Adapting to Climate Change: The urgency and some challenges to begin

Our response to the challenge of climate change will shape our future in many different and crucial ways. Adaptation is about realizing the impacts of climate change and acting in such a way to limit negative impacts and embrace positive outcomes in order to reduce our vulnerability from the effects of climate change

Adapting to Climate Change: The urgency and some challenges to begin

Our response to the challenge of climate change will shape our future in many different and crucial ways. Adaptation is about realizing the impacts of climate change and acting in such a way to limit negative impacts and embrace positive outcomes in order to reduce our vulnerability from the effects of climate change

iTV in Industry 5: Are Smartphone TV Apps Easier to Use than Remote Controls to Control TV?

This paper addresses the question: are smartphone TV apps as easy to use as remote controls for controlling TV. Although smartphone apps make it easier to navigate lists of items, such as TV shows, access to other often-used functions may be less efficient because assess requires extra navigation. Also, additional steps required to access the TV app on the smartphone may offset any inherent advantage to using it. Smartphone app designs could reduce or eliminate this extra navigation and make smartphone TV apps more efficient and thus preferred over remote controls

Discovery of a Series of 3‑Cinnoline Carboxamides as Orally Bioavailable, Highly Potent, and Selective ATM Inhibitors

We report the discovery of a novel series of 3-cinnoline carboxamides as highly potent and selective ataxia telangiectasia mutated (ATM) kinase inhibitors. Optimization of this series focusing on potency and physicochemical properties (especially permeability) led to the identification of compound <b>21</b>, a highly potent ATM inhibitor (ATM cell IC₅₀ 0.0028 μM) with excellent kinase selectivity and favorable physicochemical and pharmacokinetics properties. <i>In vivo</i>, <b>21</b> in combination with irinotecan showed tumor regression in the SW620 colorectal tumor xenograft model, superior inhibition to irinotecan alone. Compound <b>21</b> was selected for preclinical evaluation alongside AZD0156

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

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