AI Insight
Researchers developed LZ6, a small molecule that stabilizes the protein complex between CHI3L1 and Gal3BP in glioblastoma, the most aggressive form of brain cancer. In mouse models, oral administration of LZ6 reprogrammed immune cells called macrophages to attack tumors more effectively, increasing survival time from 26.3 to 52.4 days. When combined with anti-PD-1 immunotherapy, most animals survived to the end of the study period, demonstrating strong synergistic effects.
Why it matters
This approach offers a potential new treatment strategy for glioblastoma, which currently has very limited therapeutic options and poor patient outcomes. The oral availability of LZ6 and its ability to enhance existing immunotherapies could provide a more accessible and effective treatment combination for this deadly cancer.
⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
CHI3L1 (YKL-40) is associated with mesenchymal, treatment-resistant glioblastoma (GBM) and shapes macrophage programs through interactions with galectin-3 or galectin-3-binding protein (Gal3BP). However, the CHI3L1-Gal3BP interaction has not been previously targeted. A surface plasmon resonance screen identified LZ6. Ternary complex formation was assessed by fluorescence-based, biophysical, and mass spectrometry methods. Activity was evaluated in five patient-derived GBM lines, myeloid cultures from eight donors, CRISPR interference with guide-resistant rescue, and a four-arm factorial study of orthotopic GL261 tumors. LZ6 increased Gal3BP engagement 3.4-fold while reducing galectin-3 in vitro. In GBM-conditioned cultures, LZ6 raised phagocytosis 22% to 44% and MHC class II 24% to 39% and lowered CD206 45% to 31% and IL-10 105 to 67 pg/mL, with concordant transcripts. Gal3BP knockdown reduced the response 41%; guide-resistant rescue restored it. Oral LZ6 raised the intratumoral Gal3BP:galectin-3 ratio from 1.02 to 1.56 at unchanged CHI3L1. In tumor tissue LZ6 shifted 20 of 24 immune endpoints, lowering CD206 and IL-10 and raising MHC class II and CD8 effector function. Median survival with LZ6 was 52.4 versus 26.3 days (P = 0.0012), and in combination with anti-PD-1 most animals survived to the end of follow-up (median not reached), with a significant factorial interaction (hazard ratio 0.24, 95% CI 0.10-0.57, P = 0.0014). LZ6 is a molecular glue of the CHI3L1-Gal3BP complex that engages its target in brain tumor after oral dosing and extends survival alone and synergistically with PD-1 blockade.