Identification and characterization of second-generation EZH2 inhibitors with extended residence times and improved biological activity.

The histone methyltransferase EZH2 has been the target of numerous small-molecule inhibitor discovery efforts over the last 10+ years. Emerging clinical data have provided early evidence for single agent activity with acceptable safety profiles for first-generation inhibitors. We have developed kinetic methodologies for studying EZH2-inhibitor-binding kinetics that have allowed us to identify a unique structural modification that results in significant increases in the drug-target residence times of all EZH2 inhibitor scaffolds we have studied. The unexpected residence time enhancement bestowed by this modification has enabled us to create a series of second-generation EZH2 inhibitors with sub-pM binding affinities. We provide both biophysical evidence validating this sub-pM potency and biological evidence demonstrating the utility and relevance of such high-affinity interactions with EZH2.

A twenty-year experience with endoscopic therapy for symptomatic primary sclerosing cholangitis.

GOALS: The current study presents 1 tertiary endoscopy center's 20-year experience using endoscopic therapy to treat patients with symptomatic primary sclerosing cholangitis (PSC). BACKGROUND: Endoscopic therapy for patients with PSC and dominant strictures has been used for more than 20 years, but there is concern that instrumenting a sclerotic biliary tree induces risks that outweigh anticipated benefits. STUDY: In this retrospective chart review, 117 patients with PSC were identified using ICD-9 codes. Patients had a mean age of 47 years (range: 15 to 86 y). Mean duration of follow-up was 8 years (range: 2 to 20 y). Of the 117 identified patients, 106 underwent endoscopic retrograde cholangiopancreatography on one or more occasions (for a total of 317 endoscopic retrograde cholangiopancreatographies), and a subset of 84 patients received endoscopic therapy for treatment of dominant strictures and/or deteriorating clinical status. Actual survival for endoscopically treated patients was compared with predicted survival using the Mayo Clinic natural history model for PSC. RESULTS: Our chart review revealed 23 recognized complications among the 317 procedures performed (7.3%), and no procedure-related deaths. Observed patient survival at years 3 and 4 was significantly higher than that predicted by the Mayo Clinic natural history model for PSC (P=0.021). CONCLUSIONS: Patients with PSC who have a deteriorating clinical course benefited from endoscopic therapy to provide drainage of bile ducts, removal of stones, and/or temporary relief from obstructions, with acceptable procedure-related complications and higher than expected 3-year and 4-year survival.