lysosomal autophagy

Siramesine hydrochloride (Lu 28-179 hydrochloride) is a selective sigma-2 receptor agonist, which has been shown to trigger cell death of Y cells and to exhibit a potent anticancer activity in vivo.

Lys05, or Lys01 trihydrochloride, is a potent, water soluble lysosomal autophagy inhibitor. Lys05 is a previously undescribed dimeric chloroquine which more potently accumulates in the lysosome and blocks autophagy compared with HCQ. Lys05 produced more p

Ezurpimtrostat hydrochloride (GNS561 hydrochloride) is an orally available palmitoyl protein thioesterase-1 inhibitor with antifibrotic, antiviral, and anticancer effects that blocks cancer cell proliferation by interacting with palmitoyl protein thioesterase to inhibit late autophagy and dose-dependently increase lysosomal accumulation.

Chloroquine phosphate (Aralen phosphate) is an antimalarial and anti-inflammatory agent widely used for malaria and rheumatoid arthritis. Chloroquine phosphate acts as an inhibitor of autophagy and toll-like receptors, effectively suppressing SARS-CoV-2 (COVID-19) infection (EC50 = 1.13 μM). Chloroquine phosphate can be utilized in research on autophagy, lysosomal function, and tumor diseases.

Ammonium chloride is a compound commonly used in molecular biology research. As a dipolar compound that regulates pH, it can induce intracellular alkalinization and metabolic acidosis, thereby affecting enzyme activity and biological processes. Additionally, ammonium chloride acts as an inhibitor of autophagy and lysosomal function, and can be used to establish kidney stone models.

EN6-mediated ATP6V1A modification decouples the v-ATPase from the Rags, leading to inhibition of mTORC1 signaling, increased lysosomal acidification and activation of autophagy. EN6 clears TDP-43 aggregates, a causative agent in frontotemporal dementia, in a lysosome-dependent manner. EN6 is a small-molecule in vivo activator of autophagy that covalently targets cysteine 277 in the ATP6V1A subunit of the lysosomal the vacuolar H+ ATPase (v-ATPase).

Autophagy-IN-6 (compound 1u) is an inhibitor of lysosomal autophagy that induces the accumulation of the LC3-II protein. Additionally, it exhibits antiproliferative activity.

YT 6-2 is an autophagy-targeting ligand (ATL) aimed at p62/SQSTM1, used in the synthesis of AUTOTAC degrader ATC-324. ATC-324 induces the formation of AR/p62 complexes, leading to the autophagic-lysosomal degradation of AR. It reduces nuclear AR levels, downregulates the expression of AR and AR-v7 target genes, and also degrades common AR mutants in PCa.

YT 6-2-PEG3-C2-NH2 is a conjugate of the autophagy-targeting ligand (ATL) targeting p62/SQSTM1 and an AUTOTAC linker. It is used in the synthesis of the AUTOTAC degrader ATC-324 for the androgen receptor (AR). ATC-324 induces the formation of the AR/p62 complex, leading to autophagy-lysosomal degradation of AR. This action reduces nuclear AR levels and downregulates target gene expression of AR and AR-v7, effectively degrading common AR mutants found in prostate cancer (PCa).

YT 6-2 analog-1 (compound 2-3) serves as an autophagy-targeting ligand (ATL) aimed at p62/SQSTM1, useful in synthesizing the AUTOTAC degrader ATC-324 for the Androgen Receptor (AR). ATC-324 promotes the formation of AR/p62 complexes, leading to the autophagic-lysosomal degradation of AR. It effectively reduces nuclear AR levels, downregulates the expression of AR and AR-v7 target genes, and can degrade common AR mutants found in prostate cancer (PCa).

YAP-IN-1 (Compound (+)-1) is an autophagy inhibitor specifically targeting YAP1. It binds to the Hippo pathway transcription factor YAP1 with a Kd of 9.13 μM, promoting its degradation through the chaperone-mediated autophagy (CMA) pathway. This process inhibits the Rab7-mediated fusion of autophagosomes with lysosomes and decreases autophagy levels without affecting lysosomal function. YAP-IN-1 shows potential for cancer research, including in hepatocellular carcinoma and breast cancer.

ATC-324 is a potent autophagy-targeting chimera (AUTOTAC) degrader of the androgen receptor (AR) with a DC50 of 2.05 µM. It induces autophagic-lysosomal degradation of AR, decreases nuclear AR and AR-V7 activity, and exhibits cytotoxic effects on AR-positive prostate cancer cells, making it useful for prostate cancer research.

ML-20, an analog of Malabaricone C, functions as both an autophagy inhibitor and a radiosensitizer. It suppresses cell proliferation and induces apoptosis (cell death). ML-20 also causes DNA double-strand breaks, loss of mitochondrial membrane potential (MMP), and lysosomal membrane permeabilization (LMP). Due to LMP, it triggers endoplasmic reticulum stress while concurrently inhibiting autophagic flux.

SHP2protein degrader-3 is an AUTAC protein degrader specifically targeting SHP2. It induces dose-dependent degradation of SHP2 in HeLa cells, with a DC50 of 3.22 μM, and demonstrates significant antitumor activity with an IC50 of 5.59 μM. The degradation mechanism is mediated via LC3-dependent autophagy, which can be inhibited by lysosomal inhibitors. SHP2protein degrader-3 also induces apoptosis in various tumor cell lines, including cervical cancer cells (HeLa), liver cancer cells (HepG2 and Huh-7), and colon cancer cells (LoVo). [SHP2ligand: ; LC3 Ligand: ; Linker: .]

IITZ-02 is a lysosomotropic autophagy inhibitor. It enhances autophagosome accumulation but inhibits autophagosome degradation by impairing lysosomal function, ultimately leading to autophagy suppression. IITZ-02 disrupts mitochondrial membrane potential and induces apoptosis through a mitochondria-mediated pathway. It shows potent anti-tumor activity in MDA-MB-231 xenograft mouse models and is applicable in cancer research.

AP232 is a selective inhibitor of U2AF1-UHM with an IC50 value of 7.96 μM. It shows 2.8 to 24 times selectivity over other UHM-containing proteins. AP232 exhibits anti-leukemia activity and demonstrates heightened effectiveness in cell lines with splicing factor mutations. It can induce G2/M and G1 phase arrest in leukemia cells, impair lysosomal acidification, and inhibit autophagy (autophagy). AP232 is applicable in cancer research, particularly for leukemia studies.

AP232 dihydrochloride is a selective U2AF1-UHM inhibitor with an IC50 value of 7.96 μM. It exhibits 2.8-24 times selectivity over other UHM-containing proteins and demonstrates anti-leukemic activity, showing heightened effectiveness in cell lines with splice factor mutations. AP232 dihydrochloride can induce G2/M and G1 phase arrest in leukemia cells, impair lysosomal acidification, and inhibit autophagy (autophagy). This compound is applicable in cancer research, specifically for leukemia.

Vacuolin-1 is a cell-permeable inhibitor of Ca2+ dependent fusion of lysosomes to the cell membrane. It acts by inhibiting release of lysosomal content.vacuolin‐1 is a potent and selective PIKfyve inhibitor and inhibits late‐stage autophagy by impairing lysosomal maturation

ML-SA1 (Mucolipin synthetic agonist 1) is a selective TRPML agonist, inhibits Dengue virus 2 (DENV2) and Zika virus (ZIKV) by promoting lysosomal acidification and protease activity. The IC50 value of ML-SA1 against DENV2 RNA and ZIKV RNA is 8.3 μM and 52.99 μM, respectively[1].

LYS01 free base is a new lysosomal autophagy inhibitor.

Quinacrine analog 34 is a potent autophagy inhibitor (EC₅₀ = 0.5 μM, LD₅₀ = 27 μM) that upregulates the protein levels of the autophagy marker LC3-II and induces lysosomal deacidification.

DC661 is a palmitoyl-protein thioesterase 1 (PPT1) inhibitor that acts as an anti-lysosomal agent by inhibiting autophagy, demonstrating anti-cancer activity.

20-DEOXYINGENOL is a natual product.

MMRi62 (7-[(2,3-dichlorophenyl)-(pyridin-2-ylamino)methyl]quinolin-8-ol), a ferroptosis inducer targeting MDM2-MDM4 (negative regulators of tumor suppressor p53). MMRi62 shows a P53-independent pro-apoptotic activity against pancreatic ductal adenocarcinoma (PDAC) cells and induce autophagy. MMRi62 inducesferroptosis, resulting in a increase of reactive oxygen and lysosomal degradation of ferritin heavy chain (FTH1). MMRi62 also leads to proteasomal degradation of mutant p53, also inhibits orthotopic xenograft PDAC mouse model in vivo with high frequency mutation characteristics of KRAS and TP53.12.