ML-7

ML-7 is a selective and highly specific myosin light chain kinase (MLCK) inhibitor that acts as a trabecular meshwork (TM) relaxant. ML-7 enhances Quinocetone (HY-123581)-induced phosphorylation of ERK, p38 MAPK and JNK, attenuates Akt activation, and promotes apoptosis of hepatocellular carcinoma cells. ML-7 reduces Th2 cytokine secretion by inhibiting MLCK, while alleviating smooth muscle hyperplasia and collagen deposition. As a non-antibiotic adjuvant, ML-7 restores the sensitivity of drug-resistant bacteria to Tigecycline (HY-B0117). ML-7 can be used in research related to glaucoma, hepatocellular carcinoma, asthma, and Klebsiella pneumoniae infection^[1][2][3][4]. In Vitro:ML-7 (10-20 μM; 24 h) alone shows no toxicity to HepG2 cells, but enhances quinocetone-induced cytotoxicity in a dose-dependent manner, and significantly reduces cell viability when used in combination with quinocetone^[1].
ML-7 (15-20 μM; 24 h) alone does not induce significant apoptosis in HepG2 cells, but when combined with quinocetone, it significantly enhances quinocetone-induced apoptosis in a dose-dependent manner^[1].
ML-7 (20 μM; 24 h) enhances quinocetone-induced activation of both extrinsic and intrinsic apoptotic pathways in HepG2 cells by promoting the cleavage of key caspases, PARP-1 and Bid, as well as upregulating the pro-apoptotic Bax/Bcl-2 ratio^[1].
ML-7 (20 μM; 24 h) significantly amplifies quinocetone-induced loss of mitochondrial membrane potential in HepG2 cells, thereby promoting an increase in endogenous apoptosis levels^[1].
ML-7 (20 μM; 24 h) attenuates quinocetone-induced activation of the pro-survival Akt pathway and enhances quinocetone-induced activation of the JNK, p38 and ERK MAPK pathways in HepG2 cells^[1].
ML-7 (20 μM; 15 min) inhibits the increase in MLCK activity in phagocytosing human neutrophils^[2].
ML-7 (20 μM) inhibits the upregulation of cell surface ALPase activity (a marker of reactive oxygen species-producing granule exocytosis) in PMA-stimulated human neutrophils, with an inhibition rate of 86% when treated before stimulation and 75% when treated after stimulation^[2].
ML-7 (20 μM) inhibits extracellular O₂⁻ release from human neutrophils stimulated by phorbol ester (PMA) (HY-18739); administration prior to stimulation results in complete inhibition, while administration after stimulation achieves approximately 80% inhibition^[2].
ML-7 (20 μM) does not inhibit PMA-stimulated O₂⁻ production in human neutrophils, but prolongs the lag phase of oxidant production when administered prior to stimulation^[2].
ML-7 (20 μM; 5 min) fails to prevent the formation of intracellular O₂⁻-producing compartments in PMA-stimulated human neutrophils, regardless of whether it is administered before or after stimulation^[2].
ML-7 (20 μM) does not inhibit NADPH oxidase activity in phorbol ester (PMA)-stimulated human neutrophils, but reduces the association of oxidant-producing compartments with the plasma membrane^[2].
ML-7 (20 μM; 5 min) inhibits the association of pro-oxidant intracellular compartments with the plasma membrane in PMA-stimulated human neutrophils, with a suppression rate of 87% for pre-stimulation treatment and 81% for post-stimulation treatment^[2].
ML-7 (1-5 μM) dose-dependently inhibits carbachol (HY-B1208)-induced contractility of isolated bovine trabecular meshwork strips, with an inhibition rate of 25.1% at the concentration of 5 μM^[3].
ML-7 (1 μM) reduces endothelin-1-induced contractile force in isolated bovine trabecular meshwork strips to 35.9% of the maximal contractile force induced by carbachol^[3].
ML-7 (1 μM) reduces the serine phosphorylation level of myosin light chain kinase in carbachol-induced native bovine trabecular meshwork muscle strips^[3].
ML-7 (4-128 μg/mL; 18 h) acts as a potent adjuvant that synergizes with tigecycline against all tested clinical tigecycline-resistant Klebsiella pneumoniae isolates (7 sequence types), with fractional inhibitory concentration index (FICI) values ≤ 0.5, and reduces the MIC of tigecycline by 4- to 128-fold^[4].
Combination treatment with ML-7 (64 μg/mL; 24 h) and tigecycline at 2 μg/mL completely inhibits the growth of tigecycline-resistant Klebsiella pneumoniae isolates 14-R71, 14-R74 and 14-R75 within 24 h, whereas monotherapy with either drug only achieves partial growth inhibition^[4].
The combination of ML-7 (64 μg/mL; 24 h) and 2 μg/mL tigecycline exerts synergistic bactericidal activity against tigecycline-resistant Klebsiella pneumoniae isolates 14-R71 and 14-R75 (reducing CFU/mL by approximately 5-6 log₁₀), and exhibits synergistic bacteriostatic activity against isolate 14-R74 within 24 h, whereas no significant effect is observed with either drug used alone^[4].
ML-7 (32-128 μg/mL; 1 h) inhibits the activity of efflux pumps in tigecycline-resistant Klebsiella pneumoniae in a dose-dependent manner, and its combined use enhances the inhibitory effect of tigecycline on such efflux pumps^[4].
ML-7 (32-128 μg/mL; 30 min) disrupts the proton motive force of tigecycline-resistant Klebsiella pneumoniae 14-R75 by significantly increasing ΔpH, and this effect occurs when ML-7 is used alone or in combination with tigecycline^[4].
ML-7 (32-128 μg/mL) reduces the outer membrane permeability of tigecycline-resistant Klebsiella pneumoniae in a dose-dependent manner, either when used alone or in combination with tigecycline, but has no effect on inner membrane permeability^[4].
ML-7 (4 h) alters the transcriptome of tigecycline-resistant Klebsiella pneumoniae 14-R75, and genes associated with its mechanism of action are mainly enriched in ABC transporters, including downregulated expression of the efflux pump component macB^[4].
ML-7 (32-128 μg/mL; 30 min) induces dose-dependent accumulation of reactive oxygen species in tigecycline-resistant Klebsiella pneumoniae 14-R75, either when acting alone or in combination with tigecycline^[4].
ML-7 (32-128 μg/mL) dose-dependently reduces the intracellular ATP level of tigecycline-resistant Klebsiella pneumoniae 14-R75, and this effect occurs both when ML-7 acts alone and when it is used in combination with tigecycline^[4].