A Conformational Restriction Strategy for the Identification of a Highly Selective Pyrimido-pyrrolo-oxazine mTOR Inhibitor

  • J Med Chem. 2019 Sep 26;62(18):8609-8630. doi: 10.1021/acs.jmedchem.9b00972.
Chiara Borsari  1 ,  Denise Rageot  1 ,  Alix Dall'Asen  2 ,  Thomas Bohnacker  1 ,  Anna Melone  1 ,  Alexander M Sele  1 ,  Eileen Jackson  1 ,  Jean-Baptiste Langlois  1 ,  Florent Beaufils  2 ,  Paul Hebeisen  2 ,  Doriano Fabbro  2 ,  Petra Hillmann  2 ,  Matthias P Wymann  1
Affiliations
  • 1. Department of Biomedicine , University of Basel , Mattenstrasse 28 , 4058 Basel , Switzerland.
  • 2. PIQUR Therapeutics AG , Hochbergerstrasse 60 , 4057 Basel , Switzerland.
PMID: 31465220 DOI: 10.1021/acs.jmedchem.9b00972
Abstract

The mechanistic target of rapamycin (mTOR) plays a pivotal role in growth and tumor progression and is an attractive target for Cancer treatment. ATP-competitive mTOR kinase inhibitors (TORKi) have the potential to overcome limitations of rapamycin derivatives in a wide range of malignancies. Herein, we exploit a conformational restriction approach to explore a novel chemical space for the generation of TORKi. Structure-activity relationship (SAR) studies led to the identification of compound 12b with a ∼450-fold selectivity for mTOR over class I PI3K isoforms. Pharmacokinetic studies in male Sprague Dawley rats highlighted a good exposure after oral dosing and a minimum brain penetration. CYP450 reactive phenotyping pointed out the high metabolic stability of 12b. These results identify the tricyclic pyrimido-pyrrolo-oxazine moiety as a novel scaffold for the development of highly selective mTOR inhibitors for Cancer treatment.