Preclinical data show GT19630 degrades MYC and GSPT1 in TP53-mutant leukemia models

The study used cell lines, patient-derived xenografts, and single-cell RNA-seq to map a feed-forward loop in which MYC transcriptionally activates GSPT1 while GSPT1 stabilizes MYC protein. GT19630 binds both targets, recruiting the ubiquitin-proteasome system and lowering both proteins within hours. Activity persisted in TP53-mutant and venetoclax-resistant models, with selective depletion of MYC-high leukemic stem cells relative to normal hematopoietic stem cells.

Prior attempts to drug MYC directly failed because the protein lacks a suitable binding pocket. This approach instead exploits a synthetic vulnerability downstream of MYC, offering a route around structural undruggability. The same mechanism may apply to MYC-driven solid tumors, but the current dataset is restricted to hematologic malignancies.

Next steps include IND-enabling toxicology and biomarker development focused on MYC and GSPT1 transcript levels. No human safety or efficacy data exist yet.