ML-SI1 is a racemic mixture and an inhibitor of transient receptor potential cation channel (TRPML), with an IC50 value of 15μM for TRPML1[1, 2]. TRPML1 is a lysosomal cation channel involved in lysosomal biogenesis, endolysosomal trafficking (including trafficking in neuronal dendrites), and autophagy[3]. ML-SI1 and ML-SI3 are currently the only two published TRPML inhibitors[4].
In vitro, treatment of PANC1 cells with ML-SI1 (0-100μM) for 48h significantly reduced cell viability and induced significant changes in the metabolic profile[5]. Treatment of hippocampal neurons with ML-SI1 (20μM) for 2h blocked the lysosomal localization changes induced by LAMTOR1 knockdown[6]. Treatment of IPEC-J2 cells with ML-SI1 (1.25μM) for 24h significantly reduced ROS and Ca2+ levels induced by AFB1, and significantly decreased cell apoptosis and autophagy[7].
References:
[1] Reeks J, Mahajan P, Clark M, et al. High throughput cryo-EM provides structural understanding for modulators of the lysosomal ion channel TRPML1[J]. Structure, 2025.
[2] Leser C, Keller M, Gerndt S, et al. Chemical and pharmacological characterization of the TRPML calcium channel blockers ML-SI1 and ML-SI3[J]. European journal of medicinal chemistry, 2021, 210: 112966.
[3] Wang W, Zhang X, Gao Q, et al. TRPML1: an ion channel in the lysosome[J]. Mammalian Transient Receptor Potential (TRP) Cation Channels: Volume I, 2014: 631-645.
[4] Kriegler K, Leser C, Mayer P, et al. Effective chiral pool synthesis of both enantiomers of the TRPML inhibitor trans‐ML‐SI3[J]. Archiv der Pharmazie, 2022, 355(2): 2100362.
[5] Kim B, Jung J. Metabolomic approach to identify potential biomarkers in KRAS-Mutant pancreatic cancer cells[J]. Biomedicines, 2024, 12(4): 865.
[6] Sun J, Lin W, Hao X, et al. LAMTOR1 regulates dendritic lysosomal positioning in hippocampal neurons through TRPML1 inhibition[J]. Frontiers in Cellular Neuroscience, 2024, 18: 1495546.
[7] Cheng X, Liang J, Wu D, et al. Blunting ROS/TRPML1 pathway protects AFB1-induced porcine intestinal epithelial cells apoptosis by restoring impaired autophagic flux[J]. Ecotoxicology and Environmental Safety, 2023, 257: 114942.
ML-SI1是一种外消旋混合物，是瞬时受体电位阳离子通道（TRPML）的抑制剂，对TRPML1的IC50值为15μM[1, 2]。TRPML1是一种溶酶体阳离子通道，与溶酶体生物合成、内体/溶酶体运输（包括神经元树突中的运输）以及自噬有关[3]。ML-SI1和ML-SI3是目前仅发表的两种TRPML抑制剂[4]。
在体外，ML-SI1（0-100μM）处理PANC1细胞48h，显著降低了细胞的活力，诱导了代谢物谱的明显变化[5]。ML-SI1（20μM）处理海马体神经元2h，阻断了LAMTOR1敲低引起的溶酶体定位变化[6]。ML-SI1（1.25μM）处理IPEC-J2 细胞24h，显著降低了AFB1诱导的细胞中的ROS和Ca2+水平，显著降低了细胞凋亡和自噬[7]。