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Issue 13, 2020
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Systematic exploration of different E3 ubiquitin ligases: an approach towards potent and selective CDK6 degraders

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Abstract

Cyclin-dependent kinase 6 (CDK6) is an important regulator of the cell cycle. Together with CDK4, it phosphorylates and inactivates retinoblastoma (Rb) protein. In tumour cells, CDK6 is frequently upregulated and CDK4/6 kinase inhibitors like palbociclib possess high activity in breast cancer and other malignancies. Besides its crucial catalytic function, kinase-independent roles of CDK6 have been described. Therefore, targeted degradation of CDK6 may be advantageous over kinase inhibition. Proteolysis targeting chimeras (PROTACs) structurally based on the cereblon (CRBN) ligand thalidomide have recently been described to degrade the targets CDK4/6. However, CRBN-based PROTACs have several limitations including the remaining activity of immunomodulatory drugs (IMiDs) on Ikaros transcription factors as well as CRBN inactivation as a resistance mechanism in cancer. Here, we systematically explored the chemical space of CDK4/6 PROTACs by addressing different E3 ligases and connecting their respective small-molecule binders via various linkers to palbociclib. The spectrum of CDK6-specific PROTACs was extended to von Hippel Lindau (VHL) and cellular inhibitor of apoptosis protein 1 (cIAP1) that are essential for most cancer cells and therefore less likely to be inactivated. Our VHL-based PROTAC series included compounds that were either specific for CDK6 or exhibited dual activity against CDK4 and CDK6. IAP-based PROTACs caused a combined degradation of CDK4/6 and IAPs resulting in synergistic effects on cancer cell growth. Our new degraders showed potent and long-lasting degrading activity in human and mouse cells and inhibited proliferation of several leukemia, myeloma and breast cancer cell lines. In conclusion, we show that VHL- and IAP-based PROTACs are an attractive approach for targeted degradation of CDK4/6 in cancer.

Graphical abstract: Systematic exploration of different E3 ubiquitin ligases: an approach towards potent and selective CDK6 degraders

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Supplementary files

Article information


Submitted
10 Jan 2020
Accepted
28 Feb 2020
First published
04 Mar 2020

This article is Open Access
All publication charges for this article have been paid for by the Royal Society of Chemistry

Chem. Sci., 2020,11, 3474-3486
Article type
Edge Article

Systematic exploration of different E3 ubiquitin ligases: an approach towards potent and selective CDK6 degraders

C. Steinebach, Y. L. D. Ng, I. Sosič, C. Lee, S. Chen, S. Lindner, L. P. Vu, A. Bricelj, R. Haschemi, M. Monschke, E. Steinwarz, K. G. Wagner, G. Bendas, J. Luo, M. Gütschow and J. Krönke, Chem. Sci., 2020, 11, 3474
DOI: 10.1039/D0SC00167H

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