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Theilmann, W,Gericke,B,Schidlitzki, A,
Anjum, S,Borsdorf, S, Harries, T, Roberds, S.L.,
Aguiar, D,Brunner, D, Leiser, S,Song, D, Fabbro, D,Hillmann, P, Wymann, M,Loscher, W.

Mechanistic target of rapamycin (mTOR) regulates cell proliferation, growth and survival, and is activated in
cancer and neurological disorders, including epilepsy. The rapamycin derivative (“rapalog”) everolimus, which
allosterically inhibits the mTOR pathway, is approved for the treatment of partial epilepsy with spontaneous
recurrent seizures (SRS) in individuals with tuberous sclerosis complex (TSC). In contrast to the efficacy in TSC,
the efficacy of rapalogs on SRS in other types of epilepsy is equivocal. Furthermore, rapalogs only poorly
penetrate into the brain and are associated with peripheral adverse effects, which may compromise their therapeutic
efficacy. Here we compare the antiseizure efficacy of two novel, brain-permeable ATP-competitive and
selective mTORC1/2 inhibitors, PQR620 and PQR626, and the selective dual pan-PI3K/mTORC1/2 inhibitor
PQR530 in two mouse models of chronic epilepsy with SRS, the intrahippocampal kainate (IHK) mouse model of
acquired temporal lobe epilepsy and Tsc1GFAP CKO mice, a well-characterized mouse model of epilepsy in TSC.
During prolonged treatment of IHK mice with rapamycin, everolimus, PQR620, PQR626, or PQR530; only
PQR620 exerted a transient antiseizure effect on SRS, at well tolerated doses whereas the other compounds were
ineffective. In contrast, all of the examined compounds markedly suppressed SRS in Tsc1GFAP CKO mice during
chronic treatment at well tolerated doses. Thus, against our expectation, no clear differences in antiseizure efficacy were found across the three classes of mTOR inhibitors examined in mouse models of genetic and acquired
epilepsies. The main advantage of the novel 1,3,5-triazine derivatives is their excellent tolerability compared to
rapalogs, which would favor their development as new therapies for TORopathies such as TSC.