Table 3.
Clinical Development of Novel RCD Inhibitors and Therapies Currently in Use That Target RCD Pathways
| Drug | Target | RCD Pathways Impacted | Clinical Status |
|---|---|---|---|
| Small-molecule inhibitors | |||
| Z-VAD-FMK*† | Caspases | Apoptosis, pyroptosis | Preclinical |
| IDN‐6556 | Phase I/II (I,R) | ||
| VX-765 | Caspase 1 | Pyroptosis | Phase I/II trials (RA) |
| Necrostatin 1*‡ | RIP1K | Necroptosis (TNFR1) | Preclinical |
| GSK2982772 | Phase I/II trials (RA, P, UC) | ||
| DNL747, DNL788 | Phase I (RA, MS, ALS, AD) | ||
| GSK′872* | RIP3K | Necroptosis (TNFR1, TLR, ZBP1) | Preclinical |
| Pyroptosis (RIP3K-mediated) | |||
| NSA* | MLKL | Necroptosis (TNFR1, TLR, ZBP1) | Preclinical |
| Pyroptosis (RIP3K-mediated) | |||
| RWJ-445380 | Cathepsins | Lysosome-dependent cell death | Phase II (RA) |
| MDL-28170*† | Calpains | Lysosome-dependent cell death | Preclinical |
| Lysomotrophic agents | |||
| Chloroquine (and derivatives) | Lysosome | Lysosome-dependent cell death | Used as an immunosuppressive therapy in autoimmunity (lupus, RA) and as an antimicrobial (e.g., malaria) |
| Azithromycin | Lysosomal membrane | Lysosome-dependent cell death | Used as an antimicrobial and antiinflammatory therapy during respiratory infection |
| Monoclonal antibodies | |||
| Infliximab Adalimumab, Certolizumab, Golimumab | TNFα | TNFR1-dependent apoptosis, pyroptosis, and necroptosis | Used as an antiinflammatory in various inflammatory and autoimmune diseases (e.g., lupus, RA) |
Definition of abbreviations: AD = Alzheimer disease; ALS = amyotrophic lateral sclerosis; IDN-6556 = Emricasan; IFNR = type I IFN receptor; MS = multiple sclerosis; NSA = necrosulfonamide; P = psoriasis; RA = rheumatoid arthritis; RCD = regulated cell death; RIP1K = receptor-interacting serine/threonine-protein kinase 1; RIP3K = receptor-interacting serine/threonine-protein kinase 3; TNFR = TNF receptor; UC = ulcerative colitis; VX-765 = Belnacasan; Z-VAD-FMK = z-Val-Ala-Asp-(OMe)-fluoromethyl ketone.
Pharmacotherapeutic agents in development or in use for the treatment of diseases in which RCD pathways promote disease pathogenesis are shown.
Inhibitors for which clinical development has been discontinued because of high toxicity.
Inhibitors for which clinical development has been discontinued because of undesirable off target side effects are indicated with superscript numbers.
Inhibitors for which clinical development has been discontinued because of low potency.