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

Abstract

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.

Identification of 6-Anilino Imidazo[4,5-c]pyridin-2-ones as Selective DNA-Dependent Protein Kinase Inhibitors and Their Application as Radiosensitizers

“…We explored replacement of the cyclopentyl N- 1 substituent with a series of cyclic systems bearing oxygen and nitrogen atoms with potential to form additional interactions with H-acceptors at the periphery of the hydrophobic area in which the N -1 substituent sits ( Table 5 ). 48 Linear regression of the log-transformed values indicates that the changes in potency in the biochemical DNA-PK activity assay broadly track the S 50 radiosensitization parameter ( R 2 = 0.56, P = 0.0003 for non-zero slope). An aliphatic ether 75 displayed reduced potency as did the cyclobutyl ether 76 , but the 5- and 6-membered analogues, 77 and 78 , provided similar potency to 53 for DNA-PK with improved selectivity.…”

“…Thus, early inhibitors (e.g., dactosilib ( 1 ) , (Figure ), NU7441, , KU0060648, , and IC87361 , ) displayed modest selectivity for DNA-PK compared to PI3K isoforms and other PI3K-related kinase (PIKK) family members, which likely contributed to toxicities observed in preclinical studies with these agents. Recently, more selective DNA-PK inhibitors such as peposertib (aka M3814) ( 2 ), AZD7648 ( 3 ), , NU5455 ( 4 ), BAY-8400 ( 5 ) (Figure ), and compound 31t have been identified and several have been recently characterized at increased resolution in structural studies. − Two agents have advanced to clinical trial: peposertib ( 2 ) with RT − and AZD7648 ( 3 ) with pegylated doxorubicin or olaparib…”