2. Academic Validation
  3. Discovery of indolinone-based covalent ULK1 inhibitors that suppressed autophagy and induced apoptosis against colorectal carcinoma

Discovery of indolinone-based covalent ULK1 inhibitors that suppressed autophagy and induced apoptosis against colorectal carcinoma

  • Eur J Med Chem. 2026 Apr 5:307:118633. doi: 10.1016/j.ejmech.2026.118633.
Jing Ye 1,  Daihan Wang 2,  Haiying Pang 1,  Qiao Liu 2,  Zhaoping Pan 2,  Lian Wang 3,  Bo Liu 2,  Gu He 4
Affiliations

Affiliations

  • 1 Department of Dermatology & Venerology, West China Hospital, Sichuan University, Chengdu, 610041, China; Laboratory of Dermatology, Frontiers Science Center for Disease related Molecular Network and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
  • 2 Laboratory of Dermatology, Frontiers Science Center for Disease related Molecular Network and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
  • 3 Department of Dermatology & Venerology, West China Hospital, Sichuan University, Chengdu, 610041, China. Electronic address: [email protected].
  • 4 Department of Dermatology & Venerology, West China Hospital, Sichuan University, Chengdu, 610041, China; Laboratory of Dermatology, Frontiers Science Center for Disease related Molecular Network and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China. Electronic address: [email protected].
PMID: 41672028 DOI: 10.1016/j.ejmech.2026.118633
Abstract

Unc-51 Like Autophagy Activating Kinase 1 (ULK1) is an essential regulator in the initiation of Autophagy and represents a novel therapeutic target for colorectal Cancer (CRC) treatment. Herein, we developed a series of novel ULK1 covalent inhibitors through structure-based and medicinal chemistry optimizations. Notably, compound 12i was synthesized and validated to form covalent bonds with ULK1, exhibiting pronounced selectivity and potent inhibitory activity (ULK1 IC50 = 4.7 μM). Moreover, 12i demonstrated anti-proliferative effects in CRC cell lines. In vitro experiments showed that 12i effectively inhibited CRC cell growth, induced cell cycle arrest at the S or G2/M phase, and triggered Apoptosis by blocking ULK1-mediated Autophagy. Additionally, in vivo results showed that 12i also exhibited good tumor inhibitory activity in CRC murine models, with an inhibition rate of 70.4 % at 40 mg/kg. In vivo pharmacokinetic studies revealed moderate systemic absorption (Tmax = 2 h) with oral bioavailability of 39.7 % in rats. In summary, our findings highlight compound 12i as a promising lead candidate for further development of selective ULK1 covalent inhibitors, offering a potential new strategy for CRC therapy.

Keywords

Autophagy; Colorectal carcinoma; Covalent inhibitor; Kinase; ULK1.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-181668
    ULK1 Inhibitor
    ULK