Difficulties in developing active-site-directed protein tyrosine phosphatase (PTP) inhibitors have led to the perception that PTPs are “undruggable”, highlighting the need for new means to target pharmaceutically important PTPs allosterically. Recently, we characterized an allosteric-inhibition site on the PTP domain of Src-homology-2-domain-containing PTP 2 (SHP2), a key anticancer drug target. The central feature of SHP2’s allosteric site is a nonconserved cysteine residue (C333) that can potentially be labeled with electrophilic compounds for selective SHP2 inhibition. Here, we describe the first directed discovery effort for C333-targeted allosteric SHP2 inhibitors. By screening a previously reported library of reversible, covalent inhibitors, we identified a lead compound, which was modified to yield an irreversible inhibitor (12), that inhibits SHP2 allosterically and selectively through interaction with C333. These findings provide a novel paradigm for allosteric-inhibitor discovery on SHP2, one that may help to circumvent the challenges inherent in targeting SHP2’s active site.

Diabetic retinopathy is one of the leading causes of blindness in the world with the incidence of disease ever-increasing worldwide. The vitreous humor represents an extensive and complex interactive arena for cytokines in the diabetic eye. In recent decades, there has been significant progress in understanding this environment and its implications in disease pathophysiology. In this review, we investigate the vitreous ecosystem in diabetic retinopathy at the molecular level. Areas of concentration include: the current level of knowledge of growth factors, cytokine and chemokine mediators, and lipid-derived metabolites in the vitreous. We discuss the molecular patho-mechanisms of diabetic retinopathy based upon current vitreous research.

BackgroundCigarette smoking causes about one of every five deaths in the U.S. each year. In 2013 the prevalence of smoking in our institution’s trauma population was 26.7 %, well above the national adult average of 18.1 % according to the CDC website. As a quality improvement project we implemented a multimodality smoking cessation program in a high-risk trauma population.MethodsAll smokers with independent mental capacity admitted to our level I trauma center from 6/1/2014 until 3/31/2015 were counseled by a physician on the benefits of smoking cessation. Those who wished to quit smoking were given further counseling by a pulmonary rehabilitation nurse and offered nicotine replacement therapy (e.g. nicotine patch). A planned 30 day or later follow-up was performed to ascertain the primary endpoint of the total number of patients who quit smoking, with a secondary endpoint of reduction in the frequency of smoking, defined as at least a half pack per day reduction from their pre-intervention state.ResultsDuring the 9 month study period, 1066 trauma patients were admitted with 241 (22.6 %) identified as smokers. A total of 31 patients with a mean Injury Severity Score (ISS) of 14.2 (range 1–38), mean age of 47.6 (21–71) and mean years of smoking of 27.1 (2–55), wished to stop smoking. Seven of the 31 patients, (22.5 %, 95 % confidence interval [CI] of 10–41 %) achieved self-reported smoking cessation at or beyond 30 days post discharge. An additional eight patients (25.8 %, 95 % CI 12–45 %) reported significant reduction in smoking.ConclusionsTrauma patients represent a high risk smoking population. The implementation of a smoking cessation program led to a smoking cessation rate of 22.5 % and smoking reduction in 25.8 % of all identified smokers who participated in the program. This is a relatively simple, inexpensive intervention with potentially far reaching and beneficial long-term health implications. A larger, multi-center prospective study appears warranted.LEVEL OF EVIDENCE: Therapeutic Study, Level V evidence.