2. Academic Validation
  3. Structure-based design, SAR analysis and antitumor activity of PI3K/mTOR dual inhibitors from 4-methylpyridopyrimidinone series

Structure-based design, SAR analysis and antitumor activity of PI3K/mTOR dual inhibitors from 4-methylpyridopyrimidinone series

  • Bioorg Med Chem Lett. 2013 May 1;23(9):2787-92. doi: 10.1016/j.bmcl.2013.02.020.
Hengmiao Cheng 1,  Jacqui E Hoffman,  Phuong T Le,  Mason Pairish,  Robert Kania,  William Farrell,  Shubha Bagrodia,  Jing Yuan,  Shaoxian Sun,  Eric Zhang,  Cathy Xiang,  Deepak Dalvie,  Sadayappan V Rahavendran
Affiliations

Affiliation

  • 1 Cancer Chemistry, Pfizer Worldwide Research and Development, La Jolla Laboratories, 10770 Science Center Drive, San Diego, CA 92121, USA. [email protected]
PMID: 23506825 DOI: 10.1016/j.bmcl.2013.02.020
Abstract

PI3K, Akt and mTOR, key kinases from a frequently dysregulated PI3K signaling pathway, have been extensively pursued to treat a variety of cancers in oncology. Clinical trials of PF-04691502, a highly potent and selective ATP competitive kinase inhibitor of class 1 PI3Ks and mTOR, from 4-methylpyridopyrimidinone series, led to the discovery of a metabolite with a terminal carboxylic acid, PF-06465603. This paper discusses structure-based drug design, SAR and antitumor activity of the MPP derivatives with a terminal alcohol, a carboxylic acid or a carboxyl amide.

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