Related Experiment Video

Updated: Nov 24, 2025

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

Published on: January 22, 2019

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Structure-Based Drug Design and Synthesis of PI3Kα-Selective Inhibitor (PF-06843195)

Hengmiao Cheng1, Suvi T M Orr1, Simon Bailey1

  • 1La Jolla Laboratories, Pfizer Worldwide Research and Development, 10770 Science Center Drive, San Diego, California 92121, United States.

Journal of Medicinal Chemistry
|December 28, 2020
PubMed

Insights

Researchers developed a novel PI3Kα-selective inhibitor, PF-06843195, to target cancer signaling pathways. This targeted approach aims to reduce side effects compared to broader PI3K inhibitors.

Area of Science:

  • Oncology
  • Medicinal Chemistry
  • Molecular Biology

Background:

  • The phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway is crucial in human cancers.
  • PI3Kα is frequently mutated, making it a key target for cancer therapy.
  • Existing PI3K inhibitors can cause side effects due to broad class I PI3K family inhibition.

Purpose of the Study:

  • To discover a PI3Kα-selective inhibitor.
  • To minimize off-target effects and patient side effects.
  • To develop a novel therapeutic agent for PI3Kα-driven cancers.

Main Methods:

  • Structure-based drug design (SBDD).
  • Computational analysis.
  • Lead optimization and synthesis of novel compounds.

Main Results:

  • Discovery of a novel series of PI3Kα-selective inhibitors.
  • Identification of PF-06843195 (compound 1) with high PI3Kα potency.
  • Demonstration of unique selectivity for PI3K isoforms and mTOR.

Conclusions:

  • PF-06843195 represents a promising PI3Kα-selective inhibitor.
  • The developed compound offers a potential therapeutic strategy with reduced side effects.
  • Structure-based design effectively yielded a targeted cancer therapy candidate.

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