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Targeting oncoproteins for degradation by small molecules in myeloid leukemia

Hu Lei1, Weiwei Wang1, Yingli Wu1

  • 1a Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine , Chemical Biology Division of Shanghai Universities E-Institutes, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine , Shanghai , PR China.

Leukemia & Lymphoma
|December 5, 2017
PubMed

Insights

Targeting oncoproteins with small molecules that induce degradation offers a promising strategy to overcome drug resistance in myeloid leukemia. This approach degrades target proteins, bypassing common resistance mechanisms.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Oncoproteins are key drivers in myeloid leukemia pathogenesis.
  • Current targeted therapies (small molecules, monoclonal antibodies) face drug resistance via protein overexpression or mutations.
  • Targeting protein degradation pathways is a superior strategy to circumvent resistance.

Purpose of the Study:

  • To review the latest advances in small molecule-induced oncoprotein degradation for myeloid leukemia.
  • To discuss existing and candidate drugs targeting oncoprotein degradation.
  • To explore the rational design of selective protein degraders and proteolysis-targeting chimeras (PROTACs).

Main Methods:

  • Literature review of small molecule-based oncoprotein degradation strategies.
  • Analysis of existing cancer drugs and candidate drugs.
  • Examination of novel rational design principles for targeted protein degradation.
  • Review of proteolysis-targeting chimeras (PROTACs) technology.

Main Results:

  • Small molecules can induce oncoprotein degradation via ubiquitin or autophagy pathways.
  • Existing drugs and candidates demonstrate the potential of degradation-based therapies.
  • Rational design enables the development of selective protein degraders.
  • PROTACs show significant efficacy in degrading target proteins.

Conclusions:

  • Small molecule-induced oncoprotein degradation is a potent strategy against myeloid leukemia.
  • This approach effectively overcomes drug resistance mechanisms.
  • PROTAC technology represents a significant advancement in targeted protein degradation for cancer therapy.
Keywords:
PROTACsProtein degradationdrug resistanceleukemiasmall molecules

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