Discovery of DS-9300: A Highly Potent, Selective, and Once-Daily Oral EP300/CBP Histone Acetyltransferase Inhibitor.

Histone acetylation is a post-translational modification of histones that is catalyzed by histone acetyltransferases (HATs) and plays an essential role in cellular processes. The HAT domain of EP300/CBP has recently emerged as a potential drug target for cancer therapy. Here, we describe the identification of the novel, highly potent, and selective EP300/CBP HAT inhibitor DS-9300. Our optimization efforts using a structure-based drug design approach based on the cocrystal structures of the EP300 HAT domain in complex with compounds 2 and 3 led to the identification of compounds possessing low-nanomolar EP300 HAT inhibitory potency and the ability to inhibit cellular acetylation of histone H3K27. Optimization of the pharmacokinetic properties in this series resulted in compounds with excellent oral systemic exposure, and once-daily oral administration of 16 (DS-9300) demonstrated potent antitumor effects in a castrated VCaP xenograft mouse model without significant body weight loss.

Discovery of EP300/CBP histone acetyltransferase inhibitors through scaffold hopping of 1,4-oxazepane ring.

EP300 and its paralog CBP play an important role in post-translational modification as histone acetyltransferases (HATs). EP300/CBP inhibition has been gaining attention as an anticancer treatment target in recent years. Herein, we describe the identification of a novel, highly selective EP300/CBP inhibitor, compound 11 (DS17701585), by scaffold hopping and structure-based optimization of a high-throughput screening hit 1. Compound 11 (DS17701585) shows dose-dependent inhibition of SRY-box transcription factor 2 (SOX2) mRNA expression in a human lung squamous cell carcinoma cell line LK2-xenografted mouse model.

Postprandial Increase in Energy Expenditure Correlates with Body Weight Reduction in Patients with Type 2 Diabetes Receiving Diet Therapy.

AIM: The clinical significance of energy expenditure (EE) in the treatment of type 2 diabetes has not been fully elucidated. Here we analyzed the relationships between EE and clinical measurements in patients with type 2 diabetes receiving diet therapy. METHODS: A total of 100 patients (34 women and 66 men) with type 2 diabetes admitted to our hospital for glycemic control were enrolled. The participants received an energy-restricted diet during their hospitalization (median, 15 days). EE was measured in the fasted (FEE) and postprandial (PPEE) states using indirect calorimetry. The postprandial increment of EE (ΔEE) was calculated from the FEE and PPEE (ΔEE=PPEE-FEE). RESULTS: FEE, PPEE, and ΔEE were 0.997±0.203, 1.104±0.213, and 0.107±0.134 kcal/min, respectively. Body weight decreased from 68.7±16.6 to 66.8±16.0 kg (p＜0.0001) during hospitalization. FEE and PPEE showed positive correlations with height, body weight, body mass index, and abdominal circumference at admission, but ΔEE was not correlated with these anthropometric measurements. On the other hand, ΔEE was inversely correlated with the body weight change. The association between ΔEE and the body weight change was independent of age, sex, and HbA1c. CONCLUSIONS: Postprandial increase in energy expenditure may be a determinant of individual differences in weight reduction in patients with type 2 diabetes on diet therapy. As a simple surrogate for diet-induced thermogenesis, ΔEE may serve as a useful predictive marker for the efficacy of diet therapy.

Practical dietary calorie management, body weight control and energy expenditure of diabetic patients in short-term hospitalization.

AIM: We investigated how dietary management affected body weight (BW) reduction and energy expenditure in obese and normal-weight type 2 diabetic patients. METHODS: Type 2 diabetic patients who were hospitalized for diabetic control (93 men and 51 women) were checked for resting energy expenditure (REE). Subjects were divided into the two groups according to body mass index (BMI): obese (BMI > or = 25), and normal-weight (BMI <25). Following the recommendations by JDS, JAS and JASSO, ideal body weight was calculated as [IBW=height (m) x height (m) x 22 (kg/m(2))], and dietary calorie (kcal/day) was determined as 25 kcal/kg IBW. RESULTS: Dietary calorie intake during hospitalization was similar in both groups. REE was greater in obese than in normal-weight patients. The difference between the calorie intake and energy expenditure (Deltacalorie) was -222+/-26 kcal in obese patients and 69+/-27 kcal in normal-weight patients. Obese patients therefore had larger BW decreases than normal-weight patients (-171+/-12 vs. -92+/-11 g/day, p<0.005). In the obese group, a positive correlation was found between the change of BW and Deltacalorie. This correlation remained after adjusting for age, BMI, gender, and respiratory quotient. Serum lipid profiles were significantly improved in both groups. CONCLUSION: These diet instructions showed the appropriate calorie restriction depending on the BMI and induced reasonable BW reduction in both obese and normal-weight subjects. The dietary program recommended by JDS, JAS and JASSO is practically useful for BW control and for improving lipid metabolism in type 2 diabetic patients.

Absence of pseudomembranes in Clostridium difficile-associated diarrhea in patients using immunosuppression agents.

OBJECTIVE: Clostridium difficile is a major cause of diarrhea in hospitalized patients. Although pseudomembranes are crucial evidence for diagnosis of C. difficile-associated diarrhea (CDAD), some cases do not show any pseudomembranes. The aim of this study was to verify the hypothesis that pseudomembranes are not generated in immunosuppressed patients because of the absence of immunoreactions. MATERIAL AND METHODS: We investigated the endoscopic findings of patients with ulcerative colitis (UC) or who had received hematopoietic stem cell transplantation, and who presented with C. difficile toxin A and had undergone colonoscopy between April 2002 and July 2007 at our institutes. Results. In 4 patients the diagnosis was UC and C. difficile infection, and in another 4 patients the diagnosis was CDAD after hematopoietic stem cell transplantation. None of these cases showed pseudomembranes. Shallow ulcers were found in all four cases with UC. Only non-specific findings were obtained for the CDAD patients after hematopoietic stem cell transplantation. CONCLUSIONS: Pseudomembranes, the typical evidence for CDAD, were not detected in any patients using immunosuppressive agents. Additional bacterial examination is therefore essential when UC becomes exacerbated and when patients present with diarrhea after hematopoietic stem cell transplantation, even in the absence of pseudomembranes.