Table. 2.
Mitochondrion-associated Cell death | Diseases | Drugs/mode of action | Status of clinical trials | Developers | References and/or clinical trial registration number |
---|---|---|---|---|---|
1. Neurodegenerative diseases | |||||
Apoptosis | GBM | Carboplatin/DNA-damaging agent triggering apoptosis. Evaluated in combination with Bevacizumab (VEGF inhibitor). | Phase II (122), completed | Roche Products Australia Pty Ltd. |
ACTRN12610000915055 PMID: 26130744 |
Olaparib/PARP inhibitor sensitizes GBM cells to death receptor-mediated apoptosis induced by TRAIL. These agents all induce apoptosis in malignant cells. | Phase I/IIa (79), recruiting | Centre Francois Baclesse |
PMID: 30832617 |
||
Necroptosis | ALS | DNL747/RIPK1 inhibitor | Phase I (15), terminated | Sanofi | NCT03757351 |
AD | Phase I (16), completed | Denali Therapeutics Inc. | NCT03757325 | ||
Ferroptosis | PD | Deferiprone/iron chelator | Phase II (40), completed | University Hospital, Lille |
PMID: 24251381 |
Phase II (22), completed | Imperial College London |
PMID: 28469157 |
|||
AD | Deferiprone/iron chelator | Phase II (171) ongoing | Neuroscience Trials Australia | NCT03234686 | |
ALS | Deferiprone/iron chelator | Phase II (23), completed | University Hospital, Lille | NCT02164253 | |
Phase II (240) ongoing | NCT03293069 | ||||
PD | CuII(atsm)/radical scavenger | Phase I (31), completed | Collaborative Medicinal Development Pty Limited | NCT03204929 | |
ALS | Phase I (50), completed | NCT02870634 | |||
Phase I (28) Ongoing | NCT03136809 | ||||
Phase II (80) ongoing | NCT04082832 | ||||
Phase II (70) ongoing | NCT04313166 | ||||
2. Cancer | |||||
Apoptosis |
Ovarian cancer; endometrial cancer |
Selinexor/induces apoptosis by decreasing NF-κB activity | Phase I (23), completed | Memorial Sloan Kettering Cancer Center |
PMID: 28314490 |
Breast cancer | Pentoxifylline/induces apoptosis by decreasing NF-κB | Phase 2 (48), terminated | University Health Network, Toronto | NCT00188669 | |
Bortezomib/induces apoptosis by decreasing NF-κB | Phase 2, completed | Northwestern University |
PMID: 33775688 |
||
CLL, melanoma, solid tumors | Navitoclax/dual Bcl-2 and Bcl-xL inhibitor | Phase I/II (130), recruiting | National Cancer Institute (NCI) | NCT02079740 | |
Phase I (44), active | NCT02143401 | ||||
Phase I/II (75), active | NCT01989585 | ||||
Phase I (50), active | NCT02520778 | ||||
SCLC, solid tumors | APG-1252/dual Bcl-2 and Bcl-xL inhibitor | Phase I (24), terminated | Ascentage Pharma Group Inc. | NCT03387332 | |
NHL, multiple myeloma | S55746 (BCL201)/selective Bcl-2 inhibitors | Phase I (20), completed | Novartis Pharmaceuticals | NCT02603445 | |
Phase I (65), completed | Institut de Recherches Internationales Servier | NCT02920697 | |||
Solid tumors | ABBV-155/Bcl-xL inhibitors | Phase I (176), recruiting | AbbVie | NCT03595059 | |
NHL, AML | APG-2575/Selective Bcl-2 inhibitors | Early phase I (90), recruiting | Ascentage Pharma Group Inc. | NCT03537482 | |
Phase I (74), recruiting | NCT03913949 | ||||
AMG 176/MCL-1 inhibitors | Phase I (175), recruiting | Amgen | NCT02675452 | ||
AMG 176/MCL-1 inhibitors MIK665 (S64315)/MCL-1 inhibitors |
Phase I (9), terminated (Safety) | AbbVie | NCT03797261 | ||
Phase I (31), completed | Novartis Pharmaceuticals | NCT02992483 | |||
MIK665 (S64315)/MCL-1 inhibitors AZD5991/MCL-1 inhibitors |
Phase I (40), recruiting | Institut de Recherches Internationales Servier | NCT03672695 | ||
Phase I (38), completed |
Institut de Recherches Internationales Servier AstraZeneca |
NCT02979366 | |||
Phase I (70), terminated | NCT03218683 | ||||
LCL161/IAP inhibitors and SMAC mimetic antagonists | Phase I (34), terminated | SCRI Development Innovations, LLC | NCT02649673 | ||
Colorectal cancer, multiple myeloma, polycythemia vera, myelofibrosis |
LCL161/IAP inhibitors and SMAC mimetic antagonists Birinapant (TL32711)/IAP inhibitors and SMAC mimetic antagonists |
Phase II (53), completed | Anderson Cancer Center | NCT02098161 | |
Phase I (26), completed | Novartis Pharmaceuticals | NCT03111992 | |||
Phase I (34), recruiting | NCI | NCT03803774 | |||
Advanced solid tumors, NHL |
Birinapant (TL32711)/IAP inhibitors and SMAC mimetic antagonists Sorafenib/GPX4 inactivation due to GSH depletion (Class I FINs) – targeting system XC- |
Phase I/II (34), terminated | Medivir | NCT02587962 | |
Phase II (86), completed | Chinese Academy of Medical Sciences |
PMID: 34977874 |
|||
Ferroptosis | HCC, RCC, NSCLC, PDAC |
Sorafenib/GPX4 inactivation due to GSH depletion (Class I FINs) – targeting system XC- Statins/Reduce selenoproteins (such as GPX4) and CoQ10 biosynthesis |
Phase II (500), recruiting | Wake Forest University Health Sciences | NCT02559778 |
Neuroblastoma | Phase II (342), completed | Eastern Cooperative Oncology Group | NCT00064350 | ||
Non-small cell lung cancer | Phase I/II (74), recruiting | Anderson Cancer Center | NCT03247088 | ||
Acute myeloid leukemia | Phase III (314) | Peking Union Medical College Hospital |
PMID: 23471651 |
||
Breast cancer | Continue PD-1/PD-L1 Inhibitors treatment | Phase III (578), recruiting | Antoinette J Wozniak | NCT04157985 | |
Fibrosarcoma, Bladder cancer | APR-246 (eprenetapopt)/GSH depletion, thioredoxin inhibition | Phase I (37), completed | Aprea Therapeutics | NCT04383938 | |
AML, non-small cell lung cancer, bladder cancer | Altretamine/GPX4 inhibition | Phase I/II | Roswell Park Cancer Institute | NCT00002936 | |
Lymphoma, sarcoma |
Bromelain/upregulation of ACSL4 | Phase II (100), Unknown | Oeyama-Moto Cancer Research Foundation | NCT02340845 | |
Colorectal cancer | Artesunate/GPX4 inactivation due to GSH depletion (Class I FINs) – targeting glutathione S-transferase | Phase I (19), completed | Georgetown University |
PMID: 29392450 |
|
Solid tumors |
Artesunate/GPX4 inactivation due to GSH depletion (Class I FINs) – targeting glutathione S-transferase Eprenetapopt/targeting p53 |
Phase I (23), completed | Heidelberg University | NCT00764036 | |
Metastatic breast cancer | Phase II (200), recruiting | The 108 Military Central Hospital |
PMID: 26137537 |
||
Colorectal cancer (Stage II/III) | Phase II (78), recruiting | Frantz Viral Therapeutics, LLC | NCT04098744 | ||
Cervical cancer | Phase II (200), recruiting | University of London | NCT02633098 | ||
Colorectal cancer (Stage II/III) | Phase I/II (100), suspended | Aprea Therapeutics | NCT04419389 | ||
Non-Hodgkin lymphomas |
Eprenetapopt/Targeting p53 Sulfasalazine/increase in ROS levels and a depletion of GPX4 and system xc‑ levels |
Phase III (154), completed |
Aprea Therapeutics Haukeland University Hospital |
NCT03745716 | |
Myelodysplastic syndromes | Phase I/II (247), completed |
PMID: 22965953 |
|||
High-grade ovarian cancer | Phase I/II (37), completed | NCT04383938 | |||
Solid tumors | Phase I (51), completed | NCT04214860 | |||
P53-mutant myeloid malignancies | Phase I (24), recruiting | NCT04205357 | |||
Glioblastoma |
Sulfasalazine/increase in ROS levels and a depletion of GPX4 and system xc‑ levels Buthionine sulfoximine/GPX4 inactivation due to GSH depletion (Class I FINs) |
Phase I (9), completed | University of Alabama at Birmingham | NCT01577966 | |
Glioma | Phase I (18), completed | Children’s Hospital Los Angeles | NCT00002730 | ||
Neuroblastoma | Fluvastatin/GPX4 inactivation/depletion (Class II, III FINs) – targeting HMG-CoA reductase | Phase II (35), completed | University of California, San Francisco | NCT00416403 | |
Breast cancer | Withaferin A/GPX4 inactivation/depletion (Class II, III FINs) – targeting GPX4 | Phase II (24), unknown | Tata Memorial Hospital | NCT00689195 | |
Osteosarcoma | Actinomycin-D, doxorubicin, topotecan and bleomycin/Caspase1/Caspase-3/GSDMD/GSDME/DFNA/eEF-2K | Not applicable, active, not recruiting | Children’s Hospitals and Clinics of Minnesota | NCT01464606 | |
Pyroptosis | Pleuropulmonary blastoma | Metformin/miR-497/PELP1/Caspase-1/GSDMD | Phase II (93), completed | NCI | NCT01447927 |
Esophageal Cancer | Docosahexaenoic acid/Caspase-1/GSDMD/IL-1β/HMGB1 | Phase II (65), completed |
NCI Sixth Affiliated Hospital, Sun Yat-sen University |
NCT01849250 | |
Breast cancer | 5-fluorouracil/Caspase-3/GSDME | Phase II (136), recruiting | NCT04358341 | ||
Gastric cancer | Magnesium glycinate/calcium: magnesium balance, microbiota, and necroptosis and inflammation | Not applicable (240), active | Vanderbilt University Medical Center | ||
Necroptosis | Colorectal cancer | Aspirin/MLKL | Phase II (81), active | NCI | NCT02965703 |
Colorectal adenoma | Birinapant/MLKL | Phase I (34), recruiting | NCI | NCT03803774 | |
Head and neck squamous cell carcinoma | Pembrolizumab (GSK3145095)/RIPK1 | Phase II (8), terminated | GlaxoSmithKline | NCT03681951 | |
Neoplasms, pancreatic | Olaparib/inhibits parthanatos by decreasing PARP |
Phase I (98), active Phase I (197) |
AstraZeneca |
PMID: 27169564 |
|
Parthanatos | Breast cancer | Niraparib/inhibits parthanatos by decreasing PARP |
Phase I (21), completed Phase I (113), completed |
Tesaro, Inc. |
PMID: 23810788 |
Rucaparib/inhibits parthanatos by decreasing PARP |
Phase II (78), completed Phase II (41), completed |
Cancer Research UK UNICANCER |
|||
Breast cancer, ovarian cancer | Veliparib/inhibits parthanatos by decreasing PARP |
Phase I (16), completed Phase I (98), completed |
AbbVie NCI |
PMID: 28665051 |
|
Breast cancer | Talazoparib/inhibits parthanatos by decreasing PARP |
Phase I (36), completed Phase I (113), completed |
NCI Pfizer |
||
3. Infectious diseases | |||||
Apoptosis | Hepatitis C, chronic | VX-799/small-molecule caspase inhibitor | Phase I, unknown | Vertex/Serono | Unknown |
Septic organ failure | Predicted mortality of necroptosis in a septic patient | Not applicable (72), completed | Universitas Sriwijaya | NCT04169412 | |
Necroptosis | Sepsis | SAR443122/RIPK1 | Phase I (68), completed | Sanofi | NCT04469621 |
Corona virus infection | Standard treatments for sepsis | Not applicable (100), recruiting | Nanjing First Hospital, Nanjing Medical University | NCT05410665 | |
Pyroptosis | Sepsis | Pyroptosis rate | Not applicable (100), recruiting | Jianfeng Xie | NCT04427371 |
4. Cardiovascular diseases | |||||
Apoptosis | Heart disease | Minocycline/alters the mitochondrial membrane potential with apoptotic factor protein expression (JNK/p-JNK and caspase-3) | Phase I/II (60), completed | David Hess | NCT00630396 |
Acute stroke |
Minocycline/alters the mitochondrial membrane potential with apoptotic factor protein expression (JNK/p-JNK and caspase-3) MCI-186/ |
Phase II/III (100), recruiting | Stony Brook University | NCT03320018 | |
Ischemic stroke | Phase II (36), completed | Mitsubishi Tanabe Pharma Corporation | NCT00821821 | ||
Acute ischemic stroke | Erythropoietin/activates the PI3K/Akt pathway | Phase III (138), completed | Deutsches Herzzentrum Muenchen | NCT00390832 | |
Myocardial infarction | Levosimendan/soluble apoptosis signaling molecules Fas/Fas Ligand; reduction in major pro-inflammatory cytokine (TNF-α, IL-6) levels | Phase III (246), unknown | Dr. Gerhard Pölzl | NCT03437226 | |
Heart failure | Puerarin/induces the production of Reduces the production of ROS and NOX4 | Phase II (217), completed | The University of Hong Kong |
PMID: 29427658 |
|
Ferroptosis | Heart failure | Dexrazoxane/inhibits iron overload | Phase I (12) terminated | Medical City Children’s Hospital | NCT02519335 |
Heart defects, congenital | Deferoxamine/inhibits iron overload | Phase II (60), completed | Novartis Pharmaceuticals | NCT01254227 | |
Cardiac iron overload | Deferiprone/inhibits iron overload | Phase IV, completed | Ospedale Microcitemico | NCT00800761 | |
Iron overload cardiomyopathy | Puerarin/unknown | Phase II (217), completed | The University of Hong Kong | NCT03676296 | |
Heart failure | Sulfasalazine system Xc- | Not applicable (60), completed | Boston University | NCT00554203 | |
Coronary artery disease | Nicotine/ROS‐NLRP3‐ASC | Phase II (152), completed | National Institute on Drug Abuse (NIDA) | NCT00469885 | |
Pyroptosis | Cardiovascular disease | Nicotine/ROS‐NLRP3‐ASC | Phase II (152), completed | NIDA | NCT00469885 |
5. Digestive diseases | |||||
Apoptosis | Crohn’s Disease | Pathophysiology of NEC by using human-entered biorepository | Not applicable (18), unknown | Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico | NCT04549727 |
Necroptosis | Enterocolitis, necrotizing | GSK2982772/RIPK1 | Phase II (36), completed | GlaxoSmithKline | NCT02903966 |
Colitis, ulcerative | GSK2982772/RIPK1 | Phase II (36), completed | GlaxoSmithKline | NCT02903966 | |
6. Autoimmune diseases | |||||
Apoptosis | Rheumatoid arthritis | Infliximab (Remicade)/anti-inflammatory, also induces apoptosis in macrophages | Not applicable (1061), completed | Janssen Korea, Ltd., Korea | NCT00760669 |
Arthritis, rheumatoid | GSK2982772/RIPK1 | Phase II (65), completed | GlaxoSmithKline | NCT02776033 | |
Necroptosis | Psoriasis |
GSK2982772/RIPK1 SAR443820/RIPK1 |
Phase II (52), completed |
GlaxoSmithKline Sanofi |
NCT02858492 |
Arthritis, rheumatoid | Phase I (45), completed | NCT03266172 | |||
MR. IR, PK, and PD | Phase I (14), completed | NCT04982991 | |||
Multiple sclerosis, healthy subjects | SAR443122/RIPK1 | Phase II (88), recruiting | Sanofi | NCT04781816 | |
Cutaneous lupus erythematosus | |||||
7. Metabolic disease | |||||
Apoptosis | Obesity and diabetes | Pralnacasan VX-740/Caspase-1 inhibitor | Preclinical ob/ob mouse | Vertex Pharmaceuticals |
PMC3174591 PMC3683568 |
Obesity and NASH | Ac-YVAD-cmk/Caspase-1 inhibitor | Preclinical obese and NASH mouse model | NonPharmaceuticals | PMC5022108 | |
NASH | Caspase-1, -8, -9 inhibitor | Phase II NASH/completed | Gilead Sciences | PMC3779694 | |
Obesity, NAFLD, NASH | Emricasan IDN-6556; PF-03491390/broad-spectrum pancaspase inhibitor |
Preclinical obese and NASH mouse model Phase II in NAFLD/completed Phase II in NASH fibrosis/active, not recruiting Phase II in decompensated NASH cirrhosis/active, recruiting Phase II NASH cirrhosis and severe portal hypertension |
Conatus Pharmaceuticals |
PMID24750664 |
|
NASH and NAFLD | VX-166/broad-spectrum pancaspase inhibitor | Preclinical mouse models of NASH and NAFLD | Vertex pharmaceuticals |
PMID20557969 PMID19676126 |
|
Diabetes | EP1013/broad-spectrum pancaspase inhibitor | Preclinical islet-transplanted mice | EpiCept Corporation |
PMID18356409 PMID20332344 |
|
Necroptosis | Prediabetes | Necrostatin-1/RIPK1 inhibitor | Preclinical prediabetes rats | PMID34265741 | |
NAFLD | RIPA-56/RIPK1 inhibitor or necrosulfonamide/MLKL inhibitor | In vivo high-fat diet-fed mice | PMID31760070 | ||
Ferroptosis | Diabetes and its complications | Quercetin, curcumin, cryptochlorogenic acid, epigallocatechin-3-gallate, melatonin, ferrostatin-1, deferoxamine, hepcidin, liproxstation-1, rosiglitazone, baicalein, sterubin/ferroptosis inhibitors | In vitro pancreatic β-cells and in vivo diabetic rat and mouse models |
PMID33324924 PMID34487731 PMID20586147 PMID28216051 PMID26700463 PMID17569207 PMID26216672 PMID24614112 PMID30615092 PMID31102787 PMID23483669 PMID31574461 |
|
Pyroptosis | NAFLD, NASH | MCC950/NLRP3 inflammasome inhibitor | Preclinical obese diabetic mice | PMID28167322 | |
Obesity, NAFLD, NASH | CY-09/NLRP3 inflammasome inhibitor | In vivo high-fat diet-fed mice |
PMID29021150 PMID33213837 |
||
NAFLD | Glibenclamide/NLRP3 inflammasome inhibitor | In vivo streptozotocin-induced nonalcoholic fatty liver disease in rats | PMID31834465 | ||
NAFLD | Parthenolide/NLRP3, AIM2, NLRC4, MLRP1 inhibitor | In vivo NAFLD rat model | PMID28555525 |