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. Epub 2018 Dec 27.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Cyclin-Dependent Kinase 4 / chemistry
  • Cyclin-Dependent Kinase 4 / genetics
  • Cyclin-Dependent Kinase 4 / metabolism
  • Cyclin-Dependent Kinase 6 / chemistry
  • Cyclin-Dependent Kinase 6 / genetics
  • Cyclin-Dependent Kinase 6 / metabolism*
  • Gene Expression / drug effects
  • Gene Regulatory Networks / drug effects
  • Humans
  • Leukemia, Myeloid, Acute / metabolism
  • Leukemia, Myeloid, Acute / pathology
  • Phthalimides / chemistry
  • Phthalimides / pharmacology
  • Signal Transduction / drug effects
  • Small Molecule Libraries / chemistry

Substances

  • Phthalimides
  • Small Molecule Libraries
  • phthalimide
  • CDK4 protein, human
  • CDK6 protein, human
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinase 6