Therapeutics Targeting the Core Apoptotic Machinery
Abstract
:Simple Summary
Abstract
1. Introduction
1.1. Intrinsic Apoptosis
1.2. Extrinsic Apoptosis
2. Therapeutic Strategies for Promoting Apoptosis Directly—Intrinsic Pathway
2.1. Selective BCL-2 Inhibitors
2.2. Dual BCL-2/BCL-XL
2.3. Selective BCL-XL Inhibitors
2.4. Selective MCL1 Inhibitors
2.5. Alternative Approaches
2.6. BCL-2 Family Members—Emerging Resistance and Combination Approaches
3. Inhibitor of Apoptosis Proteins (IAP)
3.1. Monovalent IAP Antagonists
3.2. Bivalent IAP Antagonists
3.3. Non-Peptide Mimetic Small Molecule IAP Inhibitors
3.4. IAP Antagonists—Emerging Resistance and Combination Approaches
4. Therapeutic Strategies for Promoting Apoptosis Directly—Extrinsic Pathway
4.1. Death Receptor Targeted Cancer Therapeutics
4.1.1. First Generation TRAIL Agonists
4.1.2. Second Generation rTRAIL Preparations
4.1.3. DR4/DR5 Antibody Agonists
4.1.4. Recent Multivalent TRAIL Targeted Therapeutics under Clinical Investigation
4.1.5. Death Receptor Therapeutics-Emerging Resistance and Combination Approaches
5. Conclusions
Author Contributions
Funding
Conflicts of Interest
Abbreviations
AE | Adverse Effects |
AML | Acute myeloid leukemia |
APAF1 | Apoptotic protease activating factor-1 |
BAK | BCL-2 antagonist killer 1 |
BAX | BCL-2 associated X protein |
BCL-2 | B-cell lymphoma family |
BCL-W | B-cell lymphoma-w |
BCL-XL | B-cell lymphoma-extra large |
BH | BCL-2 homology domain |
BID | BH3 interacting-domain death agonist |
BIM | Bcl-2-like protein 11 |
BIR | Baculoviral IAP repeats |
Caspase | Cysteinyl aspartate specific protease |
cIAP | Cellular inhibitor of apoptosis |
CLL | Chronic lymphocytic leukemia |
CPT | Circularly permuted TRAIL |
CTLC | Cutaneous T-cell lymphoma |
DD | Death domain |
DED | Death effector domain |
DISC | Death inducing signaling complex |
DR | Death receptor |
DR4 | TRAIL-R1 (Death receptor 4) |
DR5 | TRAIL-R2 (Death receptor 5) |
FADD | Fas-associated death domain |
FDA | US Food and Drug Administration |
FIH | First-in-human |
FLIP | Fas-associated death domain (FADD)-like IL1β-converting enzyme-inhibitory protein |
IAP | Inhibitor of apoptosis |
IND | Investigational new drug |
ILP2 | Inhibitor of apoptosis protein-like protein 2 |
ITD | Internal tandem duplication |
izTRAIL | Isoleucine zipper TRAIL |
lzTRAIL | leucine zipper TRAIL |
MCL-1 | Myeloid cell leukemia sequence 1 |
ML-IAP | Melanoma inhibitor of apoptosis protein |
MM | Multiple myeloma |
MOMP | Mitochondrial outer membrane permeabilization |
NF-κB | Nuclear factor-kappa B |
NIAP | Neuronal apoptosis inhibitory protein |
NOXA | Phorbol-12-myristate-13-acetate-induced protein 1 |
NSCLC | Non-small cell lung cancer |
Omi | Human serine protease high temperature requirement A (HTRA2) |
PBMC | Peripheral blood monocytes |
PD-L1 | Programmed Death Ligand-1 |
PEG | Polyethylene glycol |
PK | Pharmacokinetic |
PTCL | Peripheral T-cell lymphoma |
PROTAC | Proteolysis targeting chimera |
PUMA | p53 upregulated modulator of apoptosis |
RING | Really interesting new gene |
SCLC | Small cell lung cancer |
SMAC | Second mitochondria-derived activator of caspases |
SOC | Standard of care treatment |
tBID | Truncated BID |
TNBC | Triple negative breast cancer |
TNF | Tumor necrosis factor |
TNFSF | Tumor necrosis superfamily |
TRAIL | Tumor necrosis factor (TNF)-related apoptosis-inducing ligand |
Treg | Tumor infiltrating regulatory T cells. |
XIAP | X-linked inhibitor of apoptosis |
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Drug Class | Resistance Mechanism | Mechanism to Overcome Resistance | References |
---|---|---|---|
BH3 Mimetics |
|
| [17,33,41,58,64,72] |
IAP Antagonists |
|
| [75,76,77,78,79] |
Death Receptor Targeted Therapeutics |
|
| [80,81,82,83,84,85,86,87] |
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Hamilton, C.; Fox, J.P.; Longley, D.B.; Higgins, C.A. Therapeutics Targeting the Core Apoptotic Machinery. Cancers 2021, 13, 2618. https://doi.org/10.3390/cancers13112618
Hamilton C, Fox JP, Longley DB, Higgins CA. Therapeutics Targeting the Core Apoptotic Machinery. Cancers. 2021; 13(11):2618. https://doi.org/10.3390/cancers13112618
Chicago/Turabian StyleHamilton, Claudia, Jennifer P. Fox, Daniel B. Longley, and Catherine A. Higgins. 2021. "Therapeutics Targeting the Core Apoptotic Machinery" Cancers 13, no. 11: 2618. https://doi.org/10.3390/cancers13112618