Homolog-Selective Degradation as a Strategy to Probe the Function of CDK6 in AML

  • Cell Chem Biol. 2019 Feb 21;26(2):300-306.e9. doi: 10.1016/j.chembiol.2018.11.006.
Matthias Brand  1 ,  Baishan Jiang  2 ,  Sophie Bauer  1 ,  Katherine A Donovan  2 ,  Yanke Liang  2 ,  Eric S Wang  2 ,  Radosław P Nowak  2 ,  Jingting C Yuan  3 ,  Tinghu Zhang  2 ,  Nicholas Kwiatkowski  2 ,  André C Müller  1 ,  Eric S Fischer  2 ,  Nathanael S Gray  4 ,  Georg E Winter  5
Affiliations
  • 1. CeMM Research Center for Molecular Medicine of the Austrian Academy of Science, Vienna, Austria.
  • 2. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical, Boston, USA.
  • 3. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, USA.
  • 4. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical, Boston, USA. Electronic address: [email protected].
  • 5. CeMM Research Center for Molecular Medicine of the Austrian Academy of Science, Vienna, Austria. Electronic address: [email protected].
PMID: 30595531 DOI: 10.1016/j.chembiol.2018.11.006
Abstract

The design of selective small molecules is often stymied by similar ligand binding pockets. Here, we report BSJ-03-123, a phthalimide-based degrader that exploits protein-interface determinants to achieve proteome-wide selectivity for the degradation of cyclin-dependent kinase 6 (CDK6). Pharmacologic CDK6 degradation targets a selective dependency of acute myeloid leukemia cells, and transcriptomics and phosphoproteomics profiling of acute degradation of CDK6 enabled dynamic mapping of its immediate role in coordinating signaling and transcription.

Keywords
AML; CDK6; PROTAC; acute myeloid leukemia; molecular pharmacology; phosphoproteomics; selectivity; systems biology; targeted protein degradation; transcriptomics.
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