RGT-61159, Best-in-Class Small Molecule Inhibitor of MYB Via Selective RNA Splicing Alteration, Showed Robust Anti-Tumor Activity across AML Tumor Models Harboring Common Genetic Lesions

MYB gene encodes a transcription factor that acts as a master regulator of cells self-renewal, proliferation and differentiation processes. MYB is frequently upregulated or aberrantly activated in a variety of solid cancers (e.g., adenoid cystic carcinoma [ACC], colorectal cancer [CRC], and liquid tumors). In leukemias, high MYB RNA levels are especially frequent (90%) in acute myeloid leukemia (AML). In addition, in T-cell acute lymphoblastic leukemia (T-ALL), MYB is overactivated in 20-30% of patient population due to well characterized genetic lesions (e.g., chromosomal translocations [c-MYB/AHI1; TCRB-MYB 8%], gene duplication [19%]), or somatic mutations. Importantly, a genome-wide CRISPR-Cas9 screen identified MYB as an essential gene for leukemia/lymphoma cell lines viability. Altogether, data strongly suggest MYB as a promising therapeutic target to treat blood cancers. RGT-61159 is a potent, selective oral small molecule inhibitor of the MYB oncogene via the inclusions of a cryptic exon into MYB RNA transcripts, resulting in the activation of the nonsense-mediated decay pathway promoting MYB mRNA depletion and sequentially MYB protein degradation. RGT-61159 Phase 1 study in adults with relapsed/ refractory ACC or CRC has been initiated (NCT 06462183) Here, we report RGT-61159 robust MYB RNA & protein knockdown and cell-killing activity across a broad range of different AML cell lines with different oncogenic abnormalities. Such a data set supports that RGT-61159 killing activity of leukemic cells is driven by MYB signaling inhibition and confirms MYB dependency across a broad AML patient population. In addition, we report proteomic and genomic analyses of different AML cell lines treated with RGT-61159 that provided further lights on key oncogenes (e.g., BCL2, NOTCH, MYC) directly regulated by MYB in a cell genetic context dependent. To further evaluate RGT-61159's potential to treat leukemia, RGT-61159 single agent was profiled in a battery of murine models of AML harboring the most common genetic lesions (e.g., AML-1-ETO, MLL-fusion and NPM1 mutation). RGT-61159 showed highly significant anti-tumor activity across the different AML tumor models tested along with robust MYB RNA depletion in tumor cells (up to 90% tumor growth inhibition [TGI]) in a dose dependent manner and at tolerated doses. In summary, MYB oncogene represents a therapeutic target of relevance to AML and other hematological malignancies. RGT-61159 is a potent and selective oral small molecule inhibitor of MYB RNA and protein and an attractive therapeutic avenue to treat cancers overexpressing the oncogenic MYB protein.