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

Borsari, Chiara and Rageot, Denise and Dall’Asen, Alix and Bohnacker, Thomas and Melone, Anna and Sele, Alexander M. and Jackson, Eileen and Langlois, Jean-Baptiste and Beaufils, Florent and Hebeisen, Paul and Fabbro, Doriano and Hillmann, Petra and Wymann, Matthias P. (2019) A Conformational Restriction Strategy for the Identification of a Highly Selective Pyrimido-pyrrolo-oxazine mTOR Inhibitor. Journal of Medicinal Chemistry, 62 (18). pp. 8609-8630. ISSN 0022-2623

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.

Item Type: Article
Date Deposited: 11 Oct 2019 00:45
Last Modified: 11 Oct 2019 00:45
URI: https://oak.novartis.com/id/eprint/41167

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