Abstract LB363: Discovery and characterization of TXN-A: A first-in-class, orally bioavailable ULK1 degrader with high selectivity and potency for TNBC treatment

Abstract 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. Citation Format: Yo Han Hong, Jung-eun Park, Jiah Lim, Yong-Chang Kim, Jun Young Choi, Ye Jin Kim, Young Hoon Choi, Hye Jung Park, Hee Jin Jeong, Chang Won Min, Eunmyong Lee, Hong Jun Kang, Hyouk Woo Lee, Sungjoon Kim, Chan Sun Park. Discovery and characterization of TXN-A: A first-in-class, orally bioavailable ULK1 degrader with high selectivity and potency for TNBC treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr LB363.