase (MAPK)-activated protein kinase-2 (MK2) is activated downstream of p38 MAPK and regulates stability of mRNAs encoding inflammatory cytokines. CC-99677 is a novel, irreversible, covalent MK2 inhibitor under development for the treatment of ankylosing spondylitis (AS) and other inflammatory diseases. As part of a phase I clinical trial to assess safety and tolerability, we evaluated target engagement, pharmacokinetics, and pharmacodynamics of CC- ...[more]

PMID: 35982464

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Dataset Information

CC-99677, a novel, oral, selective covalent MK2 inhibitor, sustainably reduces pro-inflammatory cytokine production.

Background

Methods

Results

Conclusions

Trial registration

Publications

CC-99677, a novel, oral, selective covalent MK2 inhibitor, sustainably reduces pro-inflammatory cytokine production.

Similar Datasets

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