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

Hengmiao Cheng; 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

doi:10.1016/j.bmcl.2013.02.020

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. Epub 2013 Feb 13.

Authors

Hengmiao Cheng¹, 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

Affiliation

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

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.

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry*
Binding Sites
Cell Line, Tumor
Crystallography, X-Ray
Drug Design*
Humans
Mice
Molecular Docking Simulation
Phosphatidylinositol 3-Kinases / metabolism
Phosphoinositide-3 Kinase Inhibitors*
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry*
Protein Structure, Tertiary
Proto-Oncogene Proteins c-akt / antagonists & inhibitors
Proto-Oncogene Proteins c-akt / metabolism
Pyridones / chemistry
Pyrimidines / chemistry
Pyrimidinones / chemical synthesis
Pyrimidinones / chemistry*
Signal Transduction
Structure-Activity Relationship
TOR Serine-Threonine Kinases / antagonists & inhibitors*
TOR Serine-Threonine Kinases / metabolism
Xenograft Model Antitumor Assays

Substances

2-amino-8-(4-(2-hydroxyethoxy)cyclohexyl)-6-(6-methoxypyridin-3-yl)-4-methylpyrido(2,3-d)pyrimidin-7(8H)-one
Antineoplastic Agents
Phosphoinositide-3 Kinase Inhibitors
Protein Kinase Inhibitors
Pyridones
Pyrimidines
Pyrimidinones
Proto-Oncogene Proteins c-akt
TOR Serine-Threonine Kinases