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.