Androgen Receptor (AR)-dependent transcription is a major driver of prostate tumor cell proliferation. Consequently, it is the target of several antitumor chemotherapeutic agents, including the AR antagonist MDV3100/enzalutamide. Recent studies have shown that a single AR mutation (F876L) converts MDV3100 action from an antagonist to an agonist. Here we describe the generation of a novel class of Selective Androgen Receptor Degraders (SARDs) to address this resistance mechanism. Molecules containing hydrophobic degrons linked to small molecule Androgen Receptor (AR) ligands induce AR degradation, reduce expression of AR target genes and inhibit proliferation in androgen-dependent prostate cancer cell lines. These results suggest that selective AR degradation may be an effective therapeutic prostate tumor strategy in the context of AR mutations that confer resistance to third generation AR antagonists.

Androgen Receptor (AR)-dependent transcription is a major driver of prostate tumor cell proliferation. Consequently, it is the target of several antitumor chemotherapeutic agents, including the AR antagonist MDV3100/enzalutamide. Recent studies have shown that a single AR mutation (F876L) converts MDV3100 action from an antagonist to an agonist. Here we describe the generation of a novel class of Selective Androgen Receptor Degraders (SARDs) to address this resistance mechanism. Molecules containing hydrophobic degrons linked to small molecule Androgen Receptor (AR) ligands induce AR degradation, reduce expression of AR target genes and inhibit proliferation in androgen-dependent prostate cancer cell lines. These results suggest that selective AR degradation may be an effective therapeutic prostate tumor strategy in the context of AR mutations that confer resistance to third generation AR antagonists. KeywordsAntiproliferation; cancer; drug design; hormones; protein degradation Targeted degradation represents an intriguing strategy to regulate the function of therapeutically relevant proteins (e.g., transcription factors and scaffolding proteins) not amenable to traditional small molecule approaches [1,2] . Moreover, targeted protein degradation could overcome resistance mechanisms that modulate the activity of small molecule drugs following target engagement. For instance, point mutants conferring agonist activity to antagonists limit efficacy of androgen-receptor (AR) antagonists for treatment of prostate cancer [3] . While deletion of the disease-causing protein offers a direct solution to this problem, strategies for doing so via genome editing or RNAi remain clinically challenging [4,5] . As an alternative, we have developed several approaches for posttranslational targeting of specific proteins to the ubiquitin-proteasome system (UPS) [6][7][8][9] . For instance, we recently reported a strategy for post-translational protein degradation whereby a hydrophobic moiety appended to the surface of a target protein engages the cellular quality control machinery. This 'hydrophobic tag' may mimic a partially denatured protein folding state, leading to degradation by the UPS. We demonstrated the feasibility of this approach by covalently coupling hydrophobic tags to engineered dehalogenase HaloTag-2 [10][11][12] fusion proteins. Recently, a similar approach was applied to degradation of E. coli DHFR by non-covalent appendage of a hydrophobic tag [13] . A key next step in the development of this nascent technology is to degrade clinically relevant target proteins with a small drug-like molecule. To this end, here we show that coupling a hydrophobic tag to an androgen receptor agonist converts it to a potent Selective Androgen Receptor Degrader (SARD) capable of inducing >50% of AR degradation (DC 50 ) at 1 μM. Remarkably, this SARD retained anti-proliferative activity in cell lines resistant to current standard-of-care drugs for castration-resistant prostate cancer (CRPC).The androgen receptor (AR) [14] is a ...

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Background. Responses of the metabolome to acute aerobic exercise may predict VO2max and longer-term outcomes, including the development of diabetes and its complications.Methods. Serum samples were collected from overweight trained (OWT) and normal weight trained (NWT) runners prior to and immediately after a supervised 90-minute treadmill run at 60% VO2max (NWT = 14, OWT = 11) in a cross-sectional study. We applied a liquid chromatography high resolution-mass spectrometry based untargeted metabolomics platform to evaluate the effect of acute aerobic exercise on the serum metabolome.Results. NWT and OWT metabolic profiles shared increased circulating acylcarnitines and free fatty acids (FFAs) with exercise while intermediates of adenine metabolism, inosine and hypoxanthine, were strongly correlated with body fat percentage and VO2max. Untargeted metabolomics-guided follow-up quantitative lipidomic analysis revealed that baseline levels of fatty acid esters of hydroxy fatty acids (FAHFAs) were generally diminished in the OWT group.FAHFAs negatively correlated with visceral fat mass and HOMA-IR. Strikingly, a 4-fold decrease in FAHFAs was provoked by acute aerobic running in NWT, an effect that negatively correlated with circulating IL-6, neither of which was observed in the OWT group. Machine learning models based on a pre-exercise metabolite profile that included FAHFAs, FFAs, and adenine intermediates predicted VO2max. Conclusion. These findings in overweight human participants and healthy controls indicate that exercise-provoked changes in FAHFAs distinguish normal weight from overweight individuals and could predict VO2max. These results support the notion that FAHFAs could modulate the inflammatory response, fuel utilization, and insulin resistance. Trial registration. ClinicalTrials.gov NCT02150889.

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