PF-3644022

PF-3644022 is an inhibitor of MAPK-activated protein kinase 2 (MK2; IC₅₀ = 5.2 nM).¹ It is selective for MK2 over MK3, MAPK-interacting protein kinase 1 (MNK-1), MNK-2, p90 ribosomal S6 kinase 1 (MSK1), MSK2, and p90 ribosomal S6 kinases 1-4 (RSK1-4; IC₅₀s = 53, 3,000, 148, >1,000, >1,000, and >1,000 nM, respectively), as well as a panel of 200 other kinases at 1 µM, but also inhibits MK5/PRAK (IC₅₀ = 5 nM). PF-3644022 inhibits LPS-induced TNF-α production in U937 cells and isolated human peripheral blood mononuclear cells (PBMCs) and whole blood (IC₅₀s = 0.159, 0.16, and 1.97 µM, respectively) and reduces paw swelling in a rat model of arthritis induced by streptococcal cell wall peptidoglycan–polysaccharide complexes (ED₅₀ = 20 mg/kg). It prevents decreases in motor function in a twy/twy mouse model of chronic cervical spinal cord compression when administered at a dose of 30 mg/kg.² Peritumoral administration of PF-3644022 (30 µl of a 50 µM solution) enhances radiation-induced decreases in tumor volume and increases in survival in a patient-derived xenograft (PDX) mouse model of head and neck squamous cell carcinoma (HNSCC).³

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1. Mourey, R.J., Burnette, B.L., Brustkern, S.J., et al. A benzothiophene inhibitor of mitogen-activated protein kinase-activated protein kinase 2 inhibits tumor necrosis factor α production and has oral anti-inflammatory efficacy in acute and chronic models of inflammation. J. Pharmacol. Exp. Ther. 333(3), 797-807 (2010).

2. Yu, L., Song, H., Fang, X., et al. Role of MK2 signaling pathway mediating microglia/macrophages polarization in chronic compression injury of cervical spinal cord. Ann. Palliat. Med. 10(2), 1304-1312 (2021).

3. Berggren, K.L., Cruz, S.R., Hixon, M.D., et al. MAPKAPK2 (MK2) inhibition mediates radiation-induced inflammatory cytokine production and tumor growth in head and neck squamous cell carcinoma. Oncogene 38(48), 7329-7341 (2019).