Machine Learning Models to Predict Inhibition of the Bile Salt Export Pump.

Cholestatic liver injury is frequently associated with drug inhibition of bile salt transporters, such as the bile salt export pump (BSEP). Reliable in silico models to predict BSEP inhibition directly from chemical structures would significantly reduce costs during drug discovery and could help avoid injury to patients. We report our development of classification and regression models for BSEP inhibition with substantially improved performance over previously published models. We assessed the performance effects of different methods of chemical featurization, data set partitioning, and class labeling and identified the methods producing models that generalized best to novel chemical entities.

Rethinking drug design in the artificial intelligence era.

Artificial intelligence (AI) tools are increasingly being applied in drug discovery. While some protagonists point to vast opportunities potentially offered by such tools, others remain sceptical, waiting for a clear impact to be shown in drug discovery projects. The reality is probably somewhere in-between these extremes, yet it is clear that AI is providing new challenges not only for the scientists involved but also for the biopharma industry and its established processes for discovering and developing new medicines. This article presents the views of a diverse group of international experts on the 'grand challenges' in small-molecule drug discovery with AI and the approaches to address them.

Impact of External Quality Assurance on the Quality of Xpert MTB/RIF Testing in Viet Nam.

Following the endorsement of the Xpert MTB/RIF assay (Cepheid, Sunnyvale, CA, USA) by the World Health Organization (WHO) in 2010, Viet Nam's National Tuberculosis Control Program (NTP) began using GeneXpert instruments in NTP laboratories. In 2013, Viet Nam's NTP implemented an Xpert MTB/RIF external quality assurance (EQA) program in collaboration with the U.S. Centers for Disease Control and Prevention (CDC) and the Foundation for Innovative New Diagnostics (FIND). Proficiency-testing (PT) panels comprising five dried tube specimens (DTS) were sent to participating sites approximately twice a year from October 2013 to July 2016. The number of enrolled laboratories increased from 22 to 39 during the study period. Testing accuracy was assessed by comparing reported and expected results; percentage scores were assigned; and feedback reports were provided to sites. On-site evaluation (OSE) was conducted for underperforming laboratories. The results from the first five rounds demonstrate the positive impact of PT and targeted OSE visits on testing quality. On average, for every additional round of feedback, the odds of achieving PT scores of ≥80% increased 2.04-fold (95% confidence interval, 1.39- to 3.00-fold). Future work will include scaling up PT to all sites and maintaining the performance of participating laboratories while developing local panel production capacity.

Development of MK-8353, an orally administered ERK1/2 inhibitor, in patients with advanced solid tumors.

BACKGROUND: Constitutive activation of ERK1/2 occurs in various cancers, and its reactivation is a well-described resistance mechanism to MAPK inhibitors. ERK inhibitors may overcome the limitations of MAPK inhibitor blockade. The dual mechanism inhibitor SCH772984 has shown promising preclinical activity across various BRAFV600/RAS-mutant cancer cell lines and human cancer xenografts. METHODS: We have developed an orally bioavailable ERK inhibitor, MK-8353; conducted preclinical studies to demonstrate activity, pharmacodynamic endpoints, dosing, and schedule; completed a study in healthy volunteers (P07652); and subsequently performed a phase I clinical trial in patients with advanced solid tumors (MK-8353-001). In the P07652 study, MK-8353 was administered as a single dose in 10- to 400-mg dose cohorts, whereas in the MK-8353-001 study, MK-8353 was administered in 100- to 800-mg dose cohorts orally twice daily. Safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity were analyzed. RESULTS: MK-8353 exhibited comparable potency with SCH772984 across various preclinical cancer models. Forty-eight patients were enrolled in the P07652 study, and twenty-six patients were enrolled in the MK-8353-001 study. Adverse events included diarrhea (44%), fatigue (40%), nausea (32%), and rash (28%). Dose-limiting toxicity was observed in the 400-mg and 800-mg dose cohorts. Sufficient exposure to MK-8353 was noted that correlated with biological activity in preclinical data. Three of fifteen patients evaluable for treatment response in the MK-8353-001 study had partial response, all with BRAFV600-mutant melanomas. CONCLUSION: MK-8353 was well tolerated up to 400 mg twice daily and exhibited antitumor activity in patients with BRAFV600-mutant melanoma. However, antitumor activity was not particularly correlated with pharmacodynamic parameters. TRIAL REGISTRATION: ClinicalTrials.gov NCT01358331. FUNDING: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co. Inc., and NIH (P01 CA168585 and R35 CA197633).

A dual role for Integrin α6ß4 in modulating hereditary neuropathy with liability to pressure palsies.

Peripheral myelin protein 22 (PMP22) is a component of compact myelin in the peripheral nervous system. The amount of PMP22 in myelin is tightly regulated, and PMP22 over or under-expression cause Charcot-Marie-Tooth 1A (CMT1A) and Hereditary Neuropathy with Pressure Palsies (HNPP). Despite the importance of PMP22, its function remains largely unknown. It was reported that PMP22 interacts with the ß4 subunit of the laminin receptor α6ß4 integrin, suggesting that α6ß4 integrin and laminins may contribute to the pathogenesis of CMT1A or HNPP. Here we asked if the lack of α6ß4 integrin in Schwann cells influences myelin stability in the HNPP mouse model. Our data indicate that PMP22 and ß4 integrin may not interact directly in myelinating Schwann cells, however, ablating ß4 integrin delays the formation of tomacula, a characteristic feature of HNPP. In contrast, ablation of integrin ß4 worsens nerve conduction velocities and non-compact myelin organization in HNPP animals. This study demonstrates that indirect interactions between an extracellular matrix receptor and a myelin protein influence the stability and function of myelinated fibers.

Rapid Ascent From Zero Quality to International Organization for Standardization Accreditation: A Case Study of Hai Duong Preventive Medicine Center in Vietnam, 2012-2013.

OBJECTIVES: In 2012, the Vietnam Ministry of Health sought to improve the quality of health laboratories by introducing international quality standards. METHODS: Strengthening Laboratory Management Toward Accreditation (SLMTA), a year-long, structured, quality improvement curriculum (including projects and mentorship) was piloted in 12 laboratories. Progress was measured using a standardized audit tool (Stepwise Laboratory Quality Improvement Process Towards Accreditation). RESULTS: All 12 pilot laboratories (a mix of hospital and public health) demonstrated improvement; median scores rose from 44% to 78% compliance. The public health laboratory in Hai Duong Province entered the program with the lowest score of the group (28%) yet concluded with the highest score (86%). Five months after the completion of the program, without any additional external support, they were accredited. Laboratory management/staff describe factors key to their success: support from the facility senior management, how-to guidance provided by SLMTA, support from the site mentor, and strong commitment of laboratory staff. CONCLUSIONS: Hai Duong preventive medical center is one of only a handful of laboratories to reach accreditation after participation in SLMTA and the only laboratory to do so without additional support. Due to the success seen in Hai Duong and other pilot laboratories, Vietnam has expanded the use of SLMTA.

Investigation of an outbreak of bloody diarrhea complicated with hemolytic uremic syndrome.

In July-August 2009, eight patients with bloody diarrhea complicated by hemolytic uremic syndrome (HUS) were admitted to hospitals in Tbilisi, Georgia. We started active surveillance in two regions for bloody diarrhea and post-diarrheal HUS. Of 25 case-patients who developed HUS, including the initial 8 cases, half were ⩾15 years old, 67% were female and seven (28%) died. No common exposures were identified. Among 20 HUS case-patients tested, Shiga toxin was detected in the stools of 2 patients (one with elevated serum IgG titers to several Escherichia coli serogroups, including O111 and O104). Among 56 persons with only bloody diarrhea, we isolated Shiga toxin-producing E. coli (STEC) O104:H4 from 2 and Shigella from 10; 2 had serologic evidence of E. coli O26 infection. These cases may indicate a previously unrecognized burden of HUS in Georgia. We recommend national reporting of HUS and improving STEC detection capacity.

Thiophene carboxamide inhibitors of JAK2 as potential treatments for myleoproliferative neoplasms.

A series of carboxamide-substituted thiophenes demonstrating inhibition of JAK2 is described. Development of this chemical series began with the bioisosteric replacement of a urea substituent by a pyridyl ring. Issues of chemical and metabolic stability were solved using the results of both in vitro and in vivo studies, ultimately delivering compounds such as 24 and 25 that performed well in an acute PK/PD model measuring p-STAT5 inhibition.

Disease surveillance system evaluation as a model for improved integration and standardization of the laboratory component in the Field Epidemiology and Laboratory Training Program (FELTP) curriculum worldwide.

Integration of laboratory training into the Centers for Disease Control and Prevention's (CDC) Field Epidemiology Training Program (FETP) began in 2004 and has advanced the training of laboratory scientists worldwide on the basic principles of epidemiology, disease surveillance, and outbreak investigation. The laboratory component of the FE(L)TP training has traditionally been disease specific, revolving around classroom and bench training on laboratory methods, and field placement in areas where services are needed. There is however a need to improve the integration of epidemiology elements used in surveillance, outbreak investigation, and evaluation activities with specific measurable laboratory activities that could in turn impact the overall disease surveillance and response. A systematic and clear evaluation guideline for the laboratory components of disease surveillance systems alongside the corresponding epidemiological indicators can better identify, address, and mitigate weaknesses that may exist in the entire surveillance system, and also help to integrate and standardize the FE(L)TP curriculum content. The institution of laboratory Quality Management System principles linked to a comprehensive surveillance evaluation scheme will result in improved disease surveillance, response, and overall laboratory capacity over time.

The discovery of tricyclic pyridone JAK2 inhibitors. Part 1: hit to lead.

This paper describes the discovery and design of a novel class of JAK2 inhibitors. Furthermore, we detail the optimization of a screening hit using ligand binding efficiency and log D. These efforts led to the identification of compound 41, which demonstrates in vivo activity in our study.