Abstract The RAS /RAF /MEK / ERK signal transduction pathway is frequently activated in several human cancers, due to a gain of function mutations in KRAS, NRAS, or BRAF. Because of the high frequency of activating mutations, this pathway has become a focus for targeted therapy. A wide spectrum of MEK and RAF inhibitors have been developed to inhibit components of the pathway. Vemurafenib and dabrafenib, selective BRAF inhibitors, and trametinib, an allosteric MEK inhibitor, have shown clinical efficacy in melanoma patients. However, the majority of responses to RAF inhibitors are transient and acquired resistance is often associated with pathway reactivation involving the downstream extracellular-signal-regulated kinases 1 and 2 (ERK1/2). Pathway blockade at ERK, the last signaling node prior to MAPK transcriptional programming, may not only be efficacious in MAPK-activated tumors but might also have utility in RAF or MEK inhibitor resistant settings. This abstract describes the identification and characterization of SCH772984, a potent and selective ATP competitive inhibitor of ERK1/2 which displays behaviors of both type I and type II kinase inhibitors. SCH772984 has nanomolar cellular potency on tumor cells with mutations in RAF, NRAS, or KRAS and induces tumor regressions in xenograft models at tolerated doses. SCH772984 effectively inhibited MAPK signaling and cell proliferation in RAF or MEK inhibitor resistant models as well as in the context of RAF/MEK combination resistance. Together these data support the clinical development of ERK inhibitors, not only in patients with MAPK activated tumors, but also in patients who have developed acquired resistance to RAF or MEK inhibitors or resistance to the recently described combination of these agents. Strategies to overcome acquired resistance to pathway inhibitors will be also described. Citation Format: Ahmed A. Samatar. Discovery of a first-in-class ERK 1,2 inhibitor. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(12 Suppl):Abstract nr IA06. doi: 10.1158/1557-3125.RASONC14-IA06