The impact of covalent binding on PROTAC-mediated degradation of BTK was investigated through the preparation of both covalent binding and reversible binding PROTACs derived from the covalent BTK inhibitor ibrutinib. It was determined that a covalent binding PROTAC inhibited BTK degradation despite evidence of target engagement, while BTK degradation was observed with a reversible binding PROTAC. These observations were consistently found when PROTACs were employed that were able to recruit either IAP or cereblon E3 ligases. Proteomics analysis determined that use of a covalently bound PROTAC did not result in the degradation of covalently bound targets, whilst degradation was observed for some reversibly bound targets. This observation highlights the importance of catalysis on successful PROTAC-mediated degradation, and highlights a potential caveat for the use of covalent target binders in PROTAC design.Protein degrading bifunctional molecules are emerging as a novel drug discovery strategy with the potential to offer pharmacologic control of biology that is not currently achievable with existing small molecule medicines. 1-3 Mechanistic hallmarks of proteolysis-targeting chimeras (PROTACs) include high cellular degradation potency (DC50, the concentration at which 50% of substrate is degraded) high target selectivity, and extended pharmacodynamic duration of action that is dependent upon both drug pharmacokinetics and target protein resynthesis rate. 4, 5 The targeted protein degradation paradigm is driven by the ability of PROTACs to catalytically promote the degradation of a desired protein in an event-driven process. This contrasts with occupancy-driven pharmacology that is characteristic of traditional small molecule inhibitors. 3

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Research into degradation of cellular proteins induced by small molecule agents known as Protacs has gathered pace recently. This article reviews recent progress and assesses the challenges to be addressed to enable clinical evaluation of agents.

High‐intensity intermittent training (HIIT) has been shown to reduce the risk of chronic conditions including the development of type 2 diabetes mellitus (T2DM). Independently, a low vitamin D status has also been linked to the prevalence of T2DM. The aim of this study was to investigate if there was a synergistic metabolic effect of HIIT and vitamin D supplementation on glycemic control. A total of 20 male and female participants (age, 34 ± 9 year; BMI, 31.4 ± 2.8 kg·m−2) completed 6 weeks HIIT, and were randomized to ingest 100 μg·day‐1 of vitamin D3 or placebo. Response to an oral glucose tolerance test (OGTT) was determined at baseline and at 72 h postintervention. Glucose tolerance was improved as a result of the HIIT intervention, shown through a reduction in glucose and insulin concentrations during the OGTT, accompanied by a decrease in glucose (829 ± 110 to 786 ± 139 mmol·h−1·L−1; P = 0.043) and insulin (8101 ± 4755–7024 ± 4489 mU·h−1·L−1; P = 0.049) area under the curve (AUC). Supplementation increased 25‐hydroxyvitamin D3 concentration by 120% to a sufficiency status (P < 0.001). However, the consumption of vitamin D3 seemed to attenuate the glucose response during an OGTT. Triglyceride content was lowered following the intervention (P = 0.025). There was no effect of the intervention on insulin sensitivity (IS) indices: ISIM atsuda and HOMA‐IR. Our findings demonstrate that HIIT improves glucose tolerance in nondiabetic overweight and obese adults; however vitamin D3 supplementation did not proffer any additional positive effects on the measured indices of metabolic health.