Discovery of Novel Non-nucleoside DOT1L^R231Q Inhibitors with Improved Pharmacokinetic Properties and Anti-lung Cancer Efficacy

Given the considerable potential of DOT1L^R231Q inhibitors in lung cancer therapy and the problematic pharmacokinetics of nucleoside inhibitors, our group launched a development program of non-nucleoside DOT1L^R231Q 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 <b>TB22</b> inhibited the proliferation of H460^R231Q cells with an IC₅₀ value of 2.85 μM, about 13-fold more potent than SGC0946. Notably, <b>TB22</b> demonstrated significant <i>in vivo</i> efficacy (TGI = 60.57%) in H460^R231Q cell-derived xenograft models and improved pharmacokinetic properties (<i>t</i>_1/2 = 6.06 ± 2.94 h and CL = 55.18 ± 8.56 mL/kg/min). Moreover, a mechanism study validated that <b>TB22</b> suppressed malignant phenotypes of lung cancer cells harboring R231Q mutation <i>via</i> the MAPK/ERK signaling pathway. This work provides a promising molecule for lung cancer therapy in favor of clinical patients.