Development of novel urea-based ATM kinase inhibitors with subnanomolar cellular potency and high kinome selectivity

Abstract

The ATM kinase is a key molecule regulating DNA damage response and can be targeted resulting in efficient radio- or chemosensitization. Due to the enormous size of this protein and the associated difficulties in obtaining high-quality crystal structures, we sought to develop an accurate in silico model to identify new targeting possibilities. We identified a urea group as the most beneficial chemical anchor point, which could undergo multiple interactions in the aspartate-rich hydrophobic region I of the atypical ATM kinase domain. Based on in silico data, we designed and synthesized a comprehensive set of novel urea-based inhibitors and characterized them in diverse biochemical assays. Using this strategy, we identified inhibitors with subnanomolar potency, which were further evaluated in cellular models, selectivity and early DMPK properties. Finally, the two lead compounds 34 and 39 exhibited subnanomolar cellular activity along with an excellent selectivity profile and favorable metabolic stability.

Keywords: ATM kinase; ATM kinase inhibitors; Cancer; DDR pathway; MD simulation; PIKK.