Global PROTAC Toolbox for Degrading BCR-ABL Overcomes Drug-Resistant Mutants and Adverse Effects

J Med Chem. 2020 Aug 13;63(15):8567-8583. doi: 10.1021/acs.jmedchem.0c00967. Epub 2020 Jul 23.

Abstract

The BCR-ABL fusion oncoprotein causes chronic myeloid leukemia or acute lymphoblastic leukemia in Ph+ patients because the ABL kinase is constitutively activated. However, current clinical treatment with ABL inhibitors is seriously limited by drug resistance and adverse effects. Although the emerging proteolysis-targeting chimeras (PROTACs) have been introduced to degrade BCR-ABL, most of them showed limited activity and could not overcome the common drug-resistant mutants, especially for T315I mutant. Herein, we systematically designed a set of unique PROTACs by globally targeting all the three binding sites of BCR-ABL, including dasatinib-, ponatinib-, and asciminib-based PROTACs. Our ponatinib-based PROTACs showed practical activity as dasatinib-based PROTACs, while no reported ponatinib-based PROTACs could degrade BCR-ABL before. As a proof of concept, some additional dasatinib-based PROTACs were then designed to degrade T315I mutant too. We provided a global PROTAC toolbox for degrading both wild-type and T315I-mutated BCR-ABL from each binding site. More importantly, these PROTACs showed better selectivity and less adverse effects than the inhibitors, indicating that PROTACs had great potential for overcoming clinical drug resistance and safety issues.

MeSH terms

  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Dasatinib / analogs & derivatives
  • Dasatinib / pharmacology*
  • Drug Design
  • Fusion Proteins, bcr-abl / antagonists & inhibitors
  • Fusion Proteins, bcr-abl / genetics
  • Fusion Proteins, bcr-abl / metabolism*
  • Humans
  • Imidazoles / chemistry
  • Imidazoles / pharmacology*
  • Models, Molecular
  • Niacinamide / analogs & derivatives*
  • Niacinamide / chemistry
  • Niacinamide / pharmacology
  • Proteolysis / drug effects*
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology*
  • Pyridazines / chemistry
  • Pyridazines / pharmacology*

Substances

  • Antineoplastic Agents
  • Imidazoles
  • Pyrazoles
  • Pyridazines
  • asciminib
  • Niacinamide
  • ponatinib
  • Fusion Proteins, bcr-abl
  • Dasatinib