Discovery of a highly potent and selective KAT6A degrader ATH-002 that demonstrates robust anti-tumor activity with a low risk of hematotoxicity in preclinical studies

KAT6A, a member of the MYST family of histone acetyltransferases, regulates gene transcription by acetylating histone H3K23 and thereby participates in multiple cellular processes, such as proliferation and differentiation. Amplification or overexpression of KAT6A have been observed in various cancers, including breast cancer, where it is amplified in approximately 15% of patients, highlighting its potential as a promising target for therapy. PF-07248144, the first KAT6A/6B dual inhibitor to enter the clinic, demonstrates durable anti-tumor activity in ER+HER2− metastatic breast cancer, especially in combination with fulvestrant. However, Phase 1 data also revealed hematologic dose-limiting toxicities of neutropenia and anemia. The on-target toxicities resulting from the simultaneous inhibition of KAT6A/6B, which synergistically promote hematopoietic stem cell development. Furthermore, studies have suggested that KAT6A has non-enzymatic functions by its role in DNA damage repair via interaction with PARP and by the observation that depletion of KAT6A more efficiently suppresses the proliferation of KMT2A-rearranged AML cells than blocking its acetyltransferase activity alone. These evidences provide the rationale to develop a KAT6A-specific degrader with the potential for improved efficacy and reduced hematotoxicity. Here we report a potent and oral KAT6A degrader, ATH-002. It effectively induced KAT6A degradation with DC 50 <1nM, and the degradation could be abolished when E3 was inactive, suggesting a direct mediation by the ubiquitin-proteasome system via E3-ligase binding. Global proteome analysis demonstrated an excellent selectivity against proteins, including KAT6B and other MYST family members. ATH-002 robustly inhibited proliferation in KAT6A amplified cell lines, but not in cells with low KAT6A expression, indicating the activity was driven by the specific KAT6A degradation. Mechanism studies further showed that ATH-002 dose-dependently blocked the H3K23 acetylation, down-regulated ER expression, and concurrently reduced BRPF-1 level, which might be induced by a bystander degradation effect. In contrast to KAT6A/6B inhibitors, ATH-002 significantly decreased hematotoxicity, especially in the myeloid lineage with EC 50 >30 μM. In a KAT6A amplified xenograft model, ATH-002 effectively inhibited tumor growth, which correlated with KAT6A degradation. Besides monotherapy, ATH-002 displayed an enhanced anti-proliferation effect in combination with SERDs or CDK4/6 inhibitors without overlapping hematotoxicity, implying a potential application of KAT6A degrader and SOC therapy. Collectively, our findings support ATH-002 as a clinical candidate for the treatment of KAT6A-amplified tumors.