DC661

DC661 is a small-molecule compound capable of inhibiting palmitoyl-protein thioesterase 1 (PPT1) and effectively suppressing cellular autophagy, serving as an antilysosomal agent^[1-2]. DC661 is primarily utilized in cancer-related research^[3-4].

In vitro, pretreatment of human umbilical vein endothelial cells (HUVECs) with DC661 (1.5–3μM) for 30 minutes, followed by 5.5 hours of hypoxia exposure, significantly inhibited PPT1 expression and reduced angiogenic responses^[5]. Pretreatment of hepatocellular carcinoma cells Hep 3B and Hep 1-6 with DC661 (0.5–3μM) for 6–24 hours, followed by stimulation with sorafenib (1.5–10μM) for 24–48 hours, significantly suppressed PPT1 expression and autophagic activity while enhancing sensitivity to sorafenib^[6].

In vivo, intraperitoneal injection of DC661 (3mg/kg/day) for 21 days in melanoma tumor-bearing mice (Ppt1 conditional knockout mice) showed no effect on melanoma tumor initiation or growth^[7]. In a lead-exposed (200mg/kg/day for 6 weeks) Wistar rat model, hippocampal stereotactic administration of DC661 (10mM, 5μl/day for 6 weeks) significantly inhibited autophagy levels in hippocampal neurons and upregulated IGF-1 signaling pathway activity. DC661 treatment markedly activated the IGF-1/PI3K/Akt/mTOR pathway, reversed lead-induced excessive autophagy, and improved hippocampal neuronal function^[8].

References:
[1] Weng J, Liu S, Zhou Q, et al. Intratumoral PPT1-positive macrophages determine immunosuppressive contexture and immunotherapy response in hepatocellular carcinoma. J Immunother Cancer. 2023 Jun;11(6):e006655.
[2] Jain V, Harper SL, Versace AM, et al. Amaravadi RK. Targeting UGCG Overcomes Resistance to Lysosomal Autophagy Inhibition. Cancer Discov. 2023 Feb 6;13(2):454-473.
[3] Bildik G, Gray JP, Mao W, et al. DIRAS3 induces autophagy and enhances sensitivity to anti-autophagic therapy in KRAS-driven pancreatic and ovarian carcinomas. Autophagy. 2024 Mar;20(3):675-691.
[4] Ferret L, Pol JG, Sauvat A, et al. Lysosomal membrane permeabilization enhances the anticancer effects of POLR1 (RNA polymerase I) transcription inhibitors. Autophagy. 2025 Oct;21(10):2246-2265.
[5] Ma Y, Yuan X, Wei A, et al. Enhancing Gpx1 palmitoylation to inhibit angiogenesis by targeting PPT1. Redox Biol. 2024 Nov;77:103376.
[6] Xu J, Su Z, Cheng X, et al. High PPT1 expression predicts poor clinical outcome and PPT1 inhibitor DC661 enhances sorafenib sensitivity in hepatocellular carcinoma. Cancer Cell Int. 2022 Mar 11;22(1):115.
[7] Crissey MAS, Versace A, Bhardwaj M, et al. Divergent effects of acute and chronic PPT1 inhibition in melanoma. Autophagy. 2025 Feb;21(2):394-406.
[8] Zhang B, Li H, Wang Y, et al. Mechanism of autophagy mediated by IGF-1 signaling pathway in the neurotoxicity of lead in pubertal rats. Ecotoxicol Environ Saf. 2023 Feb;251:114557.