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SMALL MOLECULE IMAGING AGENT FOR MUTANT KRAS G12C.

Peter D Koch1,2, Jeremy Quintana1, Maaz Ahmed1

  • 1Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge St, CPZN 5206, Boston, MA 02114.

Advanced Therapeutics
|May 17, 2021
PubMed
Summary
This summary is machine-generated.

Researchers developed fluorescent companion imaging drugs (CID) for KRAS G12C. A novel two-step method allows direct visualization of mutant KRAS G12C in cancer cells, aiding research.

Keywords:
Companion imaging drugKRAS G12C inhibitorsin situ click chemistry

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Area of Science:

  • Oncology
  • Chemical Biology
  • Molecular Imaging

Background:

  • Mutant KRAS G12C is a key driver in various cancers.
  • Small molecule inhibitors offer potential for developing companion imaging probes.
  • Existing tools for studying mutant KRAS G12C biology are limited.

Purpose of the Study:

  • To synthesize and evaluate fluorescent companion imaging drugs (CID) for mutant KRAS G12C.
  • To develop a method for direct visualization of mutant KRAS G12C in cancer cells.
  • To expand the chemical biology toolkit for investigating KRAS G12C.

Main Methods:

  • Synthesis of fluorescent derivatives of ARS-1323 and AMG-510 using BODIPY dyes.
  • Biochemical binding assays to assess KRAS G12C affinity.
  • Development of a two-step imaging procedure involving in situ click chemistry.

Main Results:

  • Two ARS-1323 derivatives showed binding to mutant KRAS and utility in binding screens.
  • Direct cellular imaging with fluorescent derivatives was hindered by non-specific membrane labeling.
  • A two-step approach using ARS-1323 alkyne and click chemistry enabled direct KRAS G12C imaging in cells.

Conclusions:

  • Fluorescent companion imaging drugs (CID) can be developed for mutant KRAS G12C.
  • A novel two-step click chemistry approach allows for specific cellular imaging of KRAS G12C.
  • These reagents provide a valuable tool for KRAS G12C research, especially in the absence of specific antibodies.