With conferences going virtual this year, the Genedata Screener team missed meeting with colleagues and customers face-to-face at SLAS 2021. Nevertheless, there’s plenty of exciting science and innovation happening in the drug discovery world. We took stock of our favorite talks and interesting trends. Some highlights:
Big Pharma Harnessing High-Throughput Mass Spectrometry (HT-MS)
In the past few years, we’ve witnessed huge strides in MS throughput, enabling adaptation of this label-free, data-rich assay to full deck HTS campaigns. This year, we’ve seen the full fruition of these developments, with multiple talks showcasing successfully completed HT-MS campaigns and the use of MS for rapid hit confirmation.
We especially appreciated that programs now incorporate not only biochemical assays—often used to pursue enzymatic targets through MS quantification of products and substrates—but now employ MS-based affinity assays to interrogate target engagement. As one impressive example, Boehringer-Ingelheim showcased a complete HT MALDI-TOF pipeline that includes both a biochemical workflow with which they’ve conducted enzyme inhibitor screens of ~1 million compounds and an affinity binding workflow with which they’ve performed screens of 23,000 compounds. With the latter workflow they can screen up to 25,000 compounds per day! They also hinted at work with electrospray ionization-MS—signaling, like many other speakers this year, their embrace of the full suite of HT-MS technologies.
Meanwhile, Merck described an LC-MS based pipeline (called the Automated Ligand Identification System, or ALIS) which they’ve used to screen 50,000 compounds for binding against 42 non-coding RNAs of various classes. Their work nicely highlights the versatility of HT-MS to probe a broad range of analytes or targets, whether protein, nucleic acid, small molecule, or even whole cell lysate.
From Pfizer came an excellent example of how orthogonal MS approaches can be used for hit triage, or even to rescue for reconsideration hits that might otherwise be deemed inactive or non-specific. They’ve applied MALDI MS-based biochemical assays, ASMS, and SPR to validate hits from a DNA-encoded chemical library screen. They also highlighted the power of MS technology for multiplexing multiple target forms.
Having ourselves built an automated solution for HT-MS analysis that integrates with both ESI-MS and Bruker MALDI instruments, here at Genedata we’re very excited about the explosion of HT-MS and look forward to seeing it mature into an HTS workhorse.
Phenotypic Screening: Triangulating Many Types of Data
Phenotypic screening has been a hot topic for a while, and this year was no exception. There continues to be great innovation in high-content image screening, including developments in brightfield image detection and broad adoption of Cell Painting assays. We were uniquely struck by work from the US Environmental Protection Agency (EPA), where they are evaluating Cell Painting for toxicity risk assessment, e.g. predicting agents to which humans might be harmfully exposed. They’ve done dose-response screens of >1,200 reference chemicals from their ToxCast library, taking into account some 1300 features. This is a fantastic example of practical applications for Cell Painting even beyond the drug discovery world.
Beyond high-content imaging, we were also inspired to see how people have integrated several types of multiplexed data to achieve the ultimate phenotypic readout. A fantastic instance of this came from AstraZeneca’s work on discovery of inflammasome regulators. In parallel phenotypic approaches, they screened fully functionalized fragments for their combined effect on multiple cytokines and cell viability and performed an arrayed CRISPR screen with expression of multiple genes as readouts. Their phenotypic approach is only poised to increase in complexity, as they explore multiplexed CRISPR and whole genome screens.
Another amazing example of this multi-pronged phenotypic approach came from Fulcrum Therapeutics, who combined HCS and Cell Painting assays with a novel HT 3’-RNAseq technology to generate a rich readout. By applying it to chemical probe or CRISPR screens in patient-derived iPSC disease models, they’ve used this phenotypic “FulcrumSeek discovery engine” to identify and select new targets. (In the talk mentioned earlier, the EPA is also examining transcriptomics methods, further foreshadowing the rise of comprehensive phenotypic approaches.)
For our part, we felt lucky to contribute to the conversation surrounding phenotypic screening, with our own tutorial showcasing the latest version of Imagence, our AI-based imaging analysis workflow (for an encore, see our recent webinar), and poster on transcriptomic screening at Evotec.
Exploring Pooled Approaches: DELs and CRISPR
Other advances that caught our eye this year: developments in DNA-encoded libraries or DELs, where chemical building blocks are tethered to a DNA barcode, pooled, and hits identified by PCR or sequencing. DELs made many appearances, including in the previously-mentioned Pfizer talk on DEL screen hit confirmation by MS, and another Pfizer talk detailing challenges of the DEL approach and how to overcome them. A third carefully considered talk from WuXi App Tech examined the informatic analysis of DEL hits and consequences of growing library complexity.
Nevertheless, we think there still is a place for plate-based screening. Backing our hunch, several talks featuring pooled CRISPR screens also cited active efforts to shift towards arrayed CRISPR screens. The costs and workflow demands of an arrayed CRISPR screen are higher, requiring—among other things—automation of cell transduction and gRNA library and Cas9 dispensing into plates. However, discovery programs are willing to tackle these obstacles, given advantages of arrayed CRISPR screening such as simpler hit deconvolution, consumption of fewer cells (useful when employing primary cell or iPSC models), and versatility with respect to the type of assays that can be applied—including high content imaging and other phenotypic approaches not amenable to a pooled format.
Several initiatives from AstraZeneca demonstrated this push, including the inflammasome campaign mentioned above. In another project, they have designed an arrayed CRISPR screens to scout out genes that make tumor cells resistant to T-cell killing, or conversely, uncover genes that can enhance CAR-T cell efficiency (called CAR-T “armoring”). By using arrayed CRISPR screening in T-cell and tumor cell co-cultures, they can incorporate multiple readouts, including live-cell imaging of cytotoxicity assays, measurement of multiple cytokines, and immunotyping by flow cytometry. In yet another presentation about CRISPR screening, GSK also previewed efforts to leverage the benefits of arrayed over pooled CRISPR.
Finally, whether the assay approach of choice is HT-MS, pooled, plate-based, phenotypic, or beyond, workflow automation and digitalization are crucial if you want to take advantage of cutting-edge technology, maximize efficiency, and enhance drug discovery output. We saw this reflected in high attendance for talks dealing with topics such as modular labs, workflow optimization, cloud labs, digital pipelines, standards, and enterprise software. This includes our own tutorial on how to generate AI-Ready data and jump-start automated assay cascades in the digital lab.
Revisit SLAS 2021!
One of the silver linings of a SLAS 2021 was that more of Genedata’s international team was able participate and learn about the advances listed above. So, despite all the challenges the world has faced this year, we’re excited and encouraged to see the drug discovery world continue to bring its best—even, as we learned at this year’s meeting, taking a lead role in fighting the pandemic.
Another perk of an online conference: since talks are available on-demand, if you participated but missed some of the talks we’ve pointed out (links below), you can go back and check them out.
Mention of companies or research organizations in this article does not indicate their endorsement of Genedata or its products. Presentations mentioned here have been selected based on our opinion of their scientific and technological interest.
Author: Ada Yee, Ph.D., Scientific Story Researcher, Genedata Screener.