Journal of Medicinal Chemistry p. 8609 - 8630 (2019)
Update date:2022-08-15
Topics:
Borsari, Chiara
Rageot, Denise
Dall'Asen, Alix
Bohnacker, Thomas
Melone, Anna
Sele, Alexander M.
Jackson, Eileen
Langlois, Jean-Baptiste
Beaufils, Florent
Hebeisen, Paul
Fabbro, Doriano
Hillmann, Petra
Wymann, Matthias P.
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.
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