Highly specific ATR inhibitors for the targeted treatment of a broad spectrum of cancers

PROJECT SUMMARY Specific targeting of the Ataxia Telangiectasia and Rad related kinase ATR represents an emerging strategy to treat a broad spectrum of cancers most notably those that currently lack effective treatments Suppression of ATR selectively kills cells subjected to oncogenic stress alternative lengthening of telomeres ALT or loss of double strand break DSB repair mechanisms ATM BRCA or BRCA deficiency Indeed levels of ATR suppression that eliminate such cancers do so with minimal toxicity to tissues under normal proliferative control including those that are the most sensitive to traditional chemotherapeutics such as the bone marrow and intestine Therefore ATR inhibitors provide a new and effective treatment for cancer one that causes fewer side effects than conventional chemotherapies Atrin Pharmaceuticals has synthesized a novel series of small molecules that inhibit ATR at low nanomolar concentrations in cultured cells These compounds have the highest known potency for inhibiting ATR and maintain andgt fold lower in vivo activity towards other kinases of the same family ATM DNA PKcs and mTOR which are substantially off targeted by all previously reported ATR inhibitors Herein we propose to complete our preliminary evaluation of Atrin s ATR inhibitor series by further defining the mechanism of action and enhancing the pharmacologic properties of the ATRN series and exploring the ability of the ATRN series to kill cancers in combination with conventional therapies The ultimate goal of this proposed research is to produce a uniquely specific small molecule inhibitor of ATR that can be applied in the clinic PROJECT NARRATIVE By inhibiting the activity of the ATR protein kinase it is possible to selectively kill cancer cells with limited side toxicity to healthy tissues It is therefore expected that our novel ATR inhibitors will be able to treat a broad spectrum of cancers with fewer adverse effects than conventional chemotherapeutic treatments Herein we propose to test this hypothesis and produce one or more compounds for clinical application