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

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 (<b>HED</b>) 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 <b>HED</b> derivatives. Among them, <b>HD15</b> demonstrated optimal activity in Jurkat cells (IC₅₀ = 0.98 μM), significantly outperforming the parent compound <b>HED</b> (IC₅₀ > 40 μM), and effectively inhibited xenograft tumor growth. Mechanistically, <b>HD15</b> 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 <b>HD15</b> 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.