Zunsemetinib

Zunsemetinib is a p38alpha MAPK inhibitor biased toward MAPK-activated protein kinase 2 (MK2). It selectively inhibits p38alpha MAPK-dependent activation of MK2 over p38alpha MAPK-dependent activation of MK5, also known as p38-regulated/activated protein kinase (PRAK), and p38alpha MAPK-dependent activation of activating transcription factor 2 (ATF2) by 750- and 700-fold, respectively. It is also greater than 350-fold selective for p38alpha 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-1beta 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 (NOMIDc) using Nlrp3fl(D301N)/+,CreER 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 (Cay-14416), DNA topoisomerase I inhibitor irinotecan (Cay-14180), and DNA-crosslinking agent oxaliplatin (Cay-13106).Formal Name: (2'S)-3-chloro-4-[(3,5-difluoro-2-pyridinyl)methoxy]-2'-[2-(1-hydroxy-1-methylethyl)-4-pyrimidinyl]-5',6-dimethyl-[1(2H),4'-bipyridin]-2-one. CAS Number: 1640282-42-3. Synonyms: ATI-450, CDD-450. Molecular Formula: C25H22ClF2N5O3. Formula Weight: 513.9. Purity: >98%. Formulation: (Request formulation change), A solid. Solubility: DMSO: Soluble: >10 mg/ml, Ethanol: Sparingly soluble: 1-10 mg/ml. SMILES: CC1=CN=C(C2=CC=NC(C(C)(C)O)=N2)C=C1N(C(C)=CC(OCC3=NC=C(F)C=C3F)=C4Cl)C4=O. InChi Code: InChI=1S/C25H22ClF2N5O3/c1-13-10-30-18(17-5-6-29-24(32-17)25(3,4)35)9-20(13)33-14(2)7-21(22(26)23(33)34)36-12-19-16(28)8-15(27)11-31-19/h5-11,35H,12H2,1-4H3. InChi Key: FQPQMJULRZINPV-UHFFFAOYSA-N.