In This Issue pubs.acs.org/acsmedchemlett
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PROBING NON-BET BROMODOMAINS Bromodomains have gained traction as important targets for treatment of a number of diseases including a number of cancers, multiple sclerosis, and cardiovascular diseases. Most drug discovery efforts to date have focused on the development of small molecule inhibitors of the BET subfamily of bromodomains, and BET inhibitors have progressed to clinical trials. Nonetheless, a large number of non-BET bromodomains, such as the BRPF family of bromodomains, also present promising targets for therapeutic intervention; however, more complex structures and functions of these proteins render them more difficult to selectively inhibit and evaluate their phenotypic effects. In this month’s Featured Letter (DOI: 10.1021/acsmedchemlett.6b00092), Bamborough et al. use a previously identified selective benzimidazolone BRPF1 inhibitor that demonstrated micromolar activity in a cellular target engagement assay as a lead for further optimization. These efforts lead to the identification of a superior BRPF1 inhibitor, GSK6853, suitable for in vivo studies. Member-specific bromodomain inhibitors such as GSK6853 will serve as valuable tools to dissect the functions of these poorly understood multidomain proteins. The discovery of this chemical probe will stimulate further investigation into the functions of the BRPF1 bromodomain and a better understanding of the therapeutic opportunities.
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TRACKING ANALGESIC ACTIVITY Painful diabetic neuropathy (PDN) is a common complication of diabetes that typically develops in the feet or lower legs and may also affect the hands. PDN can be extremely debilitating and is currently untreatable using clinically available analgesics. Recently, the nitric oxide donor, 3-methyl-4-furoxancarbaldehyde (PRG150), was shown to produce dose-dependent analgesia in a rat model of PDN; however, metabolic stability and biodistribution of PRG150 have not been characterized. Here, Pippen et al. (DOI: 10.1021/acsmedchemlett.5b00410) investigate the mechanism of analgesia of PRG150 by developing methods to radiolabel the compound and assess its in vivo biodistribution in rats. The elegant radiosynthesis described in this Letter involves the radiolabeling of this molecule with N-13 and C-11. The radiolabeled compounds were used to assess the pharmacokinetics of the drug candidate via two different routes of administration. Differences in clearance of the two different radiolabeled probes were used to determine the metabolic fate of the compound and revealed insights into a possible site of action relating to the analgesic effects of PRG150.
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DELIVERING ON OLIGONUCLEOTIDE THERAPEUTICS The concept of developing oligonucleotides as therapeutics has been around for decades; however, the realization of this potential has been limited due to problems with the functional delivery of the therapeutic agents into cells. The more recent discovery of RNA interference mechanisms has intensified efforts to ameliorate delivery mechanisms of gene-based therapeutics. In this issue, Welch et al. (DOI: 10.1021/acsmedchemlett.6b00031) develop a new series of peptides for delivering siRNA into cells by introducing a release mechanism into existing cyclic amphipathic peptides. The authors discover that disulfide-constrained cyclic amphipathic peptides efficiently form noncovalent complexes with siRNA and allow for functional delivery into cells both in vitro and in vivo. The observed knockdown efficiencies of these delivery agents rival those of the most effective known delivery agents. In addition, the delivery agents have additional advantages including convenience of preparation and use and a novel mode of activity that involves reduction-triggered degradation of the delivery agent. © 2016 American Chemical Society
Published: June 9, 2016 543
DOI: 10.1021/acsmedchemlett.6b00220 ACS Med. Chem. Lett. 2016, 7, 543−543
