We previously disclosed the identification of cereblon modulator 3 (CC-885), with potent antitumor activity mediated through the degradation of GSPT1. We describe herein the structure-activity relationships for analogs of 3 with exploration of the structurally related dioxoisoindoline class. The observed activity of protein degradation could in part be rationalized through docking into the previously disclosed 3-CRBN-GSPT1 cocrystal ternary complex. For SAR that could not be rationalized through the cocrystal complex, we sought to predict SAR through a QSAR model developed in house. Through these analyses, selective protein degradation could be achieved between the two proteins of interest, GSPT1 and Aiolos.

ABSTRACT. Objective:Prior studies of the relationship between socioeconomic status (SES) and alcohol consumption and problems in adolescence have been inconclusive. Few studies have examined all three major SES indicators and a broad range of alcohol-related outcomes at different ages. Method: In the Avon Longitudinal Study of Parents and Children cohort, we examined (by logistic regression, with differential weighting to control for attrition) the relationship between family income and parental education and occupational status, and fi ve alcohol outcomes assessed at ages 16 and 18 years. Results: At age 16, high SES-as indexed by income and education-signifi cantly predicted frequent alcohol consumption. Low SES-as measured by education and occupational status-predicted alcohol-related problems. At age 18, high SES-particularly income and education-signifi cantly predicted frequent alcohol consumption and heavy episodic drinking and, more weakly, symptoms of alcohol dependence. All three measures of SES were inversely related to high-quantity consumption and alcohol behavioral problems. Conclusions: In adolescents in the United Kingdom, the relationship between SES and alcohol-related behaviors is complex and varies as a function of age, SES measure, and specifi c outcome. High SES tends to predict increased consumption and, in later adolescence, heavy episodic drinking and perhaps symptoms of alcohol dependence. Low SES predicts alcohol-related behavioral problems and, in later adolescence, high-quantity alcohol consumption. (J. Stud. Alcohol Drugs, 75, 541-545, 2014)

AbstractmTOR is a serine/threonine kinase that regulates cell growth, metabolism, proliferation, and survival. mTOR complex-1

We report here the synthesis and structure-activity relationship (SAR) of a novel series of triazole containing mammalian target of rapamycin (mTOR) kinase inhibitors. SAR studies examining the potency, selectivity, and PK parameters for a series of triazole containing 4,6- or 1,7-disubstituted-3,4-dihydropyrazino[2,3-b]pyrazine-2(1H)-ones resulted in the identification of triazole containing mTOR kinase inhibitors with improved PK properties. Potent compounds from this series were found to block both mTORC1(pS6) and mTORC2(pAktS473) signaling in PC-3 cancer cells, in vitro and in vivo. When assessed in efficacy models, analogs exhibited dose-dependent efficacy in tumor xenograft models. This work resulted in the selection of CC-115 for clinical development.

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