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 TB22 inhibited the proliferation of H460 R231Q cells with an IC 50 value of 2.85 μM, about 13-fold more potent than SGC0946. Notably, TB22 demonstrated significant in vivo efficacy (TGI = 60.57%) in H460 R231Q cell-derived xenograft models and improved pharmacokinetic properties ( t 1/2 = 6.06 ± 2.94 h and CL = 55.18 ± 8.56 mL/kg/min). Moreover, a mechanism study validated that TB22 suppressed malignant phenotypes of lung cancer cells harboring R231Q mutation via the MAPK/ERK signaling pathway. This work provides a promising molecule for lung cancer therapy in favor of clinical patients.