PMID- 36634458 OWN - NLM STAT- MEDLINE DCOM- 20230131 LR - 20230202 IS - 1768-3254 (Electronic) IS - 0223-5234 (Linking) VI - 248 DP - 2023 Feb 15 TI - Investigation of morpholine isosters for the development of a potent, selective and metabolically stable mTOR kinase inhibitor. PG - 115038 LID - S0223-5234(22)00940-0 [pii] LID - 10.1016/j.ejmech.2022.115038 [doi] AB - Upregulation of mechanistic target of rapamycin (mTOR) signaling drives various types of cancers and neurological diseases. Rapamycin and its analogues (rapalogs) are first generation mTOR inhibitors, and selectively block mTOR complex 1 (TORC1) by an allosteric mechanism. In contrast, second generation ATP-binding site inhibitors of mTOR kinase (TORKi) target both TORC1 and TORC2. Here, we explore 3,6-dihydro-2H-pyran (DHP) and tetrahydro-2H-pyran (THP) as isosteres of the morpholine moiety to unlock a novel chemical space for TORKi generation. A library of DHP- and THP-substituted triazines was prepared, and molecular modelling provided a rational for a structure activity relationship study. Finally, compound 11b [5-(4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-(tetrahydro-2H-pyran-4-yl)-1,3,5-triazin-2-yl)-4-(difluoromethyl)pyridin-2-amine] was selected due its potency and selectivity for mTOR kinase over the structurally related class I phosphoinositide 3-kinases (PI3Ks) isoforms. 11b displayed high metabolic stability towards CYP1A1 degradation, which is of advantage in drug development. After oral administration to male Sprague Dawley rats, 11b reached high concentrations both in plasma and brain, revealing an excellent oral bioavailability. In a metabolic stability assay using human hepatocytes, 11b was more stable than PQR620, the first-in-class brain penetrant TORKi. Compound 11b also displayed dose-dependent anti-proliferative activity in splenic marginal zone lymphoma (SMZL) cell lines as single agent and when combined with BCL2 inhibition (venetoclax). Our results identify the THP-substituted triazine core as a novel scaffold for the development of metabolically stable TORKi for the treatment of chronic diseases and cancers driven by mTOR deregulation and requiring drug distribution also to the central nervous system. CI - Copyright (c) 2022 The Author(s). Published by Elsevier Masson SAS.. All rights reserved. FAU - De Pascale, Martina AU - De Pascale M AD - University of Basel, Department of Biomedicine, Mattenstrasse 28, 4058, Basel, Switzerland. FAU - Bissegger, Lukas AU - Bissegger L AD - University of Basel, Department of Biomedicine, Mattenstrasse 28, 4058, Basel, Switzerland. FAU - Tarantelli, Chiara AU - Tarantelli C AD - Institute of Oncology Research, Faculty of Biomedical Sciences, USI, Via Francesco Chiesa 5, 6500, Bellinzona, Switzerland. FAU - Beaufils, Florent AU - Beaufils F AD - University of Basel, Department of Biomedicine, Mattenstrasse 28, 4058, Basel, Switzerland. FAU - Prescimone, Alessandro AU - Prescimone A AD - University of Basel, Department of Chemistry, Mattenstrasse 24a, 4058, Basel, Switzerland. FAU - Mohamed Seid Hedad, Hayget AU - Mohamed Seid Hedad H AD - University of Basel, Department of Biomedicine, Mattenstrasse 28, 4058, Basel, Switzerland. FAU - Kayali, Omar AU - Kayali O AD - Institute of Oncology Research, Faculty of Biomedical Sciences, USI, Via Francesco Chiesa 5, 6500, Bellinzona, Switzerland. FAU - Orbegozo, Clara AU - Orbegozo C AD - University of Basel, Department of Biomedicine, Mattenstrasse 28, 4058, Basel, Switzerland. FAU - Raguz, Luka AU - Raguz L AD - University of Basel, Department of Biomedicine, Mattenstrasse 28, 4058, Basel, Switzerland. FAU - Schaefer, Thorsten AU - Schaefer T AD - University of Basel, Department of Biomedicine, Mattenstrasse 28, 4058, Basel, Switzerland. FAU - Hebeisen, Paul AU - Hebeisen P AD - University of Basel, Department of Biomedicine, Mattenstrasse 28, 4058, Basel, Switzerland. FAU - Bertoni, Francesco AU - Bertoni F AD - Institute of Oncology Research, Faculty of Biomedical Sciences, USI, Via Francesco Chiesa 5, 6500, Bellinzona, Switzerland; Oncology Institute of Southern Switzerland, Ente Ospedaliero Cantonale, Bellinzona, Switzerland. FAU - Wymann, Matthias P AU - Wymann MP AD - University of Basel, Department of Biomedicine, Mattenstrasse 28, 4058, Basel, Switzerland. Electronic address: matthias.wymann@unibas.ch. FAU - Borsari, Chiara AU - Borsari C AD - University of Basel, Department of Biomedicine, Mattenstrasse 28, 4058, Basel, Switzerland. Electronic address: chiara.borsari@unibas.ch. LA - eng PT - Journal Article DEP - 20221228 PL - France TA - Eur J Med Chem JT - European journal of medicinal chemistry JID - 0420510 RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1) RN - 0 (Morpholines) RN - W36ZG6FT64 (Sirolimus) RN - 0 (Pyrans) RN - 0 (Protein Kinase Inhibitors) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.1.1 (mTOR protein, rat) SB - IM MH - Rats MH - Animals MH - Male MH - Humans MH - Rats, Sprague-Dawley MH - *TOR Serine-Threonine Kinases/metabolism MH - Mechanistic Target of Rapamycin Complex 1 MH - Morpholines/pharmacology/chemistry MH - Sirolimus/pharmacology/therapeutic use MH - *Neoplasms/drug therapy MH - Pyrans/therapeutic use MH - Protein Kinase Inhibitors/pharmacology/therapeutic use OTO - NOTNLM OT - ATP-competitive inhibitors OT - Cancer OT - Mechanistic target of rapamycin (mTOR) OT - Metabolic stability OT - Morpholine isosters OT - mTOR kinase inhibitors COIS- Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Matthias P. Wymann reports financial support was provided by Swiss National Science Foundation and by Swiss Cancer Research Foundation. Matthias P. Wymann, Martina De Pascale and Chiara Borsari have a patent on dihydropyran- and tetrahydropyran-substituted triazines pending to University of Basel, Tech. Transfer Office, Unitectra. EDAT- 2023/01/13 06:00 MHDA- 2023/02/01 06:00 CRDT- 2023/01/12 18:09 PHST- 2022/09/28 00:00 [received] PHST- 2022/12/17 00:00 [revised] PHST- 2022/12/18 00:00 [accepted] PHST- 2023/01/13 06:00 [pubmed] PHST- 2023/02/01 06:00 [medline] PHST- 2023/01/12 18:09 [entrez] AID - S0223-5234(22)00940-0 [pii] AID - 10.1016/j.ejmech.2022.115038 [doi] PST - ppublish SO - Eur J Med Chem. 2023 Feb 15;248:115038. doi: 10.1016/j.ejmech.2022.115038. Epub 2022 Dec 28.