ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets

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Kinase Inhibitor Screening In Self-assembled Human Protein Microarrays
13:22

Kinase Inhibitor Screening In Self-assembled Human Protein Microarrays

Published on: October 23, 2019

Andrew J Souers1, Joel D Leverson, Erwin R Boghaert

  • 1AbbVie Inc., North Chicago, Illinois, USA. andrew.souers@abbvie.com

Nature Medicine
|January 8, 2013
PubMed

Insights

A new drug, ABT-199, selectively targets BCL-2 proteins, inhibiting cancer growth without causing platelet damage. This breakthrough offers a promising new treatment for BCL-2-dependent blood cancers like chronic lymphocytic leukemia.

Area of Science:

  • Molecular biology
  • Cancer research
  • Pharmacology

Background:

  • Proteins in the B cell CLL/lymphoma 2 (BCL-2) family regulate apoptosis.
  • Cancer cells evade apoptosis by increasing prosurvival BCL-2 family proteins.
  • Navitoclax, a BCL-2 and BCL-X(L) inhibitor, shows efficacy but causes thrombocytopenia.

Purpose of the Study:

  • To re-engineer navitoclax into a BCL-2-selective inhibitor.
  • To develop a potent, orally bioavailable BCL-2 inhibitor.
  • To assess the efficacy and safety of the new inhibitor in BCL-2-dependent cancers.

Main Methods:

  • Re-engineering of navitoclax to create ABT-199.
  • In vitro and in vivo testing of ABT-199's efficacy and platelet sparing.
  • Clinical evaluation in patients with refractory chronic lymphocytic leukemia.

Main Results:

  • ABT-199 is a potent, orally bioavailable, BCL-2-selective inhibitor.
  • ABT-199 inhibits BCL-2-dependent tumor growth in vivo.
  • ABT-199 spares human platelets and shows rapid tumor lysis in patients.

Conclusions:

  • Selective pharmacological inhibition of BCL-2 is a promising therapeutic strategy.
  • ABT-199 demonstrates potential for treating BCL-2-dependent hematological cancers.
  • ABT-199 offers an improved therapeutic window compared to non-selective inhibitors.

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