Identification and optimisation of a 4',5-bisthiazole series of selective phosphatidylinositol-3 kinase alpha inhibitors

  • Bioorg Med Chem Lett. 2015 Sep 1;25(17):3569-74. doi: 10.1016/j.bmcl.2015.06.078.
Robin A Fairhurst  1 ,  Patricia Imbach-Weese  2 ,  Marc Gerspacher  2 ,  Giorgio Caravatti  2 ,  Pascal Furet  2 ,  Thomas Zoller  2 ,  Christine Fritsch  2 ,  Dorothea Haasen  2 ,  Joerg Trappe  2 ,  Daniel A Guthy  2 ,  Dorothee Arz  2 ,  Jasmin Wirth  2
Affiliations
  • 1. Novartis Institutes for BioMedical Research, Global Discovery Chemistry, Novartis Pharma AG, Werk Klybeck, Postfach, CH-4002 Basel, Basel, Switzerland. Electronic address: [email protected].
  • 2. Novartis Institutes for BioMedical Research, Global Discovery Chemistry, Novartis Pharma AG, Werk Klybeck, Postfach, CH-4002 Basel, Basel, Switzerland.
PMID: 26206504 DOI: 10.1016/j.bmcl.2015.06.078
Abstract

Exploring the affinity-pocket binding moiety of a 2-aminothiazole (S)-proline-amide-urea series of selective PI3Kα inhibitors using a parallel-synthesis approach led to the identification of a novel 4',5-bisthiazole sub-series. The synthesis and optimisation of both the affinity pocket and (S)-proline amide moieties within this 4',5-bisthiazole sub-series are described. From this work a number of analogues, including 14 (A66) and 24, were identified as potent and selective PI3Kα Inhibitor in vitro tool compounds.

Keywords
Kinase inhibitor; Oncology; Phosphatidylinositol-3-kinase-alpha.