Discovery of a Highly Potent and Selective mTOR Inhibitor that Strongly Suppresses Glioblastoma Multiforme Cell Growth

As a key driver of blood and solid
malignancies, mechanistic target
of rapamycin (mTOR) is widely considered a relevant cancer target.
However, current mTOR inhibitors are either mechanistically flawed
(rapalogs) or highly promiscuous (kinase inhibitors), displaying low
clinical efficacy and/or tolerability. In search of highly selective
inhibitors that could be used to treat glioblastoma multiforme (GBM),
the most aggressive brain cancer, we explored the N1 position of the pyrazolo[3,4-d]pyrimidine scaffold
of known mTOR kinase inhibitors. Small compound libraries were iteratively
synthesized and screened against GBM cell lines to rapidly generate
structure–activity relationships (SARs). By prioritizing GBM
cell activity, potent antiproliferative inhibitors were produced through
three rounds of design, synthesis, and screening. Preclinical potential
was validated in advanced GBM stem cell models. Remarkably, the most
potent analogs also displayed the highest mTOR activity and selectivity,
identifying compound 3n (eALM1137) as a novel best-in-class
mTOR inhibitor closely matching chemical probe criteria.