Abstract 1658: REM-422, a first-in-class mRNA degrader of the MYB oncogene, demonstrates anti-tumor activity in xenograft models of adenoid cystic carcinoma and acute myeloid leukemia

The c-MYB (MYB) oncogenic transcription factor is a key regulator of hematopoietic cell differentiation and proliferation. Recurrent genetic lesions and dysregulation of MYB have been identified in a variety of cancers, including adenoid cystic carcinoma (ACC), acute myeloid leukemia (AML), colorectal cancer (CRC), and others. We describe the mechanism of action and biological activity of REM-422, a first-in-class, potent, selective, oral small molecule messenger RNA (mRNA) degrader of MYB being developed for the treatment of ACC (NCT06118086) as well as AML and high-risk myelodysplastic syndrome (HR-MDS) (NCT06297941). Using biophysical and cellular assays, REM-422 is shown to act by selectively facilitating the binding of the U1 snRNP spliceosome complex, which governs exon usage by recognizing 5’ splice sites, to a normally unused ‘poison exon’ (PE), which contains a premature termination codon, in the MYB pre-mRNA transcript. Cells treated with REM-422 demonstrated increased MYB poison exon inclusion, leading to degradation of MYB mRNA by nonsense-mediated decay and subsequent reduction in MYB protein levels. REM-422 phenocopied gene expression changes observed with shRNA hairpin-mediated knockdown of MYB and demonstrated preferential anti-proliferative activity in cell lines with high MYB expression and known MYB genetic dependency. To understand the pharmacokinetic, pharmacodynamic, and anti-tumor effects of REM-422 in vivo, ACC patient-derived xenograft (PDX) models harboring MYB translocations were established in nude mice. QD PO administration of REM-422 demonstrated strong and dose-dependent reductions in MYB mRNA and protein levels. Furthermore, REM-422 treatment led to dose-dependent inhibition of tumor growth and tumor regressions at well tolerated doses. RNAseq and immunohistochemistry analysis confirmed modulation of MYB target genes in tumors from mice exposed to REM-422. To evaluate the activity of REM-422 in a disseminated PDX model of AML, patient cells were engrafted by tail vein injection into NOG mice and mice were dosed PO QD with REM-422. After 24 days of dosing, REM-422 led to the eradication of human leukemia cells from both compartments and prevented AML cell engraftment-induced body weight loss. Immunohistochemistry staining confirmed the reduction of MYB protein in the bone marrow of treated animals. Flow cytometry analysis of bone marrow and whole blood demonstrated that REM-422 treatment led to an increase in blasts expressing CD14 and CD11b, known myeloid differentiation markers, as well as an increased frequency of Annexin V+ blasts, a marker of early apoptosis. These data illustrate the potential for REM-422 as an investigational agent for the treatment of a variety of solid tumor and hematological malignancies. Citation Format: Samantha Levin-Furtney, Michael P. Thomas, Alycen Harney, Alexander Ivliev, Jesper Maag, Sudeep Prajapati, Michael Seiler, Dominic Reynolds, Silvia Buonamici, Charles Kung. REM-422, a first-in-class mRNA degrader of the MYB oncogene, demonstrates anti-tumor activity in xenograft models of adenoid cystic carcinoma and acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1658.