TRPML3 Inhibitor

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.

(1R,2R)-ML-SI3 is an isomer of ML-SI3 and a potent inhibitor of three isoforms of TRPML. (1R,2R)-ML-SI3 inhibits TRPMLs with IC₅₀s of 1.6 μM (TRPML1), 2.3 μM (TRPML2), and 12.5 μM (TRPML3), respectively.

(rel)-ML-SI3 is one of the active ingredients of ML-SI3 (HY-139426) (another component is (cis)-ML-SI3) that targets three isoforms of TRPML. (rel)-ML-SI3 is an inhibitor of TRPML1 and TRPML3 (IC₅₀=3.1 μM/28.5 μM), and a potent activator of TRPML2 (EC₅₀=3.3 μM).

(1S,2S)-ML-SI3 is a trans-isomer of ML-SI3 that targets all three isoforms of TRPML. (1S,2S)-ML-SI3 is an activator of TRPML2 and TRPML3 (EC₅₀=2.7 μM/10.8 μM) and a potent inhibitor of TRPML1 (IC₅₀=5.9 μM).