Discovery of a Brain-Penetrant ATP-Competitive Inhibitor of the Mechanistic Target of Rapamycin (mTOR) for CNS Disorders

被引：24

作者：

Bonazzi, Simone ^{[1
]}

Goold, Carleton P. ^{[2
]}

Gray, Audrey ^{[2
]}

Thomsen, Noel M. ^{[1
]}

Nunez, Jill ^{[1
]}

Karki, Rajeshri G. ^{[1
]}

Gorde, Aakruti ^{[2
]}

Biag, Jonathan D. ^{[2
]}

Malik, Hasnain A. ^{[1
]}

Sun, Yingchuan ^{[1
]}

Liang, Guiqing ^{[3
]}

Lubicka, Danuta ^{[4
]}

Salas, Sarah ^{[2
]}

Labbe-Giguere, Nancy ^{[1
]}

Keaney, Erin P. ^{[1
]}

McTighe, Stephanie ^{[2
]}

Liu, Shanming ^{[5
]}

Deng, Lin ^{[3
]}

Piizzi, Grazia ^{[1
]}

Lombardo, Franco ^{[3
]}

Burdette, Doug ^{[3
]}

Dodart, Jean-Cosme ^{[2
]}

Wilson, Christopher J. ^{[2
]}

Peukert, Stefan ^{[1
]}

Curtis, Daniel ^{[2
]}

Hamann, Lawrence G. ^{[1
]}

Murphy, Leon O. ^{[5
]}

机构：

[1] Novartis Inst BioMed Res, Global Discovery Chem, Cambridge, MA 02139 USA

[2] Novartis Inst BioMed Res, Neurosci, Cambridge, MA 02139 USA

[3] Novartis Inst BioMed Res, Pharmacokinet Sci, Cambridge, MA 02139 USA

[4] Novartis Inst BioMed Res, Global Drug Dev Tech Res & Dev, Cambridge, MA 02139 USA

[5] Novartis Inst BioMed Res, Chem Biol & Therapeut, Cambridge, MA 02139 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2020年 / 63卷 / 03期

关键词：

MAMMALIAN TARGET; KINASE; MUTATIONS; PIKFYVE; CELLS;

D O I：

10.1021/acs.jmedchem.9b01398

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Recent clinical evaluation of everolimus for seizure reduction in patients with tuberous sclerosis complex (TSC), a disease with overactivated mechanistic target of rapamycin (mTOR) signaling, has demonstrated the therapeutic value of mTOR inhibitors for central nervous system (CNS) indications. Given that everolimus is an incomplete inhibitor of the mTOR function, we sought to develop a new mTOR inhibitor that has improved properties and is suitable for CNS disorders. Starting from an in-house purine-based compound, optimization of the physicochemical properties of a thiazolopyrimidine series led to the discovery of the small molecule 7, a potent and selective brain-penetrant ATP-competitive mTOR inhibitor. In neuronal cell-based models of mTOR hyperactivity, 7 corrected the mTOR pathway activity and the resulting neuronal overgrowth phenotype. The new mTOR inhibitor 7 showed good brain exposure and significantly improved the survival rate of mice with neuronal-specific ablation of the Tsc1 gene. These results demonstrate the potential utility of this tool compound to test therapeutic hypotheses that depend on mTOR hyperactivity in the CNS.

引用

页码：1068 / 1083

页数：16

共 29 条

[1]

[Anonymous], 2013, SCHROD REL 2013 1 LI

[2]

[Anonymous], 2013, SCHROD REL 2013 1 SC

[3] Excitatory/Inhibitory Synaptic Imbalance Leads to Hippocampal Hyperexcitability in Mouse Models of Tuberous Sclerosis [J].

Bateup, Helen S. ;

Johnson, Caroline A. ;

Denefrio, Cassandra L. ;

Saulnier, Jessica L. ;

Kornacker, Karl ;

Sabatini, Bernardo L. .

NEURON, 2013, 78 (03) :510-522

[4] A Conformational Restriction Strategy for the Identification of a Highly Selective Pyrimido-pyrrolo-oxazine mTOR Inhibitor [J].

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. .

JOURNAL OF MEDICINAL CHEMISTRY, 2019, 62 (18) :8609-8630

[5] The novel, catalytic mTORC1/2 inhibitor PQR620 and the PI3K/mTORC1/2 inhibitor PQR530 effectively cross the blood-brain barrier and increase seizure threshold in a mouse model of chronic epilepsy [J].

Brandt, Claudia ;

Hillmann, Petra ;

Noack, Andreas ;

Roemermann, Kerstin ;

Oehler, Leon A. ;

Rageot, Denise ;

Beaufils, Florent ;

Melone, Anna ;

Sele, Alexander M. ;

Wymann, Matthias P. ;

Fabbro, Doriano ;

Loescher, Wolfgang .

NEUROPHARMACOLOGY, 2018, 140 :107-120

[6]

Briard E., Patent No. [W02013/061305 A12013, 2013061305]

[7] PIKfyve, a Class III PI Kinase, Is the Target of the Small Molecular IL-12/IL-23 Inhibitor Apilimod and a Player in Toll-like Receptor Signaling [J].

Cai, Xinming ;

Xu, Yongyao ;

Cheung, Atwood K. ;

Tomlinson, Ronald C. ;

Alcazar-Roman, Abel ;

Murphy, Leon ;

Billich, Andreas ;

Zhang, Bailin ;

Feng, Yan ;

Klumpp, Martin ;

Rondeau, Jean-Michel ;

Fazal, Aleem N. ;

Wilson, Christopher J. ;

Myer, Vic ;

Joberty, Gerard ;

Bouwmeester, Tewis ;

Labow, Mark A. ;

Finan, Peter M. ;

Porter, Jeffrey A. ;

Ploegh, Hidde L. ;

Baird, Daniel ;

De Camilli, Pietro ;

Tallarico, John A. ;

Huang, Qian .

CHEMISTRY & BIOLOGY, 2013, 20 (07) :912-921

[8] Current concepts on epilepsy management in tuberous sclerosis complex [J].

Canevini, Maria Paola ;

Kotulska-Jozwiak, Katarzyna ;

Curatolo, Paolo ;

La Briola, Francesca ;

Peron, Angela ;

Slowinska, Monika ;

Strzelecka, Jolanta ;

Vignoli, Aglaia ;

Jozwiak, Sergiusz .

AMERICAN JOURNAL OF MEDICAL GENETICS PART C-SEMINARS IN MEDICAL GENETICS, 2018, 178 (03) :299-308

[9] Adjunctive everolimus therapy for treatment-resistant focal-onset seizures associated with tuberous sclerosis (EXIST-3): a phase 3, randomised, double-blind, placebo-controlled study [J].

French, Jacqueline A. ;

Lawson, John A. ;

Yapici, Zuhal ;

Ikeda, Hiroko ;

Polster, Tilman ;

Nobbout, Rima ;

Curatolo, Paolo ;

de Vries, Petrus J. ;

Diugos, Dennis J. ;

Berkowitz, Noah ;

Voi, Maurizio ;

Peyrard, Severine ;

Pelov, Diana ;

Franz, David N. .

LANCET, 2016, 388 (10056) :2153-2163

[10] The role of somatic mutational events in the pathogenesis of epilepsy [J].

Iffland, Philip H., II ;

Crino, Peter B. .

CURRENT OPINION IN NEUROLOGY, 2019, 32 (02) :191-197

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