SMAC mimetics as potential cancer therapeutics in myeloid malignancies.
Prajwal C BodduBing Z CarterSrdan VerstovsekNaveen PemmarajuPublished in: British journal of haematology (2019)
Evasion of apoptosis has been identified as one of the essential hallmarks of cancer. Inhibitor of apoptosis proteins (IAPs) are implicated in a host of myeloid malignancies, providing the rationale for strategies aimed at neutralizing IAPs to lower the cancer cell apoptosis threshold. Modes of IAP antagonism may include down-regulating IAP expression, up-regulating endogenous pro-apoptotic proteins, such as tumour necrosis factor-α or Fas ligand, or directly antagonizing IAP activity against caspases. Direct targeting of IAPs using mimetics of the second mitochondria-derived activator of caspase (SMAC) protein has shown therapeutic promise by sensitizing the effect of chemotherapy on malignant cells. In pre-clinical studies, SMAC mimetics have demonstrated broad synergistic activity with a wide range of therapeutics, including cytotoxic chemotherapy, receptor tyrosine kinase inhibitors, agents targeting death receptors and alternative mechanisms of cell death, such as necroptosis or autophagy and immune check point blockade. SMAC mimetics represent a novel approach for further investigation in patients with high-risk, chemo-refractory blood cancers, as single agents or in thoughtfully selected combinations. In this review, we discuss the development and therapeutic rationale of small molecule SMAC mimetics, with an emphasis on agents in clinical development for myeloid malignancies.
Keyphrases
- cell death
- cell cycle arrest
- small molecule
- papillary thyroid
- endoplasmic reticulum stress
- induced apoptosis
- cancer therapy
- oxidative stress
- squamous cell
- dendritic cells
- bone marrow
- acute myeloid leukemia
- locally advanced
- clinical trial
- poor prognosis
- protein protein
- childhood cancer
- immune response
- deep learning
- radiation therapy
- lymph node metastasis
- risk assessment
- pi k akt
- machine learning
- inflammatory response
- rectal cancer
- dengue virus
- human health
- chronic myeloid leukemia
- aedes aegypti