Targeting MYC/BCL2-Driven Lymphoma: The Emergence of BET Degrader K-256

A new approach to treating MYC/BCL2-associated lymphoma has been introduced, given the limited success of current intensive chemotherapy. The study presents K-256, a novel BET degrader, which has been developed to improve patient outcomes. The compound was tested for its binding specificity to various bromodomains and its therapeutic impact was compared against existing BET inhibitors and degraders in preclinical models.

K-256 showed a strong affinity for BRD2, BRD3, BRD4, and BRDT, with the lowest dissociation constant for BRD4, a key player in MYC transcription. It was found to degrade BRD4 at lower concentrations than other degraders and induced cell death at concentrations significantly lower than existing drugs. The compound was also shown to suppress MYC expression more effectively than current BET inhibitors, even at reduced concentrations.

Furthermore, the combination of K-256 with venetoclax was synergistic, inhibiting cell growth and inducing cell death in the tested cell lines. In vivo experiments with patient-derived xenograft (PDX) models also demonstrated K-256's superior therapeutic efficacy compared to other BET-targeting drugs, both in terms of inhibiting cell proliferation and inducing apoptosis.

The study concludes that K-256, with its ability to bind BET proteins at lower concentrations and its robust suppression of MYC expression, particularly through BRD4 degradation, exhibits promising therapeutic potential for MYC/BCL2-related lymphoma. The findings suggest that K-256 could be a valuable addition to the clinical treatment options for this type of lymphoma, and further exploration of its clinical application is encouraged.