SM09419

ConclusionOur results suggest that targeting RNA splicing may be a promising approach for treatment of therapy-refractory MRT. Further pre-clinical in vivo studies are warranted to fully establish a rationale for clinical evaluation of SM09419 in MRT patients.

We therefore utilized a series of selective pan-CLK/DYRK1A inhibitors, including SM09419 and SM08502, that potently suppress SR protein phosphorylation. Therapeutically, pharmacologic inhibition of SR protein function via inhibiting CLK/DYRK1A-mediated phosphorylation of splicing factors is an effective strategy used in combination with venetoclax or to overcome venetoclax resistance. Overall, our findings underscore the central importance of RNA splicing in drug response and provides a therapeutic rationale for modulating RNA splicing to enhance current AML therapies.