Preclinical Safety Assessment of a Highly Selective and Potent Dual Small-Molecule Inhibitor of CBP/P300 in Rats and Dogs.

Cyclic adenosine monophosphate-response element (CREB)-binding protein (CBP) and EP300E1A-binding protein (p300) are members of the bromodomain and extraterminal motif (BET) family. These highly homologous proteins have a key role in modulating transcription, including altering the status of chromatin or through interactions with or posttranslational modifications of transcription factors. As CBP and p300 have known roles for stimulating c-Myc oncogenic activity, a small-molecule inhibitor, GNE-781, was developed to selectively and potently inhibit the CBP/p300 bromodomains (BRDs). Genetic models have been challenging to develop due to embryonic lethality arising from germline homozygous mutations in either CBP or P300. Hence, the purpose of this study was to characterize the role of dual inhibition of these proteins in adult rats and dogs. Repeat dose toxicity studies were conducted, and toxicologic and pathologic end points were assessed. GNE-781 was generally tolerated; however, marked effects on thrombopoiesis occurred in both species. Evidence of inhibition of erythroid, granulocytic, and lymphoid cell differentiation was also present, as well as deleterious changes in gastrointestinal and reproductive tissues. These findings are consistent with many preclinical (and clinical) effects reported with BET inhibitors targeting BRD proteins; thus, the current study findings indicate a likely important role for CBP/p300 in stem cell differentiation.

The accuracy of magnetic resonance imaging in the assessment of glenohumeral articular degenerative disease.

Degenerative joint disease is a major source of disability in the world with over 43 million individuals suffering from the affliction in the United States alone. It is the most common cause of activity limitation in individuals over 65 years of age. While much of the focus in recent years has been on osteoarthritis of the hips and knees, shoulder degenerative disease is becoming a more commonly recognized source of morbidity with a wide range of associated lifestyle-limiting disabilities. At the same time therapeutic options for treatment of degenerative joint disease are rapidly increasing, both medically and surgically. This combination of factors makes it necessary to determine a reliable, noninvasive means by which to accurately diagnose the early changes of shoulder degenerative disease. The clinical diagnosis of shoulder osteoarthritis is extremely challenging. There are numerous existing mimickers such as rotator cuff injuries, bursitis, and impingement syndrome. While the conventional radiographic findings are well recognized, they are generally late developments in the course of the disease when therapeutic options are more limited and less effective. Additionally, plain film evaluation has poor sensitivity for the detection of many of the alternative diagnoses that may underlie chronic shoulder pain. Though correlative findings are seen in MR imaging, its role in evaluating glenohumeral degenerative changes has been limited, with much of the focus being on the identification of tendinous and ligamentous disease or osseous tumors. A retrospective analysis is presented which demonstrates the efficacy of MR imaging in assessing GHJ OA, as well as shows that dedicated evaluation for specific degenerative findings results in improved detection rates of GHJ degenerative disease. It is believed that with improved detection and reporting, improved clinical care for this prevalent disorder may be achieved.