Targeting oncoproteins for degradation by small molecules in myeloid leukemia

Abstract

Oncoproteins play a vital role in the pathogenesis of myeloid leukemia. Most targeted therapies for myeloid leukemia are small molecules or monoclonal antibodies that inhibit the activity of the oncoproteins. However, leukemia cells often develop resistance to these drugs through overexpression of the target protein and/or by obtaining new mutations in the target protein to render them resistant to the drug. Oncoproteins degradation induced by small molecules through ubiquitin or autophagy pathway is considered a better way to avoid drug resistance. Here, we describe the latest advances in the use of small molecules to degrade oncoproteins. We first discuss examples of existing cancer drugs and candidate drugs that act by degrading oncoproteins, and then review the latest development of rational design of small molecules that induce selective degradation of target proteins. Furthermore, small-molecule-based proteolysis-targeting chimeras (PROTACs) have demonstrated that this technology can effectively degrade target proteins.

Keywords:

• Protein degradation
• leukemia
• small molecules
• drug resistance
• PROTACs

Acknowledgments

This work was supported in part by grants from National Key Research and Development Program of China (NO. 2017YFA0505200), National Natural Science Foundation of China (81700475, 81570118).

Potential conflict of interest

Disclosure forms provided by the authors are available with the full text of this article online at http://dx.doi.org/10.1080/10428194.2017.1403600.