Discovery, Optimization, and Evaluation of Potent and Selective DNA-PK Inhibitors in Combination with Chemotherapy or Radiotherapy for the Treatment of Malignancies

Given the multifaceted biological
functions of DNA-PK encompassing
DNA repair pathways and beyond, coupled with the susceptibility of
DNA-PK-deficient cells to DNA-damaging agents, significant strides
have been made in the pursuit of clinical potential for DNA-PK inhibitors
as synergistic adjuncts to chemo- or radiotherapy. Nevertheless, although
substantial progress has been made with the discovery of potent inhibitors
of DNA-PK, the clinical trial landscape requires even more potent
and selective molecules. This necessitates further endeavors to expand
the repertoire of clinically accessible DNA-PK inhibitors for the
ultimate benefit of patients. Described herein are the obstacles that
were encountered and the solutions that were found, which eventually
led to the identification of compound 31t. This compound
exhibited a remarkable combination of robust potency and exceptional
selectivity along with favorable in vivo profiles as substantiated
by pharmacokinetic studies in rats and pharmacodynamic assessments
in H460, BT474, and A549 xenograft models.