Related Experiment Video

Updated: Jun 5, 2025

Fully Processed Recombinant KRAS4b: Isolating and Characterizing the Farnesylated and Methylated Protein
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Discovery of BBO-8520, a First-In-Class Direct and Covalent Dual Inhibitor of GTP-Bound (ON) and GDP-Bound (OFF)

Anna E Maciag1, James P Stice2, Bin Wang2

  • 1NCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland.

Cancer Discovery
|December 6, 2024
PubMed

Insights

A new dual inhibitor, BBO-8520, targets both active and inactive forms of KRASG12C. This approach overcomes resistance seen with current inhibitors and shows promise in preclinical models for cancer treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Approved KRASG12C inhibitors target the inactive (OFF) form, leaving the active (ON) form unaddressed.
  • Resistance to (OFF)-only inhibitors emerges due to increased KRASG12C(ON) activity.
  • There is a need for inhibitors that provide comprehensive KRASG12C target coverage.

Purpose of the Study:

  • To develop a novel inhibitor targeting both active and inactive KRASG12C conformations.
  • To evaluate the efficacy of this dual inhibitor in preclinical cancer models.
  • To assess its potential to overcome adaptive resistance mechanisms.

Main Methods:

  • Development of BBO-8520, a covalent dual inhibitor targeting KRASG12C(ON) and (OFF) forms.
  • In vitro assessment of signaling inhibition in growth factor-activated states.
  • In vivo studies in multiple tumor models, including those resistant to (OFF)-only inhibitors.

Main Results:

  • BBO-8520 effectively inhibits signaling in growth factor-activated states where (OFF)-only inhibitors are less active.
  • In vivo studies demonstrated rapid target engagement and significant tumor regression.
  • BBO-8520 showed efficacy in models resistant to existing KRASG12C inhibitors.

Conclusions:

  • BBO-8520 is a first-in-class covalent dual inhibitor of KRASG12C, engaging both active and inactive states.
  • This novel mechanism offers optimal target coverage and delays adaptive resistance.
  • BBO-8520 is currently in Phase 1 clinical trials for KRASG12C-mutated non-small cell lung cancer.

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