2. Academic Validation
  3. Natural Product-Inspired PROTACs for Leukemia Therapy: Hederagenin-Driven Targeted Degradation of SKP2

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

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.

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