Identification of 2-oxatriazines as highly potent pan-PI3K/mTOR dual inhibitors

  • Bioorg Med Chem Lett. 2011 Aug 15;21(16):4773-8. doi: 10.1016/j.bmcl.2011.06.063.
Christoph M Dehnhardt  1 ,  Aranapakam M Venkatesan ,  Zecheng Chen ,  Efren Delos-Santos ,  Semiramis Ayral-Kaloustian ,  Natasja Brooijmans ,  Ker Yu ,  Irwin Hollander ,  Larry Feldberg ,  Judy Lucas ,  Robert Mallon
Affiliations
  • 1. Medicinal Chemistry, Pfizer, 401 N. Middletown Rd., Pearl River, NY 10965, USA. [email protected]
PMID: 21763134 DOI: 10.1016/j.bmcl.2011.06.063
Abstract

We recently described several highly potent, triazine (1) and triazolopyrimidine (2) scaffold-based, dual PI3K/mTOR-inhibitors (e.g., 1, PKI-587) that were efficacious in both in vitro and in vivo models. In order to further optimize these compounds we devised a novel series, the 2-oxatriazines, which also exhibited excellent potency and good metabolic stability. Some 2-oxatriazines showed promising in vivo biomarker suppression and induced Apoptosis in the MDA-MB-361 Breast Cancer xenograft model.