Ceramide contributes to pathogenesis and may be targeted for therapy in VCP inclusion body myopathy.

Knock-in homozygote VCPR155H/R155H mutant mice are a lethal model of valosin-containing protein (VCP)-associated inclusion body myopathy associated with Paget disease of bone, frontotemporal dementia and amyotrophic lateral sclerosis. Ceramide (d18:1/16:0) levels are elevated in skeletal muscle of the mutant mice, compared to wild-type controls. Moreover, exposure to a lipid-enriched diet reverses lethality, improves myopathy and normalizes ceramide levels in these mutant mice, suggesting that dysfunctions in lipid-derived signaling are critical to disease pathogenesis. Here, we investigated the potential role of ceramide in VCP disease using pharmacological agents that manipulate the ceramide levels in myoblast cultures from VCP mutant mice and VCP patients. Myoblasts from wild-type, VCPR155H/+ and VCPR155H/R155H mice, as well as patient-induced pluripotent stem cells (iPSCs), were treated with an inhibitor of ceramide degradation to increase ceramide via acid ceramidase (ARN082) for proof of principle. Three chemically distinct inhibitors of ceramide biosynthesis via serine palmitoyl-CoA transferase (L-cycloserine, myriocin or ARN14494) were used as a therapeutic strategy to reduce ceramide in myoblasts. Acid ceramidase inhibitor, ARN082, elevated cellular ceramide levels and concomitantly enhanced pathology. Conversely, inhibitors of ceramide biosynthesis L-cycloserine, myriocin and ARN14494 reduced ceramide production. The results point to ceramide-mediated signaling as a key contributor to pathogenesis in VCP disease and suggest that manipulating this pathway by blocking ceramide biosynthesis might exert beneficial effects in patients with this condition. The ceramide pathway appears to be critical in VCP pathogenesis, and small-molecule inhibitors of ceramide biosynthesis might provide therapeutic benefits in VCP and related neurodegenerative diseases.

Brain-penetrant cyanoindane and cyanotetralin inhibitors of G2019S-LRRK2 kinase activity.

The G2019S variant of LRRK2, which causes an increase in kinase activity, is associated with the occurrence of Parkinson's disease (PD). Potent, mutation-selective, and brain penetrant inhibitors of LRRK2 can suppress the biological effects specific to G2019S-LRRK2 that cause pathogenicity. We report the discovery of a series of cyanoindane and cyanotetralin kinase inhibitors culminating in compound 34 that demonstrated selective inhibition of phosphorylation of LRRK2 in the mouse brain. These novel inhibitors may further enable the precision medicine path for future PD therapeutics.

Optimized Leaky-Wave Antenna for Hyperthermia in Biological Tissue Theoretical Model.

In this paper, we exploit the enhanced penetration reachable through inhomogeneous waves to induce hyperthermia in biological tissues. We will present a leaky-wave antenna inspired by the Menzel antenna which has been shortened through opportune design and optimizations and that has been designed to optimize the penetration at the interface with the skin, allowing penetration in the skin layer at a constant temperature, and enhanced penetration in the overall structure considered. Past papers both numerically and analytically demonstrated the possibility of reducing the attenuation that the electromagnetic waves are subject to when travelling inside a lossy medium by using inhomogeneous waves. In those papers, a structure (the leaky-wave antenna) is shown to allow the effect, but such a radiator suffers from low efficiency. Also, at the frequencies that are most used for hyperthermia application, a classical leaky-wave antenna would be too long; here is where the idea of the shortened leaky-wave arises. To numerically analyze the penetration in biological tissues, this paper considers a numerical prototype of a sample of flesh, composed of superficial skin layers, followed by fat and an undefined layer of muscles.

Management and 1-year outcomes of anastomotic leakage after elective colorectal surgery.

PURPOSE: To analyze different types of management and one-year outcomes of anastomotic leakage (AL) after elective colorectal resection. METHODS: All patients with anastomotic leakage after elective colorectal surgery with anastomosis (76/1,546; 4.9%), with the exclusion of cases with proximal diverting stoma, were followed-up for at least one year. Primary endpoints were as follows: composite outcome of one-year mortality and/or unplanned intensive care unit (ICU) admission and additional morbidity rates. Secondary endpoints were as follows: length of stay (LOS), one-year persistent stoma rate, and rate of return to intended oncologic therapy (RIOT). RESULTS: One-year mortality rate was 10.5% and unplanned ICU admission rate was 30.3%. Risk factors of the composite outcome included age (aOR = 1.08 per 1-year increase, p = 0.002) and anastomotic breakdown with end stoma at reoperation (aOR = 2.77, p = 0.007). Additional morbidity rate was 52.6%: risk factors included open versus laparoscopic reoperation (aOR = 4.38, p = 0.03) and ICU admission (aOR = 3.63, p = 0.05). Median (IQR) overall LOS was 20 days (14-26), higher in the subgroup of patients reoperated without stoma. At 1 year, a stoma persisted in 32.0% of patients, higher in the open (41.2%) versus laparoscopic (12.5%) reoperation group (p = 0.04). Only 4 out of 18 patients (22.2%) were able to RIOT. CONCLUSION: Mortality and/or unplanned ICU admission rates after AL are influenced by increasing age and by anastomotic breakdown at reoperation; additional morbidity rates are influenced by unplanned ICU admission and by laparoscopic approach to reoperation, the latter also reducing permanent stoma and failure to RIOT rates. TRIAL REGISTRATION: ClinicalTrials.gov # NCT03560180.

Dual cyclooxygenase-fatty acid amide hydrolase inhibitor exploits novel binding interactions in the cyclooxygenase active site.

The cyclooxygenases COX-1 and COX-2 oxygenate arachidonic acid (AA) to prostaglandin H2 (PGH2). COX-2 also oxygenates the endocannabinoids 2-arachidonoylglycerol (2-AG) and arachidonoylethanolamide (AEA) to the corresponding PGH2 analogs. Both enzymes are targets of nonsteroidal anti-inflammatory drugs (NSAIDs), but NSAID-mediated COX inhibition is associated with gastrointestinal toxicity. One potential strategy to counter this toxicity is to also inhibit fatty acid amide hydrolase (FAAH), which hydrolyzes bioactive fatty acid ethanolamides (FAEs) into fatty acids and ethanolamine. Here, we investigated the mechanism of COX inhibition by ARN2508, an NSAID that inhibits both COXs and FAAH with high potency, target selectivity, and decreased gastrointestinal toxicity in mouse models, presumably due to its ability to increase levels of FAEs. A 2.27-Å-resolution X-ray crystal structure of the COX-2·(S)-ARN2508 complex reveals that ARN2508 adopts a binding pose similar to that of its parent NSAID flurbiprofen. However, ARN2508's alkyl tail is inserted deep into the top channel, an active site region not exploited by any previously reported NSAID. As for flurbiprofen, ARN2508's potency is highly dependent on the configuration of the α-methyl group. Thus, (S)-ARN2508 is more potent than (R)-ARN2508 for inhibition of AA oxygenation by both COXs and 2-AG oxygenation by COX-2. Also, similarly to (R)-flurbiprofen, (R)-ARN2508 exhibits substrate selectivity for inhibition of 2-AG oxygenation. Site-directed mutagenesis confirms the importance of insertion of the alkyl tail into the top channel for (S)-ARN2508's potency and suggests a role for Ser-530 as a determinant of the inhibitor's slow rate of inhibition compared with that of (S)-flurbiprofen.

European association for endoscopic surgery (EAES) consensus statement on single-incision endoscopic surgery.

BACKGROUND: Laparoscopic surgery changed the management of numerous surgical conditions. It was associated with many advantages over open surgery, such as decreased postoperative pain, faster recovery, shorter hospital stay and excellent cosmesis. Since two decades single-incision endoscopic surgery (SIES) was introduced to the surgical community. SIES could possibly result in even better postoperative outcomes than multi-port laparoscopic surgery, especially concerning cosmetic outcomes and pain. However, the single-incision surgical procedure is associated with quite some challenges. METHODS: An expert panel of surgeons has been selected and invited to participate in the preparation of the material for a consensus meeting on the topic SIES, which was held during the EAES congress in Frankfurt, June 16, 2017. The material presented during the consensus meeting was based on evidence identified through a systematic search of literature according to a pre-specified protocol. Three main topics with respect to SIES have been identified by the panel: (1) General, (2) Organ specific, (3) New development. Within each of these topics, subcategories have been defined. Evidence was graded according to the Oxford 2011 Levels of Evidence. Recommendations were made according to the GRADE criteria. RESULTS: In general, there is a lack of high level evidence and a lack of long-term follow-up in the field of single-incision endoscopic surgery. In selected patients, the single-incision approach seems to be safe and effective in terms of perioperative morbidity. Satisfaction with cosmesis has been established to be the main advantage of the single-incision approach. Less pain after single-incision approach compared to conventional laparoscopy seems to be considered an advantage, although it has not been consistently demonstrated across studies. CONCLUSIONS: Considering the increased direct costs (devices, instruments and operating time) of the SIES procedure and the prolonged learning curve, wider acceptance of the procedure should be supported only after demonstration of clear benefits.

Endogenous N-acyl taurines regulate skin wound healing.

The intracellular serine amidase, fatty acid amide hydrolase (FAAH), degrades a heterogeneous family of lipid-derived bioactive molecules that include amides of long-chain fatty acids with taurine [N-acyl-taurines (NATs)]. The physiological functions of the NATs are unknown. Here we show that genetic or pharmacological disruption of FAAH activity accelerates skin wound healing in mice and stimulates motogenesis of human keratinocytes and differentiation of human fibroblasts in primary cultures. Using untargeted and targeted lipidomics strategies, we identify two long-chain saturated NATs-N-tetracosanoyl-taurine [NAT(24:0)] and N-eicosanoyl-taurine [NAT(20:0)]-as primary substrates for FAAH in mouse skin, and show that the levels of these substances sharply decrease at the margins of a freshly inflicted wound to increase again as healing begins. Additionally, we demonstrate that local administration of synthetic NATs accelerates wound closure in mice and stimulates repair-associated responses in primary cultures of human keratinocytes and fibroblasts, through a mechanism that involves tyrosine phosphorylation of the epidermal growth factor receptor and an increase in intracellular calcium levels, under the permissive control of transient receptor potential vanilloid-1 receptors. The results point to FAAH-regulated NAT signaling as an unprecedented lipid-based mechanism of wound-healing control in mammalian skin, which might be targeted for chronic wound therapy.

Safety of single-incision robotic cholecystectomy for benign gallbladder disease: a systematic review.

BACKGROUND: Multiport laparoscopic cholecystectomy (MLC) is the gold standard technique for cholecystectomy. In order to reduce postoperative pain and improve cosmetic results, the application of the single-incision laparoscopic cholecystectomy (SILC) technique was introduced, leading surgeons to face important challenges. Robotic technology has been proposed to overcome some of these limitations. The purpose of this review is to assess the safety of single-incision robotic cholecystectomy (SIRC) for benign disease. METHODS: An Embase and Pubmed literature search was performed in February 2017. Randomized controlled trial and prospective observational studies were selected and assessed using PRISMA recommendations. Primary outcome was overall postoperative complication rate. Secondary outcomes were postoperative bile leak rate, total conversion rate, operative time, wound complication rate, postoperative hospital stay, and port site hernia rate. The outcomes were analyzed in Forest plots based on fixed and random effects model. Heterogeneity was assessed using the I2 statistic. RESULTS: A total of 13 studies provided data about 1010 patients who underwent to SIRC for benign disease of gallbladder. Overall postoperative complications rate was 11.6% but only 4/1010 (0.4%) patients required further surgery. A postoperative bile leak was reported in 3/950 patients (0.3%). Conversion occurred in 4.2% of patients. Mean operative time was 86.7 min including an average of 42 min should be added as for robotic console time. Wound complications occurred in 3.7% of patients. Median postoperative hospital stay was 1 day. Port site hernia at the latest follow-up available was reported in 5.2% of patients. CONCLUSIONS: The use of the Da Vinci robot in single-port cholecystectomy seems to have similar results in terms of incidence and grade of complications compared to standard laparoscopy. In addition, it seems affected by the same limitations of single-port surgery, consisting of an increased operative time and incidence of port site hernia.

Multitarget fatty acid amide hydrolase/cyclooxygenase blockade suppresses intestinal inflammation and protects against nonsteroidal anti-inflammatory drug-dependent gastrointestinal damage.

The ability of nonsteroidal anti-inflammatory drugs (NSAIDs) to inhibit cyclooxygenase (Cox)-1 and Cox-2 underlies the therapeutic efficacy of these drugs, as well as their propensity to damage the gastrointestinal (GI) epithelium. This toxic action greatly limits the use of NSAIDs in inflammatory bowel disease (IBD) and other chronic pathologies. Fatty acid amide hydrolase (FAAH) degrades the endocannabinoid anandamide, which attenuates inflammation and promotes GI healing. Here, we describe the first class of systemically active agents that simultaneously inhibit FAAH, Cox-1, and Cox-2 with high potency and selectivity. The class prototype 4: (ARN2508) is potent at inhibiting FAAH, Cox-1, and Cox-2 (median inhibitory concentration: FAAH, 0.031 ± 0.002 µM; Cox-1, 0.012 ± 0.002 µM; and Cox-2, 0.43 ± 0.025 µM) but does not significantly interact with a panel of >100 off targets. After oral administration in mice, ARN2508 engages its intended targets and exerts profound therapeutic effects in models of intestinal inflammation. Unlike NSAIDs, ARN2508 causes no gastric damage and indeed protects the GI from NSAID-induced damage through a mechanism that requires FAAH inhibition. Multitarget FAAH/Cox blockade may provide a transformative approach to IBD and other pathologies in which FAAH and Cox are overactive.

Second-Generation Non-Covalent NAAA Inhibitors are Protective in a Model of Multiple Sclerosis.

Palmitoylethanolamide (PEA) and oleoylethanolamide (OEA) are endogenous lipid mediators that suppress inflammation. Their actions are terminated by the intracellular cysteine amidase, N-acylethanolamine acid amidase (NAAA). Even though NAAA may offer a new target for anti-inflammatory therapy, the lipid-like structures and reactive warheads of current NAAA inhibitors limit the use of these agents as oral drugs. A series of novel benzothiazole-piperazine derivatives that inhibit NAAA in a potent and selective manner by a non-covalent mechanism are described. A prototype member of this class (8) displays high oral bioavailability, access to the central nervous system (CNS), and strong activity in a mouse model of multiple sclerosis (MS). This compound exemplifies a second generation of non-covalent NAAA inhibitors that may be useful in the treatment of MS and other chronic CNS disorders.

Transanal endoscopic microsurgery after endoscopic resection of malignant rectal polyps: a useful technique for indication to radical treatment.

BACKGROUND: Management of malignant rectal polyps (MRPs) after endoscopic polypectomy (EP) is still debated. It is sometimes difficult to decide whether to simply follow-up (FU) or to treat such a removed lesion. Transanal endoscopic microsurgery (TEM) could have a role both in T staging and in treating MRPs after EP. METHODS: Patients who underwent a full-thickness TEM within 3 months after an EP between January 2008 and October 2012 were retrospectively analyzed. If post-TEM histology showed locally advanced rectal cancer, patients underwent a total mesorectal excision (TME) within 4-6 weeks. Patients without malignant disease or pT1sm1 cancers at post-TEM histology were followed up every 3 months for 2 years with clinical examination, flexible rectal endoscopy, and neoplastic markers monitoring. RESULTS: A total of 39 patients were included. Post-EP histology was adenocarcinoma in 27/39 cases (69.2 %) and adenoma in 12/39. Mean operative time was 64.2 min; no 30-day mortality occurred; 30-day morbidity was 2.7 % (rectal bleeding in 1/39 cases). Post-TEM histology showed a T2 cancer in 5/39 patients, four with and one without a previous cancer diagnosis, who were further treated by TME (four RARs and one APR) and are disease free with a mean FU of 24.2 months. Post-TEM histology showed adenoma in 10/39 cases and fibrosis in 24/39. These patients are disease free with a mean FU of 13 months. CONCLUSIONS: A full-thickness TEM after EP of MRPs can establish the presence of residual malignant disease and its depth of invasion, precisely defining the indication to TME. In event of benign post-EP histology, TEM must be performed in presence of macroscopic residual disease, in order to obtain an RO resection and finally exclude cancer, while, in absence of macroscopic residual disease, only close FU is required.

Which treatment for large rectal adenoma? Preoperative assessment and therapeutic strategy.

In the present review the authors discuss the standard ways of preoperative work-up for a suspected large rectal non-invasive lesion, comparing East and West different attitudes both in staging and treatment. Looking at the literature and analyzing recent personal data, neither pit-pattern classification, nor EUS, nor biopsy histology, nor lifting sign verification, nor digital examination allow a specificity of more than three fourth of such cases. The authors disquisition about which optimal treatment excludes a role for EMR for the impossibility to obtain a single en-bloc specimen, minimum requirement for a correct lateral and vertical margin assessment. For the same reason ESD should be preferred, although a recent meta-analysis of the literature defined that one fourth of patients undergoing ESD for a preoperatively assessed non-invasive large rectal lesion fail to receive an R0 en-bloc resection. This forces about 10% of patients treated by flexible endoscopy to undergo abdominal surgery, which is about fourfold higher than TEM. While awaiting further implementation of modern technologies both to improve staging and to reduce invasiveness, a full-thickness excision of the rectal wall by TEM still represents the standard treatment even for suspected benign diseases.

NextGEM: Next-Generation Integrated Sensing and Analytical System for Monitoring and Assessing Radiofrequency Electromagnetic Field Exposure and Health.

The evolution of emerging technologies that use Radio Frequency Electromagnetic Field (RF-EMF) has increased the interest of the scientific community and society regarding the possible adverse effects on human health and the environment. This article provides NextGEM's vision to assure safety for EU citizens when employing existing and future EMF-based telecommunication technologies. This is accomplished by generating relevant knowledge that ascertains appropriate prevention and control/actuation actions regarding RF-EMF exposure in residential, public, and occupational settings. Fulfilling this vision, NextGEM commits to the need for a healthy living and working environment under safe RF-EMF exposure conditions that can be trusted by people and be in line with the regulations and laws developed by public authorities. NextGEM provides a framework for generating health-relevant scientific knowledge and data on new scenarios of exposure to RF-EMF in multiple frequency bands and developing and validating tools for evidence-based risk assessment. Finally, NextGEM's Innovation and Knowledge Hub (NIKH) will offer a standardized way for European regulatory authorities and the scientific community to store and assess project outcomes and provide access to findable, accessible, interoperable, and reusable (FAIR) data.

Post-pregnancy recurrent biliary colic with intraoperative diagnosis of limy bile syndrome.

INTRODUCTION: Limy bile syndrome (LBS) is an unusual condition in which gallbladder and/or bile ducts are filled with paste-like radiopaque material with a high calcium carbonate content. It can be rarely associated with PTH disorder and hypercalcemia. PRESENTATION OF CASE: A 35-year-old woman presented with epigastric and right hypochondrium pain since a few hours. Similar attacks occurred in the past months soon after a pregnancy with vaginal delivery. Laboratory findings were not significant. The abdominal ultrasound highlighted a micro-lithiasis of gallbladder without complications. Considering the recurrent biliary attacks, laparoscopic cholecystectomy was performed with intraoperative diagnosis of LBS. A subsequent endocrinological screening highlighted a normocalcemic hyperparathyroidism associated with Vitamin D deficiency, likely related to the recent pregnancy and not to LBS. DISCUSSION: LBS is a rare condition with not clear etiology, frequently associated with cholelithiasis, of which it shares clinical presentation and potential complications. Diagnosis of LBS is based on abdominal X-ray/computed tomography scan, or it could be an intraoperative finding. The gold standard treatment is represented by laparoscopic cholecystectomy. The pregnancy with its related cholestatic phenotype could facilitate the LBS manifestation. An endocrinological screening should be performed to rule out a concomitant calcium metabolism disorder. CONCLUSION: Knowledge of this rare condition could help general surgeons handle it properly.

Robotic versus laparoscopic right colectomy within a systematic ERAS protocol: a propensity-weighted analysis.

The purpose of this study is to compare the early postoperative and pathological outcomes of robotic right colectomy (RRC) to those of laparoscopic right colectomy (LRC) with intracorporeal anastomosis (IA) within the systematic application of an enhanced recovery after surgery (ERAS) program. A single-institution prospective database of patients who underwent elective RRC or LRC with IA for neoplastic lesions between April 2010 and June 2018 was retrospectively reviewed. The patients' demographic characteristics, and perioperative and pathological outcomes were analyzed. Propensity-weighted analysis was employed to address potential selection biases of treatment allocation. A total of 216 patients (46 RRC, 170 LRC) were included. RRC demonstrated a significantly longer operative time (mean 242.43 min, SD 47.51) compared to LRC (mean 187.60 min, SD 56.60) (p = 0.001), confirmed by the propensity-weighted analysis (Coefficient 50.65; p < 0.001). Conversion rate between the two groups was comparable (p = 0.99). Median length of hospital stay (LOS) was the same in the RRC and the LRC group (4 days, p = 0.35). Readmission rate within 30 days in the RRC and LRC group was 2.2% and 2.4%, respectively (p = 0.99). Overall 30-day morbidity and 30-day mortality was 32.6% versus 27.1% (p = 0.46), and 0% versus 1.2% (p = 0.99) in the robotic and laparoscopic groups, respectively. No difference was found in the number of harvested lymph nodes (p = 0.75). In an ERAS environment, without the bias of mixed techniques of anastomosis, RRC had similar postoperative and pathological outcomes compared to the laparoscopic approach, but was associated with a longer operative time.

Anastomosis configuration and technique following ileocaecal resection for Crohn's disease: a multicentre study.

A limited ileocaecal resection is the most frequently performed procedure for ileocaecal CD and different anastomotic configurations and techniques have been described. This manuscript audited the different anastomotic techniques used in a national study and evaluated their influence on postoperative outcomes following ileocaecal resection for primary CD. This is a retrospective, multicentre, observational study promoted by the Italian Society of Colorectal Surgery (SICCR), including all adults undergoing elective ileocaecal resection for primary CD from June 2018 May 2019. Postoperative morbidity within 30 days of surgery was the primary endpoint. Postoperative length of hospital stay (LOS) and anastomotic leak rate were the secondary outcomes. 427 patients were included. The side to side anastomosis was the chosen configuration in 380 patients (89%). The stapled anastomotic (n = 286; 67%), techniques were preferred to hand-sewn (n = 141; 33%). Postoperative morbidity was 20.3% and anastomotic leak 3.7%. Anastomotic leak was independent of the type of anastomosis performed, while was associated with an ASA grade ≥ 3, presence of perianal disease and ileocolonic localization of disease. Four predictors of LOS were identified after multivariate analysis. The laparoscopic approach was the only associated with a reduced LOS (p = 0.017), while age, ASA grade ≥ 3 or administration of preoperative TPN were associated with increased LOS. The side to side was the most commonly used anastomotic configuration for ileocolic reconstruction following primary CD resection. There was no difference in postoperative morbidity according to anastomotic technique and configuration. Anastomotic leak was associated with ASA grade ≥ 3, a penetrating phenotype of disease and ileo-colonic distribution of CD.

Design, Synthesis, and Biological Evaluation of a Series of Oxazolone Carboxamides as a Novel Class of Acid Ceramidase Inhibitors.

Acid ceramidase (AC) is a cysteine hydrolase that plays a crucial role in the metabolism of lysosomal ceramides, important members of the sphingolipid family, a diversified class of bioactive molecules that mediate many biological processes ranging from cell structural integrity, signaling, and cell proliferation to cell death. In the effort to expand the structural diversity of the existing collection of AC inhibitors, a novel class of substituted oxazol-2-one-3-carboxamides were designed and synthesized. Herein, we present the chemical optimization of our initial hits, 2-oxo-4-phenyl-N-(4-phenylbutyl)oxazole-3-carboxamide 8a and 2-oxo-5-phenyl-N-(4-phenylbutyl)oxazole-3-carboxamide 12a, which resulted in the identification of 5-[4-fluoro-2-(1-methyl-4-piperidyl)phenyl]-2-oxo-N-pentyl-oxazole-3-carboxamide 32b as a potent AC inhibitor with optimal physicochemical and metabolic properties, showing target engagement in human neuroblastoma SH-SY5Y cells and a desirable pharmacokinetic profile in mice, following intravenous and oral administration. 32b enriches the arsenal of promising lead compounds that may therefore act as useful pharmacological tools for investigating the potential therapeutic effects of AC inhibition in relevant sphingolipid-mediated disorders.

Selective Inhibitors of G2019S-LRRK2 Kinase Activity.

Pathogenic variants in the leucine-rich repeat kinase 2 (LRRK2) gene have been identified that increase the risk for developing Parkinson's disease in a dominantly inherited fashion. These pathogenic variants, of which G2019S is the most common, cause abnormally high kinase activity, and compounds that inhibit this activity are being pursued as potentially disease-modifying therapeutics. Because LRRK2 regulates important cellular processes, developing inhibitors that can selectively target the pathogenic variant while sparing normal LRRK2 activity could offer potential advantages in heterozygous carriers. We conducted a high-throughput screen and identified a single selective compound that preferentially inhibited G2019S-LRRK2. Optimization of this scaffold led to a series of novel, potent, and highly selective G2019S-LRRK2 inhibitors.