ML-346 is an activator of the heat shock response that induces the expression of the heat shock protein HSP70, with an EC50 value of 4.6µM[1]. ML-346 molecule covalently modified the cysteine (Cys) at position 208 of the active site of the housekeeping sorting enzyme A (SrtA) of Staphylococcus aureus, significantly reducing the virulence phenotype of Staphylococcus aureus[2]. ML-346 has been widely used in transplantation tumor models to promote tumor cell apoptosis and reduce tumor growth[3].
In vitro, ML-346 treatment (10µM) for 24 hours significantly inhibited the viability of MDA-MB-435 cells and reduced the activities of CDK7 and CDK9[4]. Treatment with 10µM ML-346 for 24 hours significantly inhibited the LC3 I/II conversion in A549 cells, and promoted the accumulation of p62 as well as a significant increase in the phosphorylation level of mTOR at the Ser2448 site[5]. 15µM of ML-346 pretreatment for 1 hour significantly inhibited the accumulation of sphingomyelin induced by V8 in Jurkat cells and the co-localization with Lysotracker Red[6]. 10µM of ML-346 pretreatment for 4 hours alleviated the mitochondrial damage and cell apoptosis induced by the combined action of Fumonisin B1 (FB1) and ochratoxin A (OTA) in pK-15 cells[7].
References:
[1] Calamini B, Silva M C, Madoux F, et al. ML346: a novel modulator of proteostasis for protein conformational diseases[M]//Probe Reports from the NIH Molecular Libraries Program [Internet]. National Center for Biotechnology Information (US), 2013.
[2] Guan X N, Zhang T, Yang T, et al. Covalent sortase A inhibitor ML346 prevents Staphylococcus aureus infection of Galleria mellonella[J]. RSC Medicinal Chemistry, 2022, 13(2): 138-149.
[3] Chen W, Wang Z, Ji J, et al. The regulatory mechanism of HSP70 in endoplasmic reticulum stress in pepsin-treated laryngeal epithelium cells and laryngeal cancer cells[J]. Aging (Albany NY), 2022, 14(20): 8486.
[4] Chiang S K, Chang W C, Chen S E, et al. CDK7/CDK9 mediates transcriptional activation to prime paraptosis in cancer cells[J]. Cell & Bioscience, 2024, 14(1): 78.
[5] Alhasan B, Gladova Y A, Sverchinsky D V, et al. Hsp70 negatively regulates autophagy via governing AMPK activation, and dual Hsp70-autophagy inhibition induces synergetic cell death in NSCLC Cells[J]. International Journal of Molecular Sciences, 2024, 25(16): 9090.
[6] Qing Y, Guo Y, Zhao Q, et al. Targeting lysosomal HSP70 induces acid sphingomyelinase‐mediated disturbance of lipid metabolism and leads to cell death in T cell malignancies[J]. Clinical and translational medicine, 2023, 13(3): e1229.
[7] Li H, He W, Yue D, et al. Low doses of fumonisin B1 exacerbate ochratoxin A-induced renal injury in mice and the protective roles of heat shock protein 70[J]. Chemico-Biological Interactions, 2023, 369: 110240.