Michael Scott Visser

Identification of NVP-TNKS656: The Use of Structure-Efficiency Relationships To Generate a Highly Potent, Selective, and Orally Active Tankyrase Inhibitor.

Tankyrase 1 and 2 have been shown to be redundant, druggable nodes in the Wnt pathway. As such, there has been intense interest in developing agents suitable for modulating the Wnt pathway in vivo by targeting this enzyme pair. By utilizing a combination of structure-based design and LipE-based structure efficiency relationships, the core of XAV939 was optimized into a more stable, more efficient, but less potent dihydropyran motif 7. This core was combined with elements of screening hits 2, 19, and 33 and resulted in highly potent, selective tankyrase inhibitors that are novel three pocket binders. NVP-TNKS656 (43) was identified as an orally active antagonist of Wnt pathway activity in the MMTV-Wnt1 mouse xenograft model. With an enthalpy-driven thermodynamic signature of binding, highly favorable physicochemical properties, and high lipophilic efficiency, NVP-TNKS656 is a novel tankyrase inhibitor that is well suited for further in vivo validation studies.

The role of the acidity of N-heteroaryl sulfonamides as inhibitors of bcl-2 family protein-protein interactions.

Overexpression of the antiapoptotic members of the Bcl-2 family of proteins is commonly associated with cancer cell survival and resistance to chemotherapeutics. Here, we describe the structure-based optimization of a series of N-heteroaryl sulfonamides that demonstrate potent mechanism-based cell death. The role of the acidic nature of the sulfonamide moiety as it relates to potency, solubility, and clearance is examined. This has led to the discovery of novel heterocyclic replacements for the acylsulfonamide core of ABT-737 and ABT-263.

Lipophilic Isosteres of a π–π Stacking Interaction: New Inhibitors of the Bcl-2-Bak Protein–Protein Interaction

The discovery of new Bcl-2 protein-protein interaction antagonists is described. We replaced the northern fragment of ABT737 (π-π stacking interactions) with structurally simplified hydrophobic cage structures with much reduced conformational flexibility and rotational freedom. The binding mode of the compounds was elucidated by X-ray crystallography, and the compounds showed excellent oral bioavailability and clearance in rat PK studies.

Discovery of Orally Active Inhibitors of Brahma Homolog (BRM)/ SWI/SNF Related Matrix Associated Actin Dependent Regulator Of Chromatin Subfamily A Member 2 (SMARCA2) ATPase Activity for the Treatment of Brahma Related Gene 1 (BRG1)/ SMARCA4-Mutant Cancers

SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin subfamily A member 2 (SMARCA2), also known as Brahma homologue (BRM), is a Snf2-family DNA-dependent ATPase. BRM and its close homologue Brahma-related gene 1 (BRG1), also known as SMARCA4, are mutually exclusive ATPases of the large ATP-dependent SWI/SNF chromatin-remodeling complexes involved in transcriptional regulation of gene expression. No small molecules have been reported that modulate SWI/SNF chromatin-remodeling activity via inhibition of its ATPase activity, an important goal given the well-established dependence of BRG1-deficient cancers on BRM. Here, we describe allosteric dual BRM and BRG1 inhibitors that downregulate BRM-dependent gene expression and show antiproliferative activity in a BRG1-mutant-lung-tumor xenograft model upon oral administration. These compounds represent useful tools for understanding the functions of BRM in BRG1-loss-of-function settings and should enable probing the role of SWI/SNF functions more broadly in different cancer contexts and those of other diseases.

Oral Communication III: Nutritional Assessment, Epidemiology and FormulationsOR25: Validity of Predictive Equations for Resting Energy Expenditure for Overweight Older Adults with and without Diabetes

Rationale: Predictive equations for resting energy expenditure (REE) are used in the treatment of overweight and obesity, but the validity of these equations in overweight older adults is unknown. This study evaluates which predictive REE equation is the best alternative to indirect calorimetry in overweight older adults with and without diabetes. Methods: In total 273 adults aged ≥55 years with a BMI of ≥25 kg/m2 were included. REE (by indirect calorimetry), body weight, body height, age, gender, and fat-free and fat mass (from air-displacement plethysmography) were measured. The measured REE was used as a reference and compared with 28 existing REE equations. The accuracy of the equations was evaluated by the percentage accurate predictions (within 10% of REE measured), the root mean squared error (RMSE), and the mean percentage difference (bias) between predicted and measured REE. Subgroup analyses were performed for type 2 diabetics (T2D) and non-T2D. Results: Mean age was 64 ± (SD 6) years, 42% had T2D (n = 116), and mean BMI was 32.8 ± (SD 4.5) with range 25–54 kg/m2. The adjusted Harris & Benedict (1984) provided the highest percentage accurate predictions in all adults (70%) and in T2D (74%), and second best in non-T2D (67%). RMSE was 184, 175 and 191 kcal/day, and bias −1.2%, −1.5% and −1.0% for all adults, T2D and non-T2D, respectively. Conclusion: For Dutch overweight older adults with and without diabetes the adjusted Harris–Benedict (1984) predictive equation for REE seems to be the best alternative to indirect calorimetry.

MON-PP209: Effect of a High Protein Diet and/or Resistance Exercise on Preservation of Fat Free Mass During Weight Loss in Overweight Older Adults: a Randomized Controlled Trial

Correspondence a.verreijen@hva.nl, Amely Verreijen, MSc., School of Sports and Nutrition, Amsterdam University of Applied Sciences, Dr. Meurerlaan 8, 1067 AM, Amsterdam, Netherlands Conclusion Although the targeted high protein diet was not completely achieved, the contrast of 23 gram protein per day had no effect on changes in FFM and FM during weight loss in older overweight subjects. Supervised resistance exercise increased the loss of relative FM but had no effect on FFM. However, in the group receiving the protein and exercise combination a significant increase in FFM was observed. Results At baseline, mean±SD BMI was 32±4 kg/m2. During intervention, protein intake was 1.15±0.27 g/kg in the protein groups vs. 0.93±0.19 g/kg in the non-protein groups, corresponding to a 23±5 g/day (p<0.001) higher protein intake. Mean adherence to the exercise program was 2.8±0.3 times/week. No interaction was observed between protein*exercise for all outcomes. Overall, subjects lost weight (-3.1±2.8 kg, p<0.01) without significant between-group effects, and had no significant change in FFM (+0.4±1.9 kg, p=0.12). Effects of protein and effects of exercise on body composition are displayed in the Table and Figure. Table: Outcome measures for protein vs. non-protein groups and for exercise vs. non-exercise groups in means ± SD. Protein (n=40) Non-protein (n=32) Protein effect