biostudies-literatureUnknown13(4)Li XERK1/2 kinase is a key downstream node of the RAS-RAF-MEK-ERK signaling pathway. A highly potent and selective ERK1/2 inhibitor is a promising option for cancer treatment that will provide a potential solution for overcoming drug resistance. Herein we designed and synthesized a novel scaffold featuring a pyrrole-fused urea template. The lead compound, SHR2415, was shown to be a highly potent ERK1/2 inhibitor that exhibited high cell potency based on the Colo205 assay. In addition, SHR2415 displayed favorable PK profiles across species as well as robust <i>in vivo</i> efficacy in a mouse Colo205 xenograft model.ACS medicinal chemistry letters701-706https://www.ebi.ac.uk/biostudies/studies/S-EPMC9014502biostudies-literatureDiscovery of SHR2415, a Novel Pyrrole-Fused Urea Scaffold ERK1/2 Inhibitor.PMC9014502He FBai CZhang LDong PYang FCai GLi XZhang TFeng JTao WDong HChen YMao YfalseDiscovery of SHR2415, a Novel Pyrrole-Fused Urea Scaffold ERK1/2 Inhibitor.ERK1/2 kinase is a key downstream node of the RAS-RAF-MEK-ERK signaling pathway. A highly potent and selective ERK1/2 inhibitor is a promising option for cancer treatment that will provide a potential solution for overcoming drug resistance. Herein we designed and synthesized a novel scaffold featuring a pyrrole-fused urea template. The lead compound, SHR2415, was shown to be a highly potent ERK1/2 inhibitor that exhibited high cell potency based on the Colo205 assay. In addition, SHR2415 displayed favorable PK profiles across species as well as robust <i>in vivo</i> efficacy in a mouse Colo205 xenograft model.2022-01-01T00:00:00Z2022 Apr2025-04-20T02:23:22.371Z2025-04-20T02:23:22.371ZS-EPMC90145023545037210.1021/acsmedchemlett.2c00029