Allosteric Inhibition of ABL Kinases: Therapeutic Potential in Cancer

Mol Cancer Ther. 2020 Sep;19(9):1763-1769. doi: 10.1158/1535-7163.MCT-20-0069. Epub 2020 Jun 30.


Tyrosine kinase inhibitors have revolutionized the world of cancer treatment in recent years, profoundly improving survival of patients with chronic myeloid leukemia (CML) and beyond. However, off-target toxicities of these inhibitors are well-described, and resistance has become a paramount concern. Novel allosteric inhibitors of the Abelson (ABL) family of tyrosine kinases, including GNF-2, GNF-5, and ABL-001, are equipped to overcome these issues. Several contemporary studies have demonstrated their potential efficacy in three key areas: primary hematologic and solid malignancies, metastasis, and combination with other small molecules. Further, ongoing clinical trials are investigating the efficacy of ABL-001 for the treatment of CML and recurrent solid tumors. This work reviews the current literature of the preclinical testing of GNF-2 and GNF-5 and the preclinical and clinical testing of ABL-001. Future research will continue to evaluate these promising inhibitors as both first-line therapy for solid tumors and salvage therapy when more traditional drugs such as imatinib fail.

Publication types

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

MeSH terms

  • Allosteric Regulation / drug effects*
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Benzamides / pharmacology
  • Benzamides / therapeutic use
  • Clinical Trials as Topic
  • Drug Screening Assays, Antitumor
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Neoplasms / drug therapy*
  • Neoplasms / metabolism
  • Niacinamide / analogs & derivatives
  • Niacinamide / pharmacology
  • Niacinamide / therapeutic use
  • Proto-Oncogene Proteins c-abl / metabolism*
  • Pyrazoles / pharmacology
  • Pyrazoles / therapeutic use
  • Pyrimidines / pharmacology
  • Pyrimidines / therapeutic use


  • Benzamides
  • GNF-2 compound
  • N-(2-hydroxyethyl)-3-(6-((4-(trifluoromethoxy)phenyl)amino)-4-pyrimidinyl)benzamide
  • Pyrazoles
  • Pyrimidines
  • asciminib
  • Niacinamide
  • Proto-Oncogene Proteins c-abl