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Updated: Jun 16, 2025

Efficient Construction of Drug-like Bispirocyclic Scaffolds Via Organocatalytic Cycloadditions of α-Imino γ-Lactones and Alkylidene Pyrazolones
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Efficient Construction of Drug-like Bispirocyclic Scaffolds Via Organocatalytic Cycloadditions of α-Imino γ-Lactones and Alkylidene Pyrazolones

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Rational Design of a Novel 6H-Benzo[c]chromen Series as Selective PI3Kα Inhibitors

Xue Shi1, Heng Feng2, Haigang Tian2

  • 1Biobank, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, People's Republic of China.

Journal of Medicinal Chemistry
|August 19, 2024
PubMed

Insights

Researchers developed a novel PI3Kα inhibitor, XJTU-L453, offering targeted cancer therapy with fewer side effects. This selective inhibitor shows preclinical potential for treating cancers driven by PI3Kα mutations.

Area of Science:

  • Medicinal Chemistry
  • Oncology
  • Molecular Pharmacology

Background:

  • The phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway is crucial in human cancers.
  • PI3Kα is frequently mutated in various cancers, making it a key therapeutic target.
  • Broad inhibition of PI3K isoforms can lead to significant side effects; selective PI3Kα inhibition is desirable.

Purpose of the Study:

  • To discover novel, selective PI3Kα inhibitors.
  • To identify drug candidates with improved safety profiles compared to non-selective PI3K inhibitors.
  • To evaluate the preclinical potential of identified inhibitors.

Main Methods:

  • Employed structure-based drug design and molecular docking.
  • Synthesized and tested a series of 6H-benzo[c]chromen derivatives.
  • Assessed PI3Kα inhibitory potency, selectivity across PI3K isoforms and other kinases, pharmacokinetic properties, and in vivo efficacy.

Main Results:

  • Identified XJTU-L453 (compound 21) as a potent and selective PI3Kα inhibitor.
  • XJTU-L453 demonstrated unique selectivity over other PI3K isoforms and kinases.
  • Pharmacokinetic profiling and in vivo studies supported the preclinical potential of XJTU-L453.

Conclusions:

  • XJTU-L453 represents a promising novel inhibitor targeting PI3Kα.
  • Its high selectivity offers a potential therapeutic advantage by minimizing off-target effects.
  • XJTU-L453 warrants further development as a targeted cancer therapy.

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