Abstract Dysregulation of c-Myc is implicated in over half of all cancers, making it the most important undrugged oncogene. As a transcription factor, the c-Myc protein is not amenable to traditional small molecule inhibition. Recent attempts to reduce c-Myc activity with novel modalities have had limited success in the clinic, highlighting the need for Myc-targeted therapeutics with improved potency and cell permeability. We previously reported discovery of small molecules that bind to structured elements in the 5’ UTR of the c-Myc mRNA and repress translation of the c-Myc protein. Here, we describe our hit-to-lead campaign, in which we dramatically improved the potency (70x), selectivity (5x) and oral bioavailability (13x) of our c-Myc RNA-targeting small molecules, yielding a lead series that suppresses tumor growth in an in vivo cell line-derived xenograft (CDX) model of small cell lung cancer (SCLC). Using a ligand-based approach, we designed and synthesized over 150 analogs of our top hit series and characterized their ability to repress c-Myc protein levels and reduce viability of the highly MYC-amplified SCLC cell line NCI-H82. Notably, we observe excellent correlation between c-Myc protein repression and compound potency, supporting an on-target mechanism. Our compounds demonstrate rapid (∼30 min half-life), selective and reversible protein knockdown, consistent with inhibition of c-Myc translation initiation followed by normal protein turnover. We have now achieved single-digit nanomolar potency and continue to make improvements thanks to the establishment of a strong structure-activity relationship for our lead series. In parallel, we dramatically improved the ADME/PK properties of our series by identifying and correcting a structural liability for liver metabolism. The resulting tool molecule achieved 60% oral bioavailability and exposure above the in vitro IC50 for extended periods, enabling twice-daily oral dosing. This compound achieved significant tumor growth inhibition in a SCLC CDX model and, importantly, dosing was well tolerated by all animals. Beyond SCLC, we observe in vitro efficacy against cell lines from a range of solid and heme cancers, opening the door for xenograft studies in additional indications. Together, our results validate an RNA-targeted small molecule approach to repress c-Myc. Our promising in vivo data, coupled with sustained oral exposure and favorable tolerability, highlight the potential of this modality to overcome long-standing barriers in MYC drug discovery. Ongoing xenograft and mechanistic studies are expected to further expand the clinical opportunities for treating MYC-driven solid and hematologic cancers. Citation Format: Michelle Kriner, Chuhern Hwang, Fusayo Koyanagi, Brett Israels, Tien Phan-Everson, Wanling Kratzman, Isha Gupta, Jason Fontana, David Sparkman-Yager, . Potent, orally bioavailable small molecules that inhibit c-Myc translation and suppress tumor growth in vivo abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6732.
Kriner et al. (Fri,) studied this question.