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Isolating Malignant and Non-Malignant B Cells from lck:eGFP Zebrafish
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Published on: February 22, 2019

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SMAC mimetics as potential cancer therapeutics in myeloid malignancies

Prajwal Boddu1, Bing Z Carter2, Srdan Verstovsek2

  • 1Department of Hematology and Oncology, Yale University School of Medicine, New Haven, CT, USA.

British Journal of Haematology
|March 6, 2019
PubMed

Insights

Small molecule SMAC mimetics offer a novel therapeutic strategy for myeloid malignancies by sensitizing cancer cells to apoptosis. These agents show promise in pre-clinical studies, particularly for high-risk, chemo-refractory blood cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Development

Background:

  • Evasion of apoptosis is a key hallmark of cancer, with Inhibitor of Apoptosis Proteins (IAPs) playing a significant role in myeloid malignancies.
  • Targeting IAPs is a rational strategy to lower the cancer cell apoptosis threshold and enhance treatment efficacy.

Purpose of the Study:

  • To review the development and therapeutic rationale of small molecule second mitochondria-derived activator of caspase (SMAC) mimetics.
  • To emphasize SMAC mimetics in clinical development for myeloid malignancies.

Main Methods:

  • Discussing various modes of IAP antagonism, including expression modulation and direct caspase antagonism.
  • Highlighting the use of SMAC mimetics to directly antagonize IAP activity against caspases.
  • Reviewing pre-clinical data on SMAC mimetic synergy with diverse therapeutic agents.

Main Results:

  • SMAC mimetics have shown therapeutic promise by sensitizing malignant cells to chemotherapy.
  • Pre-clinical studies demonstrate broad synergistic activity of SMAC mimetics with cytotoxic chemotherapy, TKIs, death receptor agents, and immune checkpoint inhibitors.
  • SMAC mimetics also show synergy with alternative cell death mechanisms like necroptosis and autophagy.

Conclusions:

  • SMAC mimetics represent a novel therapeutic approach for high-risk, chemo-refractory blood cancers.
  • Further investigation of SMAC mimetics as single agents or in combination therapies is warranted.
  • This review focuses on the clinical development of small molecule SMAC mimetics for myeloid malignancies.
Keywords:
LCL-161MyelofibrosisMyeloproliferative NeoplasmsSMACinhibitor of apoptosis protein

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