EDITORIAL
Opening CFTR in the Intestine: Flushing on Demand

A new paper by Cil et al1 has described the discovery and characterization of a small molecule capable of opening the Cl- channel cystic fibrosis transmembrane regulator (CFTR). CFTR accounts for the majority of salt and water secretion across mucosal surfaces and into the ducts of secretory glands, and it is important for mucosal hydration in the intestine, lung, and cornea. The new channel opener was identified from a library of 120,000 drug-like synthetic compounds by using a high-throughput, singlecell screen for agonists of Cl- transport. It is a phenylquinoxalinone named CFTRactJ027. The investigators tested the idea that CFTRactJ027 may be applied clinically as a possible therapy for constipation. Constipation remains a significant and widespread clinical problem. The mainstays of management for decades have been various types of osmotic agents to hydrate the stool, or gut motility–stimulating drugs. More recently, new drugs have emerged that have sought to harness the natural flushing and lubrication mechanism in the intestine by promoting transepithelial fluid secretion. Prosecretory drugs currently approved include linaclotide, a peptide agonist of the guanylate cyclase C receptor, which activates CFTR. The drug also activates the other cyclic-nucleotide gated transporters responsible for the secretory response (basolateral Kþ channels and the Naþ/Kþ/2Cl- cotransporter NKCC1). Lubiprostone is a prostaglandin analog that is thought to increase intracellular cyclic adenosine monophosphate and activate CFTR along with the other cyclicnucleotide gated transporters in a similar way. Unlike linaclotidea and lubiprostone, however, CFTRactJ027 appears to act on CFTR alone, without affecting other transporters, and without affecting intracellular signaling intermediates such as the cyclic nucleotides. The benefit of direct action on the CFTR channel is clear: a defined mechanism of action, lower likelihood of side effects, and the possibility of mucosal targeting without systemic absorption. However, there are some disadvantages related to such a narrow scope of action. Cyclic guanosine monophosphate agonists such as linaclotide and plecanatide also modulate ascending sensory nerve pathways and colonic motor pathways to inhibit visceral pain proprioception and to promote motility. Both effects likely contribute to the clinical efficacy of these compounds in the treatment of patients with irritable bowel syndrome or other functional gastrointestinal disorders. Still, the article by Cil et al1 outlines a number of properties that make CFTRactJ027 a promising candidate for clinical applications. The investigators used a classic opioid mouse model of constipation and showed that CFTRactJ027 is both highly specific and effective at improving constipation. Strikingly, they showed that head-to-head, at least in this mouse model, CFTRactJ027 is more effective than

both linaclotide and lubiprostone despite much higher equivalent doses for these drugs than would be used clinically. The study also described some initial pharmacology and toxicity for CFTRactJ027, suggesting that the compound may undergo rapid first-pass metabolism, which likely would limit (unwanted) systemic accumulation. The flip side of CFTR function is that prolonged and irreversible activation of CFTR in the intestine causes the massive secretory diarrhea seen in Vibrio cholerae and toxigenic Escherichia coli infections. Fortunately, and perhaps because of CFTRactJ027’s lack of action on the other pathways that regulate and drive fluid secretion, cholera-like diarrhea does not occur after administration. In fact, by directly targeting and opening CFTR, the compound primarily may potentiate the normal physiological regulation of intestinal fluid secretion, although this remains to be proven.
Constipation-associated conditions such as constipationpredominant irritable bowel syndrome and opioid-induced constipation affect a large and growing proportion of the US population. This study is therefore an important and timely advance toward increasing the therapeutic options for these disorders. There are still many hurdles to overcome before application clinically. However, perhaps CFTRactJ027, or another more refined compound that opens CFTR, will be found effective in treating constipation in human beings. This would have a big impact.
WAYNE I. LENCER, MD Boston Children’s Hospital Harvard Medical School Boston, Massachusetts
Reference
1. Cil O, Phuan P-W, Lee S, et al. CFTR activator increases intestinal fluid secretion and normalizes stool output in a mouse model of constipation. Cell Mol Gastroenterol Hepatol 2016;2:317–327.
Correspondence Address correspondence to: Wayne I. Lencer, MD, Boston Children’s Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, Massachusetts 02115. e-mail: Wayne.Lencer@childrens.harvard.edu.
Conflicts of interest The author discloses no conflicts.
Funding Supported by grants DK048106 (NIH), DK084424 (NIH), and the Harvard Digestive Disease Center DK034854.
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© 2016 The Author. Published by Elsevier Inc. on behalf of the AGA
Institute. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). 2352-345X http://dx.doi.org/10.1016/j.jcmgh.2016.02.005

Cellular and Molecular Gastroenterology and Hepatology 2016;2:256