Abstract Lung cancer is the leading cause of cancer-associated deaths worldwide. SCLC entails ∼15% of cases1 and is considered one of the most aggressive forms associated a dismal prognosis. Unfortunately, the treatment options for SCLC are practically unchanged since the 80s. In SCLC 20% of patients show amplification or transcriptional upregulation of Myc family members. Myc is also amplified in up to 33% of NSCLC patients and is a prognostic marker of early-stage tumors2,3. Thus c-MYC represents an attractive therapeutic target in lung cancer. However, the intra-nuclear localization and intrinsically disordered nature of the protein renders successful small molecule or antibody drug development extremely problematic. Consequent to these challenges, no direct inhibitor of c-MYC has yet advanced into the clinic.4Here, we present the mechanism of action, in vivo lung cancer efficacy and the drug-like properties of IDP-121, a stapled peptide specifically designed to directly target the c-MYC protein (see Abstract 1). IDP-121 penetrates tumor cells at nanomolar concentrations by a translocation mechanism, avoiding endosomal trapping and presenting a prolonged intra-nuclear half-life. IDP-121 leads to c-MYC/MAX complex disruption as demonstrated by immunoprecipitation, promotes c-MYC degradation and a decrease in DNA-binding activity to its consensus-binding site by ELISA-based assays. A reduction of c-MYC protein binding at promoters of Myc-occupied gene is observed in IDP-121 treated cells through the genome by ChIP-seq. Furthermore, c-Myc gene expression levels remain unaffected, consistent with a direct c-MYC inhibitor. Flow cytometry shows increase in apoptosis by Annexin V staining. In vivo, IDP-121 shows significant reduction of tumor growth in syngenic and orthotopic SCLC models administered i.v. and s.c. The HPLC-MS and IHC analyses of tumor tissue after treatment confirm effective tumoral tissue distribution and target engagement, with significant reduction of c-MYC protein and cell proliferation in vivo. IDP-121 is highly stable in plasma, is not affected by hepatic metabolism and it is highly bound to plasma proteins. Thus, evidence suggests that we have identified a first-in-class stapled peptide direct inhibitor of MYC that shows efficacy in lung cancers at low exposure levels with no systemic toxicity. The efficacy in hematological tumors of IDP-121 have been also demonstrated in vivo (see Abstract 2). In addition, IDP-121 has progressed through GLP toxicology studies without evidence of major systemic toxicity, allowing for the first viable Myc-targeted therapy to enter Phase 1 clinical trials in 2021. 1Bragelmann J. et al. Cell Cycle 2017;16:1489-14982Georige J. et al. Nature. 524(7563), 47–53 (2015) 3Mollaoglu G. et al. Cancer Cell. 31(2), 270–285 (2017)4 Whitfield J. R. et al. Front. Cell Dev. Biol. 2017 Citation Format: Haritz Moreno, Borja Ruiz Fernández-de-Córdoba, Carolina Zandueta, Susana Martínez-Canarias, Miguel Moreno, Joan J. Albertí, Laura Nevola, Santiago Esteban, Silvestre Vicent, Fernando Lecanda. A first-in-class c-MYC inhibitor shows in vivo efficacy in lung cancer models and has appropriate drug-like characteristics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1264.