Improving the metabolic stability of a selective mTOR inhibitor through scaffold deconstruction and carbamate exploration.

We describe a focused medicinal chemistry program directed towards the metabolic stability optimization of eALM1137, a highly potent and selective mTOR inhibitor with demonstrated antiproliferative activity in cancer cell lines. Through scaffold deconstruction and systematic nitrogen atom exploration of the central pyrazolo[3,4-d]pyrimidine core, combined with optimization of the carbamate moiety, we identified the key structural features governing both mTOR inhibitory activity and metabolic liability in this chemotype. This effort culminated in the discovery of 2w (eALM1192), a pyrrolo[2,3-d]pyrimidine-based analog bearing a propargyl carbamate, an underexplored motif in the field, which exhibits sub-nanomolar antiproliferative activity across colorectal cancer cell lines, an mTOR IC50 of 2.3 nM with 37-fold selectivity over DNA-PK, excellent kinome selectivity, and an 8-fold improvement in the metabolic half-life (t ½ = 109 min).