Zunsemetinib

Zunsemetinib is a p38α MAPK inhibitor biased toward MAPK-activated protein kinase 2 (MK2).¹ It selectively inhibits p38α MAPK-dependent activation of MK2 over p38α MAPK-dependent activation of MK5, also known as p38-regulated/activated protein kinase (PRAK), and p38α MAPK-dependent activation of activating transcription factor 2 (ATF2) by 750- and 700-fold, respectively. It is also greater than 350-fold selective for p38α MAPK over a panel of 193 other kinases at 5 µM. Zunsemetinib (10 µM) reduces LPS-induced increases in the levels of mRNA encoding Il-1β in isolated mouse bone marrow macrophages (BMMs). It reduces body weight loss, neutrophilia, and the number of osteoclasts at trabecular and cortical bone surfaces in a model of conditional neonatal-onset multisystem inflammatory disease (NOMID^c) using Nlrp3^fl(D301N)/+;Cre^ER mice. Zunsemetinib enhances decreases in tumor volume and increases in survival in an autochthonous KPC murine pancreatic ductal adenocarcinoma (PDAC) model when used with FIRINOX, which is a combination of the FdUMP prodrug 5-fluorouracil (Item No. 14416), DNA topoisomerase I inhibitor irinotecan (Item No. 14180), and DNA-crosslinking agent oxaliplatin (Item No. 13106).²

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1. Wang, C., Hockerman, S., Jacobsen, E.J., et al. Selective inhibition of the p38α MAPK-MK2 axis inhibits inflammatory cues including inflammasome priming signals. J. Exp. Med. 215(5), 1315-1325 (2018).

2. Grierson, P.M., Dodhiawala, P.B., Cheng, Y., et al. The MK2/Hsp27 axis is a major survival mechanism for pancreatic ductal adenocarcinoma under genotoxic stress. Sci. Transl. Med. 13(622), eabb5445 (2021).