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Structure-based design, SAR analysis and antitumor activity of PI3K/mTOR dual inhibitors from

Hengmiao Cheng1, Jacqui E Hoffman, Phuong T Le

  • 1Cancer Chemistry, Pfizer Worldwide Research and Development, La Jolla Laboratories, 10770 Science Center Drive, San Diego, CA 92121, USA. henry.cheng@pfizer.com

Bioorganic & Medicinal Chemistry Letters
|March 20, 2013
PubMed

Insights

Researchers explored novel cancer drug candidates based on PI3K/mTOR inhibitors. Structure-based design yielded new compounds with potential antitumor activity, advancing cancer therapy research.

Area of Science:

  • Oncology
  • Medicinal Chemistry
  • Pharmacology

Background:

  • The phosphoinositide 3-kinase (PI3K) signaling pathway, involving key kinases like PI3K, AKT, and mTOR, is frequently dysregulated in various cancers.
  • Targeting this pathway is a significant strategy in oncology drug development.

Purpose of the Study:

  • To discuss structure-based drug design, structure-activity relationships (SAR), and antitumor activity of novel 4-methylpyridopyrimidinone (MPP) derivatives.
  • To explore MPP derivatives featuring terminal alcohol, carboxylic acid, or carboxyl amide functionalities.

Main Methods:

  • Structure-based drug design principles were applied.
  • Synthesis and characterization of MPP derivatives.
  • Evaluation of antitumor activity and structure-activity relationships (SAR).

Main Results:

  • Discovery of PF-06465603, a metabolite of PF-04691502, with a terminal carboxylic acid.
  • Identification of MPP derivatives with terminal alcohol, carboxylic acid, or carboxyl amide groups.
  • Assessment of the antitumor potential of these novel derivatives.

Conclusions:

  • The study presents advancements in the design and evaluation of PI3K/mTOR inhibitors for cancer treatment.
  • MPP derivatives with specific terminal functional groups show promise for further drug development in oncology.

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