Discovery of CC-99677, a selective targeted covalent MAPKAPK2 (MK2) inhibitor for autoimmune disorders

Malona, John; Chuaqui, Claudio; Seletsky, Boris M.; Beebe, Lisa; Cantin, Susan; Kalken, Daniel van; Fahnoe, Kelly; Wang, Zhigang; Browning, Beth; Szabo, Hilary; Koopman, Louise A.; Oravecz, Tamás; McDonald, Joseph J.; Ramírez‐Valle, Francisco; Gaur, Rajula; Mensah, Kofi A.; Thomas, Michael A.; Connarn, Jamie; Hu, Haijun; Alexander, Matthew; Corin, Alan F.

doi:10.1016/j.trsl.2022.06.005

Cited by 14 publications

(19 citation statements)

References 60 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We have previously shown that CC-99677 inhibits inflammatory cytokine production from LPS-stimulated healthy donor PBMCs, including TNF, IL-6, and granulocyte-macrophage colony-stimulating factor (GM-CSF) [23]. We investigated the effect of CC-99677 in AS patient samples and observed a similar concentration-dependent inhibition of TNF production in LPS-stimulated PBMCs (Fig.…”

Section: Cc-99677 Inhibited Cytokine Production In Pbmcs From Patient...mentioning

confidence: 78%

“…The effects of CC-99677 in vitro and in vivo supported the initiation of a FIH clinical study in healthy volunteers [23]. The PK and PD of single ascending doses of CC-99677 have been reported [23].…”

Section: Cc-99677 Was Safe and Well-tolerated In A Multiple Ascending...mentioning

confidence: 88%

“…Target engagement of MK2 was measured using the streptavidin mass shift (SMaSh) assay in PBMCs, which is designed to indicate amounts of MK2 occupied and unoccupied by covalently bound CC-99677 [23,27]. Blood was collected for PBMC isolation at pre-specified time points, before dosing on days 1, 2, 3, 5, 7, and 14 and then following the last dose on days 15, 17, 21, and 28.…”

Section: Target Engagement Assaymentioning

confidence: 99%

“…MK2 knockout mice, unable to stabilize transcripts of pro-inflammatory cytokines via TTP, are protected from inflammation in various inflammatory disease models [15,21]. MK2 inhibitors have demonstrated efficacy in models of arthritis and AS [21][22][23].…”

Section: Introductionmentioning

confidence: 99%

“…We explore the relationship between drug exposure and tachyphylaxis potential in a novel in vitro assay in THP-1 cells and contrast CC-99677 activity with activity of p38 inhibitors. We also report data from the phase I first-in-human (FIH) multiple ascending-dose (MAD) study to characterize the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of CC-99677 in healthy volunteers treated with CC-99677; single ascending-dose data are reported elsewhere [23,24]. and washed with phosphate-buffered saline (PBS).…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

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

et al. 2022

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Cc-99677 Inhibited Cytokine Production In Pbmcs From Patient...mentioning

confidence: 78%

Section: Cc-99677 Was Safe and Well-tolerated In A Multiple Ascending...mentioning

confidence: 88%

Section: Target Engagement Assaymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

et al. 2022

Self Cite

View full text Add to dashboard Cite

show abstract

Remodeling tumor‐associated macrophage for anti‐cancer effects by rational design of irreversible inhibition of mitogen‐activated protein kinase‐activated protein kinase 2

Wang,

Sun,

Wang

et al. 2024

MedComm

View full text Add to dashboard Cite

Mitogen‐activated protein kinase‐activated protein kinase 2 (MK2) emerges as a pivotal target in developing anti‐cancer therapies. The limitations of ATP‐competitive inhibitors, due to insufficient potency and selectivity, underscore the urgent need for a covalent irreversible MK2 inhibitor. Our initial analyses of The Cancer Genome Atlas database revealed MK2's overexpression across various cancer types, especially those characterized by inflammation, linking it to poor prognosis and highlighting its significance. Investigating MK2's kinase domain led to the identification of a unique cysteine residue, enabling the creation of targeted covalent inhibitors. Compound 11 was developed, demonstrating robust MK2 inhibition (IC50 = 2.3 nM) and high selectivity. It binds irreversibly to MK2, achieving prolonged signal suppression and reducing pathological inflammatory cytokines in macrophages. Furthermore, compound 11 or MK2 knockdown can inhibit the tumor‐promoting macrophage M2 phenotype in vitro and in vivo. In macrophage‐rich tumor model, compound 11 notably slowed growth in a dose‐dependent manner. These findings support MK2 as a promising anticancer target, especially relevant in cancers fueled by inflammation or dominated by macrophages, and provide compound 11 serving as an invaluable chemical tool for exploring MK2's functions.

show abstract

Progress in the development of kinase inhibitors for treating asthma and COPD

McClean¹,

Hasday²,

Shapiro³

2023

Advances in Pharmacology

View full text Add to dashboard Cite

Discovery of CC-99677, a selective targeted covalent MAPKAPK2 (MK2) inhibitor for autoimmune disorders

Cited by 14 publications

References 60 publications

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

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

Remodeling tumor‐associated macrophage for anti‐cancer effects by rational design of irreversible inhibition of mitogen‐activated protein kinase‐activated protein kinase 2

Progress in the development of kinase inhibitors for treating asthma and COPD

Contact Info

Product

Resources

About