THERAPY

Selective p38α MAPK inhibitor shows promise

CDD-450, a newly developed inhibitor that selectively blocks the mitogen-activated protein kinase p38α (p38α MAPK)–MAPK-activated protein kinase 2 (MK2) axis, is a potential drug candidate for autoimmune and autoinflammatory diseases such as rheumatoid arthritis (RA) and cryopyrinopathies, according to findings published in the Journal of Experimental Medicine.

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“Global p38α MAPK inhibitors have failed in phase II RA clinical studies owing to transient efficacy. We hypothesize that this transient efficacy is a result of inhibition of multiple downstream pathways, including those with anti-inflammatory functions,” remarks corresponding author Gabriel Mbalaviele. “CDD-450 selectively blocks p38α MAPK activation of the pro-inflammatory kinase MK2, while sparing p38α MAPK activation of several other downstream pathways.”

MK2 regulates the expression of pro-inflammatory cytokines by phosphorylating downstream effectors that bind to and regulate mRNA stability. In the study by Wang et al., CDD-450 treatment promoted the degradation of mRNA encoding IL-1β and TNF in lipopolysaccharide (LPS)-stimulated bone marrow macrophages.

Oral administration of either CDD-450 or the global p38α MAPK inhibitor CDD-111 inhibited LPS-induced serum expression of TNF in healthy mice. However, unlike CDD-111, the efficacy of CDD-450 persisted for up to 4 weeks.

Mbalaviele and colleagues investigated the therapeutic potential of CDD-450 in two disease models. In a mouse model of neonatal onset multisystem inflammatory disease (NOMID), CDD-450-treated mice lost less weight and produced less IL-1β and IL-18 in their bone marrow compared with untreated mice. CDD-450 treatment also prevented the development of skin lesions, bone destruction and death in these mice. Similarly, in a rat model of streptococcal cell wall-induced arthritis, CDD-450 treatment inhibited paw swelling and preserved bone mineral density.

“CDD-450 treatment inhibited paw swelling and preserved bone mineral density”

“These findings have clinical translation implications as CDD-450 offers the potential to avoid tachyphylaxis associated with classical p38α MAPK inhibitors,” says Mbalaviele “Studies are underway to support the clinical development of CDD-450.”

References

Original article

  1. Wang, C. et al. Selective inhibition of the p38α MAPK–MK2 axis inhibits inflammatory cues including inflammasome priming signals. J. Exp. Med. https://doi.org/10.1084/jem.20172063 (2018)

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Correspondence to Jessica McHugh.

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McHugh, J. Selective p38α MAPK inhibitor shows promise. Nat Rev Rheumatol 14, 321 (2018). https://doi.org/10.1038/s41584-018-0003-y

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