Discovery of Novel Non-nucleoside DOT1L Inhibitors with Improved Pharmacokinetic Properties and Anti-lung Cancer Efficacy.

Given the considerable potential of DOT1L inhibitors in lung cancer therapy and the problematic pharmacokinetics of nucleoside inhibitors, our group launched a development program of non-nucleoside DOT1L inhibitors to improve the pharmacokinetic properties. Herein, two series of non-nucleoside compounds bearing piperidine or 3-(aminomethyl)pyrrolidin-3-ol as "ribose mimics" were designed and evaluated through antiproliferation assay and western blot analysis. The optimal inhibited the proliferation of H460 cells with an IC value of 2.85 μM, about 13-fold more potent than SGC0946. Notably, demonstrated significant efficacy (TGI = 60.57%) in H460 cell-derived xenograft models and improved pharmacokinetic properties ( = 6.06 ± 2.94 h and CL = 55.18 ± 8.56 mL/kg/min). Moreover, a mechanism study validated that suppressed malignant phenotypes of lung cancer cells harboring R231Q mutation the MAPK/ERK signaling pathway. This work provides a promising molecule for lung cancer therapy in favor of clinical patients.