891016-02-7

ML-SI3 is a mixture of cis/trans ML-SI3 (HY-139426A), which is a TRPML1/2 channel inhibitor with IC50s of 4.7 μM and 1.7 μM, respectively. ML-SI3 also inhibits lysosomal calcium efflux and blocks downstream TRPML1-mediated autophagy. The cis/trans ML-SI3 (HY-139426A) components of ML-SI3 are TRPML2 activators with EC50s of 3.3 μM and 9.4 μM, respectively[1][2].

ML-SI3 is a 4-diastereomer racemate (2 cis and 2 trans isomers) with a cation channel TRPML1-blocking (IC50 = 3.1 μM/trans18.5 μM/cis against 5 μM ML-SA1-induced cellular calcium response) and TRPML2-activating activity (EC50 = 3.3 μM/trans9.4 μM/cis)while exhibiting much weaker TRPML3 potency (EC50 = 28.5 μM/transIC50 = 29.0 μM/cis). ML-SI3 is shown to compete against ML-SA1 for binding the same TRPML1 hydrophobic cavity. Comparing with ML-SI1 (GW405833)ML-SI3 is more potent and not agonist-dependenteffectively antagonizing against TRPML1 activation by both MK6-83 and ML-SA1.

Schistosome; TRPML1: 4.7 μM (IC₅₀); TRPML2: 1.7 μM (IC₅₀); TRPML3: 12.5 μM (IC₅₀)

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