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Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries
08:49

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Published on: January 22, 2019

Discovery and optimization of potent and selective imidazopyridine and imidazopyridazine mTOR inhibitors

Emily A Peterson1, Alessandro A Boezio, Paul S Andrews

  • 1Medicinal Chemistry, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA. epeterso@amgen.com

Bioorganic & Medicinal Chemistry Letters
|July 7, 2012
PubMed

Insights

Researchers developed novel ATP-competitive mTOR inhibitors for cancer therapy. These new compounds show enhanced selectivity and improved drug properties compared to earlier versions.

Area of Science:

  • Biochemistry
  • Oncology
  • Medicinal Chemistry

Background:

  • The mechanistic target of rapamycin (mTOR) pathway is crucial for cell signaling and frequently altered in cancers.
  • The PI3K/AKT/mTOR pathway is a significant target in oncology drug discovery.
  • Previous research identified benzimidazole scaffolds as mTOR inhibitors but with limitations.

Purpose of the Study:

  • To discover novel ATP-competitive mTOR inhibitors with improved pharmacokinetic properties and selectivity.
  • To overcome limitations of previous mTOR inhibitor lead compounds.
  • To identify new chemical scaffolds for targeting the mTOR pathway in cancer.

Main Methods:

  • Structure-guided drug design and targeted structure-activity relationship (SAR) studies.
  • Synthesis and evaluation of novel imidazopyridine and imidazopyridazine scaffolds.
  • In vitro cellular assays for mTOR inhibition and selectivity profiling against PIKK family members.
  • In vivo pharmacokinetic studies assessing clearance.

Main Results:

  • Identified novel imidazopyridine and imidazopyridazine scaffolds with potent mTOR inhibition.
  • Achieved superior selectivity over closely related phosphoinositide 3-kinase-related kinases (PIKKs).
  • Demonstrated improved in vivo pharmacokinetic profiles, specifically reduced clearance, compared to benzimidazole series.

Conclusions:

  • New imidazopyridine and imidazopyridazine scaffolds represent promising candidates for developing next-generation mTOR inhibitors.
  • These compounds offer enhanced selectivity and pharmacokinetic properties, crucial for effective oncology therapeutics.
  • The findings advance the development of targeted therapies for cancers driven by the mTOR pathway.

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