Table 2 Inhibitors of autophagy
Drug | Systematic name | Known targets | Status | Limitations | References |
|---|---|---|---|---|---|
MRT68921 | N-[3-[[5-Cyclopropyl-2-[(1,2,3,4-tetrahydro-2-methyl-6-isoquinolinyl)amino]-4-pyrimidinyl]amino]propyl]-cyclobutanecarboxamide dihydrochloride | ULK1, ULK2, NUAK1 | Preclinical | Mitotic dysregulation; crosstalk with endocytic pathways | |
3-MA | 3-Methyladenine | PI3Ks | preclinical | non-selectivity; activation of autophagy in a longer period of treatment; cytotoxicity; crosstalk with endocytic pathways | |
Wortmannin | (1alpha,11alpha)-11-(Acetyloxy)-1-(methoxymethyl)-2-oxaandrosta-5,8-dieno(6,5,4-bc)furan-3,7,17-trione | PI3Ks, DNA-PK | preclinical | failed clinical translation due to drug-delivery challenges; proteosynthesis inhibition; crosstalk with endocytic pathways | |
LY294002 | 2-(4-Morpholinyl)-8-phenyl-4H-1-benzopyran-4-one | PI3Ks | preclinical | activation of autophagy; proteosynthesis inhibition; crosstalk with endocytic pathways | |
Spautin-1 | C43, 6-Fluoro-N-[(4-fluorophenyl)methyl]-4-quinazolinamine | USP10, USP13 | preclinical | ROS-mediated DNA damag; Beclin1 degradation; crosstalk with endocytic pathways | |
Autophinib | 6-Chloro-N-(5-methyl-1H-pyrazol-3-yl)-2-(4-nitrophenoxy)-pyrimidinamine | VPS34 | preclinical | pleiotropic impact of VPS34 inhibition; impaired T-cell–mediated immunity | |
SAR405 | (8S)-9-[(5-chloro-3-pyridinyl)methyl]-6,7,8,9-tetrahydro-2-[(3R)-3-methyl-4-morpholinyl]-8-(trifluoromethyl)-4H-pyrimido[1,2-a]pyrimidin-4-one | VPS34 | preclinical | pleiotropic impact of VPS34 inhibition; defects in endosomal trafficking; impaired T-cell–mediated immunity | |
VPS34-IN1 | 1-((2-((2-chloropyridin-4-yl)amino)-4'-(cyclopropylmethyl)-[4,5'-bipyrimidin]-2'-yl)amino)-2-methylpropan-2-ol | VPS34 | preclinical | pleiotropic impact of VPS34 inhibition; defects in endosomal trafficking; impaired T-cell–mediated immunity | |
Cpd18 | 3-methyl-6-(3-methylpiperidin-1-yl)-3H-purine | omegasomes | preclinical | toxicity; decreased ubiquitin/proteasome-dependent proteolysis | |
Chloroquine | 4-N-(7-chloroquinolin-4-yl)-1-N,1-N-diethylpentane-1,4-diamine | autolysosomes; lysosomes; endosomes | 21 clinical trials phase 1 or 2; only one phase 3 study (NCT00224978) | lysosomal stress; crosstalk with endocytic pathways; uptake may differ based on pH | |
HCQ | 2-[4-[(7-chloroquinolin-4-yl)amino]pentyl-ethylamino]ethanol | autolysosomes; lysosomes; endosomes | 94 clinical trials; only one phase 2/3 study (NCT03008148) | uptake may differ based on pH | |
Bafilomycin A1 | (3Z,5E,7R,8S,9S,11E,13E,15S,16R)-16-[(2S,3R,4S)-4-[(2R,4R,5S,6R)-2,4-dihydroxy-5-methyl-6-propan-2-yloxan-2-yl]-3-hydroxypentan-2-yl]-8-hydroxy-3,15-dimethoxy-5,7,9,11-tetramethyl-1-oxacyclohexadeca-3,5,11,13-tetraen-2-one | V-ATPase | preclinical | cytotoxicity and caspase activation; effects on Golgi trafficking; crosstalk with endocytic pathways | |
YM201636 | 6-amino-N-[3-(6-morpholin-4-yl-8-oxa-3,5,10-triazatricyclo[7.4.0.02,7]trideca-1(9),2(7),3,5,10,12-hexaen-4-yl)phenyl]pyridine-3-carboxamide | PIKfyve | preclinical | block of protein sorting; crosstalk with endocytic pathways and exocytosis | |
Vacuolin-1 | 2-N-[(E)-(3-iodophenyl)methylideneamino]-6-morpholin-4-yl-4-N,4-N-diphenyl-1,3,5-triazine-2,4-diamine | PIKfyve | preclinical | block of protein sorting; crosstalk with endocytic pathways and exocytosis | |
Apilimod mesylate | methanesulfonic acid;N-[(E)-(3-methylphenyl)methylideneamino]-6-morpholin-4-yl-2-(2-pyridin-2-ylethoxy)pyrimidin-4-amine | PIKfyve | preclinical | block of protein sorting; crosstalk with endocytic pathways and exocytosis | |
EACC | ethyl (2-(5-nitrothiophene-2-carboxamido) thiophene-3-carbonyl) carbamate. | STX17 | preclinical | crosstalk with endocytic pathways and exocytosis |