Natural Product-Inspired PROTACs for Leukemia Therapy: Hederagenin-Driven Targeted Degradation of SKP2

  • J Med Chem. 2026 Feb 26;69(4):4579-4601. doi: 10.1021/acs.jmedchem.5c03213.
Lei Chen  1 ,  Tao Bi  2 ,  Juan Huang  3 ,  Bingwen Zhu  4 ,  Xuemei Yang  3 ,  Shengdan Yao  3 ,  Xiyu Dai  3 ,  Chunyan Liu  3 ,  Ting Wang  3 ,  Li Liu  5 ,  Qin Sun  3  6 ,  Jinxiang Wang  7 ,  Pei Luo  2 ,  Jun Bai  1 ,  Zengjin Liu  3  8
Affiliations
  • 1. Environmental Health Effects and Risk Assessment Key Laboratory of Luzhou, School of Public Health, Southwest Medical University, Luzhou 646000, China.
  • 2. State Key Laboratory of Mechanism and Quality of Chinese Medicine, Faculty of Chinese Medicine, Macau University of Science and Technology, Macau 999078, China.
  • 3. Drug Research Center of Integrated Traditional Chinese and Western Medicine, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan 646000, China.
  • 4. Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China.
  • 5. Skin Structure and Function Key Laboratory of Luzhou, Department of Dermatology, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan 646000, China.
  • 6. Luzhou Key Laboratory of Research and Development of Medical Institution Preparations and Large-Scale Health Products, Luzhou, Sichuan 646000, China.
  • 7. Department of Urology, Pelvic Floor Disorders Center, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen 518107, China.
  • 8. Institute of Integrated Chinese and Western Medicine, Southwest Medical University, Luzhou, Sichuan 646000, China.
PMID: 41665125 DOI: 10.1021/acs.jmedchem.5c03213
Abstract

Leukemia is a malignant neoplasm originating from the hematopoietic system. T-cell acute lymphoblastic leukemia (T-ALL) represents a typical subtype, posing a particularly serious threat to children. Hederagenin (HED) is a natural product with broad-spectrum antitumor potential, yet its activity remains insufficient and requires optimization. Here, we employed PROTAC technology to design and synthesize a series of HED derivatives. Among them, HD15 demonstrated optimal activity in Jurkat cells (IC50 = 0.98 μM), significantly outperforming the parent compound HED (IC50 > 40 μM), and effectively inhibited xenograft tumor growth. Mechanistically, HD15 effectively degraded SKP2 (DC50 = 0.29 μM), stabilizing SOCS1 expression and modulating immunoproteasome expression via the JAK/STAT pathway, thereby suppressing tumor cell proliferation. The discovery of HD15 demonstrates the promise of PROTAC technology in enhancing the efficacy of natural products and identifying therapeutic targets, offering a novel strategy for developing therapeutics from natural products.

Products