TABLE 2.
Known autophagy pharmacological activators and their potential application in disease
| Class | Agent | Mechanism of action | Biological effects and application in disease | References |
|---|---|---|---|---|
| AMPK activator | A769662 | Allosterically activating AMPK | Type‐II diabetes and associated metabolic disorders (preclinical) | 429 , 430 |
| AICAR | Allosterically activating AMPK via its metabolite ZMP, which is an AMP mimetic | Type‐II diabetes (clinical trials); intestinal barrier function and epithelial differentiation (preclinical) | 431 , 432 | |
| Metformin | Inhibiting RCC1 (respiratory chain complex‐1) to raise the cellular ATP/AMP ratio; upregulating of SIRT1 expression | First‐line antidiabetic drug (approved); potential application of in cancer treatment (clinical trials), including osteosarcoma, prostate cancer, and so on | 433 , 434 , 435 | |
| Thiazolidinediones | Inhibiting RCC1, to raise the cellular ATP/AMP ratio | Potential application of in cancer treatment (preclinical); diabetes, obesity (clinical trials) | 436 , 437 | |
| Simvastatin | Raising cellular ATP/AMP ratio via inhibiting cholesterol biosynthesis | Antihypercholesterolaemia (approved); cardioprotective effects (approved); potential application of in cancer treatment (clinical trials) | 438 , 439 , 440 | |
| Sertraline | Antagonizing the mitochondrial VDAC1 (voltage‐dependent anion channel 1), resulting in reduced cellular ATP level | Antidepressant drug (approved) | 441 | |
| Resveratrol | Enhancing CamKKβ‐AMPK; SIRT1 signaling; upregulating cytoplasmic (de)acetylation reactions | Antioxidant (over‐the‐counter (OTC) supplements); antiaging effects, including anti‐inflammatory, cancer prevention, antidiabetic, cardioprotective, and neuroprotective properties (clinical trials) | 442 , 443 , 444 , 445 , 446 , 447 , 448 | |
| MTORC1 inhibitor | Rapamycin and rapalogs (Sirolimus) | Destabilization of MTOR–RAPTOR complex | Life‐span extension (preclinical studies); to prevent transplant rejection and to treat a rare pulmonary disease (approved); neuroprotective properties (preclinical); anticancer, including breast cancer; advanced pancreatic; non‐small‐cell lung cancer (clinical trials) | 193 , 449 , 450 , 451 |
| Everolimus (RAD‐001) | Destabilization of MTOR–RAPTOR complex | Anticancer effects (approved for breast cancer and renal cell carcinoma treatment), kidney transplant failure and rejection | 452 , 453 , 454 , 455 | |
| Temsirolimus | Destabilization of MTOR–RAPTOR complex | Potential treatment for treatments of LMNA cardiomyopathy, Huntington disease (preclinical); anticancer effects (approved for advanced renal cell carcinoma treatment) | 456 , 457 , 458 , 459 | |
| Torin1/2 | An ATP‐competitive inhibitor for MTOR | Experiment tools | 460 , 461 , 462 | |
| PP242 | An ATP‐competitive inhibitor for MTOR | Reduce tumor size in xenograft models (preclinical) | 460 , 463 , 464 , 465 | |
| AZD8055 | An ATP‐competitive inhibitor for MTOR | Advanced solid malignancies (clinical trials) | 188 , 466 , 467 , 468 , 469 | |
| EN6 | Targeting the ATP6V1A subunit of the lysosomal V‐ATPase, which stimulates MTORC1 via the Rag GTPase | Clears TDP‐43 aggregates, a causative agent in frontotemporal dementia (preclinical) | 470 | |
| AcCoA inhibitor | Hydroxycitrate acid | Competitive inhibiting the ATP citrate lyase (ACLY) to block the AcCoA synthesis, which activates MTOR vis EP300‐induced acetylation | Potential anticancer effects; immunosurveillance (OTC supplements) | 471 |
| Triethylenetetramine | A Cu(II)‐selective chelator, which depleting AcCoA via activating of SAT1; | Wilson's disease (approved); corrects diet‐induced metabolic syndrome; prevention or treatment of obesity (preclinical); cancer prevention (clinical trials) | 472 | |
| PI3K and MTOR inhibitor | BEZ235 | Binding to the ATP‐binding clefts of PI3K class I and MTOR kinase | Promote survival of drug‐resistant glioma; T‐cell acute lymphoblastic leukemia; hepatocellular carcinoma (clinical trials) | 473 , 474 , 475 |
| PI3K inhibitor | Idelalisib (CAL‐101) | Small‐molecule inhibitor of the delta isoform (p110δ) of PI3K | Chronic lymphocytic leukemia (approved) | 476 , 477 |
| AKT inhibitor | MK‐2206 | Allosterically inhibiting AKT in a pH‐domain‐dependent inhibitor | Anticancer effect, including colorectal cancer, melanoma, and advanced liver cancer (clinical trials), inhibiting COVID‐19 propagation in vitro (preclinical) | 478 , 479 , 480 |
| Perifosine | Allosterically inhibiting Akt in a pH‐domain‐dependent inhibitor | Chronic lymphocytic leukemia, small lymphocytic lymphoma (clinical trials) | 481 | |
| Multiple targets (AMPK or MTOR related) | Aspirin (and salicylate) | Activating AMPK; inhibiting EP300, COX (cyclooxygenase)‐1, COX‐2 and MTOR; | Anti‐inflammatory, antimicrobial, antipyretic, and analgesic drug (approved); cardiovascular diseases (clinical trials); anticancer (clinical trials) | 482 , 483 , 484 |
| Spermidine | Inhibiting acetyltransferases (such as EP300) leading to increased cytoplasmic deacetylation reactions; inhibiting MTOR; activating AMPK | Antioxidant; antiaging effects, including anti‐inflammatory, cancer prevention (clinical trials), antidiabetic, cardioprotective (clinical trials), and neuroprotective properties | 442 , 471 , 485 , 486 , 487 , 488 , 489 , 490 , 491 | |
| EGCG | CaMKKβ–AMPK signaling; MTOR, HATs, and KDACs | Potential therapeutic reagent to prevent cardiovascular complication, metabolic syndromes and potential anticancer effect (clinical trials) | 492 , 493 | |
| Curcumin | AMPK‐MTOR; TFEB‐lysosome pathway | Potential anticancer effect (clinical trials) | 494 , 495 , 496 | |
| Trehalose | Inhibition of glucose transporter SLC2A (also known as GLUT) to induce AMPK‐dependent autophagy; low‐grade lysosomal stress‐mediated TFEB activation | Neurodegenerative diseases, cardioprotective effects, atherosclerosis, hepatic steatosis; bipolar disorders, dry eye syndrome and vascular ageing, Alzheimer disease, nonalcoholic fatty live, infertility (clinical trials) | 497 , 498 , 499 , 500 , 501 , 502 , 503 , 504 , 505 | |
| Cucurbitacin | Mitochondrial ROS; ERK–MTOR–STAT3 | Potential anticancer, anti‐inflammatory, antibacterial and antidepressant effects (preclinical) | 506 , 507 , 508 | |
| Quercetin | Modulation of AKT‐MTOR signaling and hypoxia‐induced factor 1α (HIF‐1α) signaling, mitochondria ROS, SIRT1 | Antitumor, antioxidant, anti‐inflammatory, antidiabetic, hepatoprotective, and cardioprotective; COVID‐19 treatment (clinical trials) | 509 , 510 | |
| ROS enhancer | Antimycobacterial antibiotics (isoniazid or pyrazinamide) | Activation of cellular and mitochondrial ROS | Tuberculosis infection (approved) | 511 |
| BECN1 activator | Tat‐BECN1 | A cell‐permeable peptide derived from BECN1; interacting with a negative regulator of autophagy, GAPR‐1 | Antivirual, anticancer, cardioprotective, cerebrovascular, and cardiovascular protective, neuroprotective properties (preclinical) | 512 , 513 , 514 , 515 , 516 , 517 , 518 , 519 , 520 , 521 , 522 , 523 |
| Isorhynchophylline | Dependent on BECN1 function | Neuroprotective properties against neurodegenerative diseases including Parkinson disease (preclinical) | 524 | |
| BRD1991 | Bcl‐2–BECN1 PPI (protein–protein interaction) inhibitors | Experimental agents | 525 | |
| Xestospongin B | The IP(3)R antagonist inhibit IP(3)R interaction with BECN1 | Experimental agents; potential anticancer effects (preclinical) | 526 , 527 , 528 , 529 | |
| Inositol monophosphatase (IMPase) inhibitor | Carbamazepine | Reduction in Ins(1,4,5)P3 and inositol levels; a voltage‐dependent sodium channels blocker | Reduces hepatic fibrosis; fatty liver conditions; neuroprotection (preclinical); treatment of seizures and bipolar disorders (approved) | 530 , 531 , 532 , 533 |
| Lithium | Depletion of free inositol, reduction of IP3 levels, and increase in levels of Beclin1; inhibitor of GSK3β. | Bipolar disorder (approved); neurodegenerative disorders, including huntingtin or Parkinson's disease (clinical trials) | 534 , 535 , 536 , 537 , 538 | |
| TFEB/TFE3 activator | 3,4‐Dimethoxychalcone (3,4‐DC) | Stimulating the translocation of TFEB and TFE3 into nuclei; | Cardioprotective effects, and improved the efficacy of anticancer chemotherapy (preclinical) | 539 |
| Thiostrepton | Activation of TFEB and TFE3 | Stimulate anticancer immune responses of immunogenic cell death (ICD)‐inducing chemotherapeutics (clinical trials) | 540 | |
| HDACI inhibitors | Trichostatin A | FOXO1‐dependent pathways | Anti‐cancer property (clinical trials) | 541 , 542 , 543 |
| Suberoylanilide hydroxamic acid | FOXO1‐dependent pathways | Cutaneous T‐cell lymphoma treatment (approved); epilepsy, Cushing's disease, breast cancer with a combination with pembrolizumab, tamoxifen (clinical trials) | 541 , 544 | |
| p38 kinases inhibitor | SB202190 | p38alpha/beta kinases inhibitor; TFEB/TFE3‐dependent autophagy and lysosomal biogenesis | Treatment of colorectal cancer (preclinical) | 545 , 546 |
| Ca2+ channel antagonist | Fluspirilene | Ca2+ channel antagonist | Antipsychotic drugs (approved) | 547 , 548 |
| Verapamil | L‐type Ca2+ channel antagonist | Nonalcoholic fatty liver, extends lifespan (preclinical); ischemic stroke; type 1 diabetes (clinical trials) | 273 , 549 , 550 , 551 | |
| Felodipine | Ca2+ channel antagonist | Hypertension, cardiovascular diseases (clinical trials); neurodegenerative disorders | 552 | |
| Loperamide | An opioid receptor agonist that also inhibits voltage‐gated P/Q‐type Ca2+ channels; ER stress | Anticancer property (clinical trials) | 551 , 553 , 554 | |
| Amiodarone | Ca2+ channel antagonist | Antiarrhythmic agent (approved); hepatitis B virus‐associated hepatocellular carcinoma (preclinical) | 555 , 556 | |
| Cholesterol depleting agent | MBCD | Enhancing lysosomal V‐ATPase assembly and promoting VAMP3‐mediated autophagosome formation | Experiment agents | 557 , 558 |
| Mitophagy inducer | Urolithin A | Reducing mitochondria membrane potential | Antiaging effects via clearance of dysfunctional mitochondria (preclinical) | 559 |
| Selective autophagy | Autophagy‐targeting chimera (AUTAC) | Hijack autophagy to selectively degrade destines substrate via a standalone tag, S‐Guanylation | Experimental tools | 560 |
| Unclear mechanism | SMER‐28 | Unclear (independent of MTORC1) | Clearance of aggregation‐prone proteins, including amyloid‐β (preclinical) | 561 |
| BRD5631 | Unclear (independent of MTORC1) | Bacterial clearance; suppresses NPC1‐induced cell death (preclinical) | 562 | |
| 10‐NCP | Unclear (independent of MTORC1) | Against toxicity in a Huntington disease model (preclinical) | 563 | |
| Alpha‐lipoic acid | Upregulation of autophagy‐related genes | Antiaging effects (as a nutritional supplement), including anti‐inflammatory, cancer prevention, antidiabetic, cardioprotective, and neuroprotective properties, atherosclerosis, hypertension and Alzheimer's disease; nonalcoholic fatty liver disease (clinical trials) | 564 |