TXN-A的发现与表征：一种首创的、口服生物利用度良好的ULK1降解剂，具有高选择性和强效性，用于TNBC治疗

Background: Triple-negative breast cancer (TNBC) remains a clinical challenge due to its aggressive nature and limited targeted therapy options. ULK1 (Unc-51 like autophagy activating kinase 1) plays a critical role in initiating autophagy, which serves as a survival mechanism for TNBC cells under chemotherapeutic stress. In this study, we developed TXN-A, a first-in-class highly selective, potent and orally bioavailable ULK1 degrader to overcome chemoresistance and enhance anti-tumor therapeutic efficacy of Paclitaxel (PTX) in TNBC. Methods: Autophagosome formation was measured using the Cyto-ID. The synergy of TXN-A in combination with PTX was assessed in 2D proliferation assay using CellTiter-Glo ® . Xenograft models were used to assess pharmacodynamics (PD), as well as anti-tumor efficacy in vivo. Results: TXN-A potently and selectively degrades ULK1 protein in CRBN-dependent and ubiquitin-proteosome-system dependent manners. ULK1 degradation by TXN-A effectively suppressed autophagy, as demonstrated by reduced PTX mediated activation of autophagosome formation and autophagic flux LC3-II/I level in TNBC cells. TXN-A showed a strong synergistic anti-tumor activity in combination with PTX in TNBC cells, but not normal cells in vitro cellular assay. TXN-A had favorable PK profile suitable for oral administration with excellent exposure in mouse. In combination with PTX, TXN-A exhibited significant tumor growth inhibition compared to PTX alone in Hs578T xenograft model, verifying synergistic anti-tumor effect in combination setting. Conclusion: This study with TXN-A, a first-in-class highly selective, potent and orally bioavailable ULK1 degrader, demonstrated that it interferes with autophagy-dependent survival in TNBC cells, resulting in enhancing the anti-tumor effects of chemotherapy. Selective ULK1 degradation, in combination with PTX, is a promising therapeutic approach for TNBC. Synergistic anti-tumor activity of TXN-A with taxanes suggests potential clinical development for refractory and resistant TNBC patients.