Optimization of a Series of RIPK2 PROTACs.

Receptor-interacting serine/threonine protein kinase 2 (RIPK2) is an important kinase of the innate immune system. Herein, we describe the optimization of a series of RIPK2 PROTACs which recruit members of the inhibitor of apoptosis (IAP) family of E3 ligases. Our PROTAC optimization strategy focused on reducing the lipophilicity of the early lead which resulted in the identification of analogues with improved solubility and increased human and rat microsomal stability. We identified a range of IAP binders that were successfully incorporated into potent RIPK2 PROTACs with attractive pharmacokinetic profiles. Compound 20 possessed the best overall profile with good solubility, potent degradation of RIPK2, and associated inhibition of TNFα release. A proof-of-concept study utilizing a slow release matrix demonstrated the feasibility of a long-acting parenteral formulation with >1 month duration. This represents an attractive alternative dosing paradigm to oral delivery, especially for chronic diseases where compliance can be challenging.

Extended pharmacodynamic responses observed upon PROTAC-mediated degradation of RIPK2.

Proteolysis-Targeting Chimeras (PROTACs) are heterobifunctional small-molecules that can promote the rapid and selective proteasome-mediated degradation of intracellular proteins through the recruitment of E3 ligase complexes to non-native protein substrates. The catalytic mechanism of action of PROTACs represents an exciting new modality in drug discovery that offers several potential advantages over traditional small-molecule inhibitors, including the potential to deliver pharmacodynamic (PD) efficacy which extends beyond the detectable pharmacokinetic (PK) presence of the PROTAC, driven by the synthesis rate of the protein. Herein we report the identification and development of PROTACs that selectively degrade Receptor-Interacting Serine/Threonine Protein Kinase 2 (RIPK2) and demonstrate in vivo degradation of endogenous RIPK2 in rats at low doses and extended PD that persists in the absence of detectable compound. This disconnect between PK and PD, when coupled with low nanomolar potency, offers the potential for low human doses and infrequent dosing regimens with PROTAC medicines.

Which modifiable health risks are associated with changes in productivity costs?

The purpose of this retrospective, longitudinal study was to assess longitudinal associations between modifiable health risks and workplace absenteeism and presenteeism and to estimate lost productivity costs. Across the 4-year study period (2007-2010), 17,089 unique employees from a large US computer manufacturer with a highly technical workforce completed at least 1 health risk assessment. Generalized estimating equation models were used to estimate the mean population-level absenteeism and presenteeism for 11 modifiable health risks and adjust for 9 sociodemographic and employment-related factors. Because patient age was highly correlated with several other variables, the analysis was stratified by age (<45 vs. ≥45 years). For all ages, poor emotional health, inadequate exercise, tobacco use, and having a body mass index (BMI) greater than 35 (all P<.05) were consistently associated with both absenteeism and presenteeism. Having a BMI over 35 and poor emotional health were associated with the largest impact in absenteeism (0.46 days) and presenteeism (4.03 days), respectively. Younger and older workers had similar associations between health risks and presenteeism; however, hypertension, blood sugar, inadequate exercise, and alcohol were associated (P⋜.01) with greater absenteeism among older but not younger workers. The results suggest that productivity loss is strongly related to emotional health and obesity-related health risks (eg, BMI, exercise) but differs by age. These findings could help prioritize preventive health programs offered by employers at their worksite health centers. Given the aging of the US workforce, keeping older workers healthy and productive will be crucial to remaining competitive in the global economy. (Population Health Management 2015;18:30-38).

Balloon aortic valvuloplasty for aortic stenosis using a novel percutaneous dilation catheter and power injector.

Calcific aortic stenosis is the most common valvular heart disease in the Western world. Although definitive treatment is valve replacement, many patients are not replacement candidates due to high surgical risk from older age and comorbid illness or lack of desire for a surgical or replacement procedure. Percutaneous balloon aortic valvuloplasty (BAV) is an option for palliative treatment in nonsurgical patients, although this procedure is complicated during the immediate postprocedure period by bleeding requiring transfusion for about 1 in 5 patients and subsequent restenosis. This report describes BAV using a smaller profile balloon designed to withstand higher pressures, rapidly inflated with a power injector. Twenty consecutive high-risk patients with severe aortic stenosis were treated. In all cases, New York Heart Association (NYHA) class improved from IV before BAV to I or II at 30 days follow-up. Six-month posttreatment follow-up data were available for 19 of 20 patients: 15 patients were either NYHA class I or II, 1 patient was class III, and 3 deaths occurred unrelated to aortic stenosis. One patient was lost to follow-up. Average systolic gradient peak-to-peak pressure decreased by 40.0% (range 18.0-70.0%) and mean gradient decreased by 30.0% (range 13.7-70.8%). Aortic valve area increased from 0.59 ± 0.16 cm(2) to 0.92 ± 0.23 cm(2), representing a mean increase of 30.0% (range 7.8%-58.2%). There were no significant bleeding complications. The only procedural complication was a single case of pericardial tamponade. There were no other complications during the first 24 hours post-BAV. These data support that the reported BAV technique may offer an effective alternative for patients with severe aortic stenosis who are not surgical candidates or prefer to avoid aortic valve replacement.