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. 2023 Aug 23;55(8):1595–1619. doi: 10.1038/s12276-023-01046-5

Table. 2.

Current list of clinical trials targeting mitochondria-associated programmed cell death in human diseases.

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

NCT03212742

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

NCT00943748

PMID: 24251381

Phase II (22), completed Imperial College London

NCT01539837

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

NCT02269293

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

NCT00028639

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

NCT03535259

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

NCT03971019

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

NCT02353026

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

NCT03093129

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

NCT02098343

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

NCT04229992

NCT01105169

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

NCT00516373

NCT00777582

PMID: 27169564

Parthanatos Breast cancer Niraparib/inhibits parthanatos by decreasing PARP

Phase I (21), completed

Phase I (113), completed

Tesaro, Inc.

NCT03329937

NCT00749502

PMID: 23810788

Rucaparib/inhibits parthanatos by decreasing PARP

Phase II (78), completed

Phase II (41), completed

Cancer Research UK

UNICANCER

NCT00664781

NCT02505048

Breast cancer, ovarian cancer Veliparib/inhibits parthanatos by decreasing PARP

Phase I (16), completed

Phase I (98), completed

AbbVie

NCI

NCT02210663

NCT00892736

PMID: 28665051

Breast cancer Talazoparib/inhibits parthanatos by decreasing PARP

Phase I (36), completed

Phase I (113), completed

NCI

Pfizer

NCT01989546

NCT01286987

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

NCT03676296

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

NCT02077374

NCT02686762

NCT03205345

NCT02960204

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
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