Additional file 1: of Radiation and PD-(L)1 treatment combinations: immune response and dose optimization via a predictive systems model

Further information on model development and testing can be found in Additional file 1: the biological rationale for the proposed mathematical model structure; the structure of the mathematical model; population model development to describe inter-animal variability in tumor growth; model parameter estimations; model diagnostics; experimental data used for model development; model diagnostics; model validation against newly, independently generated sets of experimental tumor size data; design of efficacy simulations; a model sensitivity analysis. Additional file 1 also contains supplemental figures and references. (ZIP 6120 kb

The Identification of Potent, Selective, and Orally Available Inhibitors of Ataxia Telangiectasia Mutated (ATM) Kinase: The Discovery of AZD0156 (8-{6-[3-(Dimethylamino)propoxy]pyridin-3-yl}-3-methyl-1-(tetrahydro‑2<i>H</i>‑pyran-4-yl)-1,3-dihydro‑2<i>H</i>‑imidazo[4,5‑<i>c</i>]quinolin-2-one)

ATM inhibitors, such as <b>7</b>, have demonstrated the antitumor potential of ATM inhibition when combined with DNA double-strand break-inducing agents in mouse xenograft models. However, the properties of <b>7</b> result in a relatively high predicted clinically efficacious dose. In an attempt to minimize attrition during clinical development, we sought to identify ATM inhibitors with a low predicted clinical dose (<50 mg) and focused on strategies to increase both ATM potency and predicted human pharmacokinetic half-life (predominantly through the increase of volume of distribution). These efforts resulted in the discovery of <b>64</b> (AZD0156), an exceptionally potent and selective inhibitor of ATM based on an imidazo­[4,5-<i>c</i>]­quinolin-2-one core. <b>64</b> has good preclinical phamacokinetics, a low predicted clinical dose, and a high maximum absorbable dose. <b>64</b> has been shown to potentiate the efficacy of the approved drugs irinotecan and olaparib in disease relevant mouse models and is currently undergoing clinical evaluation with these agents