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.

No relevant conflicts of interest to declare.