Breaking News
October 23, 2018 - Spectrum Pharmaceuticals Announces Release of Updated Poziotinib Data From MD Anderson Phase 2 Study in Non-Small Cell Lung Cancer Patients
October 23, 2018 - Cancer stem cells use ‘normal’ genes in abnormal ways
October 23, 2018 - Bad Blood: A conversation with investigative reporter John Carreyrou | News Center
October 23, 2018 - As U.S. fertility rates collapse, finger-pointing and blame follow
October 23, 2018 - Researchers develop promising targeted strategy to treat chemo-resistant blood cancer
October 23, 2018 - Pilot clinical trial shows effectiveness of bioelectronic medicine device for lupus
October 23, 2018 - Genentech’s combination therapy improves outcome in patients with non-squamous non-small cell lung cancer
October 23, 2018 - 11th World Stroke Congress examines high stroke impact in low- and middle-income countries
October 22, 2018 - Breast cancer survival could be extended with two new drug combinations
October 22, 2018 - Researchers discover how acne-causing bacteria resist treatment
October 22, 2018 - Cancer trial shows treating the prostate with radiotherapy improves survival
October 22, 2018 - New hope for a drug to treat lymphedema symptoms
October 22, 2018 - Immune-Based Treatment Helps Fight Aggressive Breast Cancer, Study Finds
October 22, 2018 - Takeda announces positive Phase 3 ALTA-1L data in first-line therapy for advanced ALK+ NSCLC
October 22, 2018 - Paternal exercise has significant impact on child’s lifelong metabolic health
October 22, 2018 - Targeting specific genomic mutation in breast cancer improves survival
October 22, 2018 - Loss of tumor protein p53 helps cancer cells grow in hostile environment
October 22, 2018 - IDT to demonstrate CRISPR expertise at European-focused events
October 22, 2018 - Breathing through the nose improves memory consolidation
October 22, 2018 - Recreational Marijuana Now Legal in Canada
October 22, 2018 - Scientists reveal drumming helps schoolchildren diagnosed with autism
October 22, 2018 - A stage IV cancer patient discusses what it means to live well with serious illness
October 22, 2018 - In Kids with Autism, Short Questionnaire May Detect GI Disorders
October 22, 2018 - Merck presents MK-1454 Phase 1 data for treatment of advanced solid tumors or lymphomas
October 22, 2018 - Aspirin may be effective in preventing blood clots after knee replacement
October 22, 2018 - Drug cocktail that increases lifespan discovered
October 22, 2018 - Gilead Sciences presents Phase 3 results of filgotinib in biologic-experienced rheumatoid arthritis at 2018 ACR/ARHP Annual Meeting
October 22, 2018 - Study shows potential positive impact of group prenatal care on birth outcomes
October 22, 2018 - Immunotherapy with pembrolizumab extends survival in metastatic or recurrent head and neck cancer
October 22, 2018 - Health Tip: Keep Ticks Away
October 22, 2018 - Obsessive-compulsive disorder – Genetics Home Reference
October 22, 2018 - Researchers find disrupted functional connectivity in cerebellum of adults with HF-ASD
October 22, 2018 - Deciphera presents Phase 1 clinical results of DCC-2618 in patients with gastrointestinal stromal tumors
October 22, 2018 - Combination of Opdivo and Yervoy shows four-year survival benefits in patients with advanced melanoma
October 22, 2018 - Overcoming bottlenecks in early drug discovery with the power of sound
October 22, 2018 - Scientists discover genes that contribute to ADHD development
October 22, 2018 - Incyte announces Phase 2 FIGHT-202 trial data in patients with cholangiocarcinoma
October 22, 2018 - FDA approves update to Rituxan label to include information on treatment of rare forms of vasculitis
October 22, 2018 - At-home biofeedback therapy effective in relieving difficult-to-treat constipation
October 22, 2018 - Merck presents KEYNOTE-057 trial results for patients with high-risk non-muscle invasive bladder cancer
October 22, 2018 - People with periodontal disease less likely to reach healthy blood pressure ranges
October 22, 2018 - Phase III LONSURF study shows progression-free survival in patients with refractory metastatic gastric cancer
October 22, 2018 - Primary care doctors ‘not doing enough’ to curb STDs
October 22, 2018 - Pfizer announces PALOMA-3 trial results in patients with HR+, HER2- metastatic breast cancer
October 22, 2018 - ImmunoGen announces study results of platinum-resistant ovarian cancer therapy at ESMO 2018 Congress
October 22, 2018 - Study findings could set new standard of care for advanced anal cancer
October 22, 2018 - Erlotinib improves progression-free survival in EGFR mutated NSCLC
October 22, 2018 - Pain, insomnia, and depression often drive osteoarthritis patients to seek medical care
October 22, 2018 - The International Society of Refractive Surgery honors Vivior Chairman with Casebeer Award
October 22, 2018 - Multi-strain probiotic helps reduce chemotherapy-induced diarrhea in cancer patients
October 22, 2018 - Study shows potential of avelumab plus axitinib as new treatment option for patients with advanced RCC
October 22, 2018 - Vertex gets European CHMP positive opinion for KALYDECO to treat patients with cystic fibrosis
October 22, 2018 - Phase III trial reports positive results with HDAC inhibitor in advanced breast cancer patients
October 22, 2018 - Prostate radiotherapy improves survival in men with low burden of metastatic disease
October 22, 2018 - Duration of respiratory disturbances may better predict mortality risk from OSA
October 22, 2018 - Free phone app helps low-income obese patients to lose weight
October 22, 2018 - Immunotherapy with nivolumab and ipilimumab may improve survival in patients with MSI-high metastatic colorectal cancers
October 22, 2018 - FOTIVDA expected to be included in new ESMO guidelines for advanced renal cell carcinoma
October 22, 2018 - Compression Collar May Protect Brain of Female Soccer Players
October 22, 2018 - Technique visualizes neuron communication
October 22, 2018 - Advancement in medical imaging methods for health care
October 22, 2018 - Takeda presents vedolizumab phase 3 VISIBLE 1 trial results for treatment of moderately to severely active ulcerative colitis
October 22, 2018 - Immunotherapy increases survival in some patients with metastatic triple negative breast cancer
October 22, 2018 - Exelixis presents CABOSUN and METEOR trial results in patients with advanced renal cell carcinoma
October 22, 2018 - LYNPARZA Phase III SOLO-1 results show improved outcome for patients with advanced BRCA-mutated ovarian cancer
October 22, 2018 - Brainlab unveils ExacTrac Dynamic at ASTRO meeting in San Antonio, Texas
October 22, 2018 - Not exercising is worse than smoking, diabetes or heart disease finds study
October 22, 2018 - Shorter course of trastuzumab could be an option for women with HER2+ early breast cancer
October 22, 2018 - Map of Mouse Hippocampus Could Be Weapon Against Alzheimer’s
October 22, 2018 - Psychotropic polypharmacy is common in Alzheimer’s disease
October 22, 2018 - Texas A&M and UTA establish Texas Genomics Core Alliance
October 22, 2018 - Analyzing mouse’s potential as animal model of decision-making
October 22, 2018 - Radiotherapy can prolong survival in prostate cancer
October 22, 2018 - A genetic mutation involved in relapse
October 21, 2018 - Report reveals growing impact of cannabis on young people
October 21, 2018 - NSF awards $5 million grant to help scientists magnify societal impact of research
October 21, 2018 - Fertility Rates Down for Each Urbanization Level 2007 to 2017
October 21, 2018 - Genetically engineered 3-D human muscle transplant in a murine model
October 21, 2018 - Moms’ tight work schedules may affect their children’s sleep
October 21, 2018 - AHA: No Direct Link Between Preeclampsia and Cognitive Impairment, Study Finds
Developing a High Throughput Mass Spectrometry Platform for Drug Discovery

Developing a High Throughput Mass Spectrometry Platform for Drug Discovery

image_pdfDownload PDFimage_print

Your presentation at Pittcon 2018 focussed on Mass Spectroscopy (MS) based high-throughput screening for drug discovery. What are the current challenges associated with screen samples?

Acoustic mass spectrometry offers us the ability to screen very, very quickly in a very clean way. This is a huge benefit for the high-throughput screening community. As a result, we are able to have a direct measurement of substrate to product conversion, and that’s great because we don’t have to buy extra reagents. We also don’t have to buy labels, which obviously add cost. Higher costs mean we can only screen a reduced number of samples. So, keeping the cost down is important for us too.

In a recent paper co-authored by yourself and Mattias Rohman, you describe the use of RapidFire™ coupled to a triple-quadrupole MS for high-throughput screening. How does this compare to traditional liquid chromatography for electrospray ionization (ESI)?

In the high-throughput screening space, the RapidFire platforms that are now marketed by Agilent are considered to be state of the art for high-throughput screening. It is because they are using a simple solid phase extraction methodology, rather than an LC, that means they can process a sample every eight to ten seconds. However, even at that speed, it’s really not fast enough. Of course, taking away the LC component, to a certain extent also demystifies some of the technology around mass spectrometry and makes it a little bit more user friendly as well.

Can you please tell us about your collaboration with Labcyte and Waters to build a prototype high throughput mass spectrometry platform?

The aim of the collaboration that AstraZeneca has with LabCyte and Waters is really to try and push forwards the boundaries of high-throughput mass spectrometry. Electrospray mass spectrometry is broadly applicable across may areas of drug discovery, and although there are some other high-throughput techniques such as MALDI, many labs will probably have access to electrospray mass spectrometry platforms.

So being able to convert those into a high-throughput technology was really the main aim for this. The use of acoustics is exciting because it gives us an opportunity to use all of the advantages of acoustics, low sample handling and very high-throughput potential, in a way that’s not been used in terms of coupling it to mass spectrometry in the past.

Mass Spec High Throughput Screening from AZoNetwork on Vimeo.

What modification have you made to the acoustic dispenser and what have been the benefits?

Fundamentally, we’ve taken the LabCyte 555 and essentially taken the transducer from inside and brought it outside the instrument, then coupled this to a plate transfer system so that the plate can now move around over the top of this transducer.

The frequency of the transducer has been tuned and the power offset is subtly different from a standard two and a half nanoliter droplet. This enables us to generate a droplet that’s much smaller and therefore more straight forward to ionize. It also gives us better signal in the mass spectrometer itself.

What is the Echo-MS system and what sampling speeds have you been able to obtain?

By coupling the acoustic front end to a standard time of flight or triple quad mass spec, we can achieve throughputs of around three samples per second. When you compare it to the state of the art electrospray system, the RapidFire, which processes samples once every eight to 10 seconds, it gives us a considerable speed advantage. At that sort of throughput, we’re able to process more than 100,000 samples per day and half a million samples per week.

What level of sample screening do you hope to achieve at these levels?

Well so far, within AstraZeneca, we’ve been able to use this technology even though it is still in its prototype stage to support our high-throughput screening campaigns. Last year we ran a full collection screen, 2.2 million samples, and today we’ve probably processed around about 5 million samples through the platform. This is something we’ve never been able to do in the past with a single MS system.

Why is this important to drug discovery in general?

One of the things that it really enables us to do is to build the assays very quickly. We can get a very fast proof of concept using the mass spec to see whether our enzymes can convert substrates into products. Once we’ve established that proof of concept, moving from there to having a proper assay fit for high-throughput screening is a relatively quick process.

Of course, as I said, costs really come down as well without having to invest in additional label it brings the prices down to a much more affordable level. It’s also a very simple process. We simply add the reagents to our plates, and we have the reactions occur, and then the same plate is used to fire samples into the mass detector itself. For example, our last high-throughput screening campaign was probably about 90,000 pounds cheaper than if we had screened using traditional label-based technologies.

What are the next steps in the development of this prototype platform?

We’re still working with prototype systems. I don’t even believe they’re beta products yet, they’re still in the alpha stage. As with any type of research project like this, I think it’s probable that we will get significant improvements in sensitivity, which will really add value as we move much more towards a commercial instrument.

I think we’re still a year to 18 months away from having any kind of commercial offering available, but hopefully we’d like to see it broadly applied in the biochemical screening space. We’re now starting to broaden our view to look at other potential application avenues as well. We’ll be sharing some data here around cell based assays, which would be a first application with the acoustic mass spec in that area as well. We’re very excited about that and hopefully we’ll see more applications in the future.

Why is Pittcon important in helping you share your research?

Pittcon is really important to us because it gives us a really great opportunity to talk to a really broad audience. Pittcon’s renowned for being at the forefront of analytical sciences, and acoustic mass spectrometry is just another analytical tool. Being able to come to a conference such as this one, and be able to talk and access such a wide spectrum of scientific excellence, I think is really important for any project.

About Dr. Jonathan Wingfield

Jonathan joined AstraZeneca in 2000, as part of a team responsible for delivering automation solutions and technology into the disease area teams post HTS.

He was invited to establish a Lead Generation Automation team within Oncology and this evolved into a centralised biochemical screening team in 2006. The centralised team utilized leading edge technology to deliver high quality data to global projects, this included delivery of acoustic droplet ejection technology.

In 2008 the team was awarded the Microsoft Innovation in Pharma award for the innovative development of a LIMS platform. When the Discovery Sciences function was established within AZ, Jonathan moved into a science role supporting biochemical SAR.

He remains interested in landing technologies that can add value to the core drug discovery business, one such example is the acoustic mass spectrometry collaboration between Labcyte and AZ. This project won the SLAS Innovation award (2015) and has generated a significant amount of external interest.

Tagged with:

About author

Related Articles