High-Throughput Screening Services for Molecular Glues & Degraders

Targeted protein degraders, molecular glues, and other induced-proximity modalities have significant potential to expand the pharmaceutical toolbox, enabling previously undruggable proteins to be readily targeted for therapeutic intervention. However, the discovery and development of these powerful modalities pose distinct challenges to researchers. One way that teams can accelerate research timelines is by partnering with specialized CROs like Momentum Biotechnologies, who have specific expertise in high-throughput screening techniques relevant to TPD and glue discovery. These CROs have cutting-edge instrumentation, validated workflows, and decades of scientific experience that can meaningfully accelerate the process of discovering promising leads.  As a result, novel therapeutics can progress from bench to bedside faster and more efficiently. Below, we’ll explore several of the CRO services for high-throughput screening offered by Momentum Biotechnologies to support the discovery of molecular glues, targeted protein degraders, and other allied modalities.

Affinity Selection Mass Spectrometry (ASMS) Screening for Molecular Glue & Degrader Discovery

Affinity selection mass spectrometry, or ASMS, is a powerful technique for the high-throughput screening of non-covalent compounds against a wide variety of targets, including DNA/RNA oligos, multi-protein and protein-oligo complexes, and challenging proteins such as membrane proteins and intrinsically disordered proteins (IDPs). This mass spectrometry-based approach enables the rapid, label-free screening of small-molecule compounds with minimal need for assay optimization. As a CRO, Momentum Biotechnologies has established specialized ASMS workflows for molecular glue discovery, leveraging a screen/counterscreen approach that allows the efficient identification of promising glue leads.

Momentum’s ASMS screening services is also well-suited for the discovery of chemistries that can be subsequently developed into targeted degraders; once a ligand is discovered by ASMS, it can be incorporated into a heterobifunctional degrader (such as a PROTAC) or another similar molecule. ASMS can also be used to screen E3 ligases and identify binders for downstream development. Momentum Biotechnologies is an expert CRO service provider of ASMS screening with deep experience serving clients to advance drug discovery and development programs. Momentum offers a 400K in-house small-molecule screening library, as well as compound management services to facilitate the screening of client and third-party libraries.

Intact-MS Covalent Screening for Covalent Degrader Discovery

While PROTACs and similar targeted protein degraders have traditionally incorporated non-covalent ligands as a protein-targeting domain, more recent variations on this technology have instead leveraged covalent warheads to achieve their therapeutic effects. This strategy can be particularly valuable for otherwise ‘undruggable’ targets that lack appropriate binding pockets. Both reversible and irreversible covalent inhibitors have been exploited as targeted protein degraders. Core to the development of these modalities is the discovery of covalent ligands capable of binding a target of interest. To facilitate the discover of promising covalent chemistries, Momentum Biotechnologies offers Intact MS covalent screening. This mass spectrometry-based approach accurately and efficiently screens covalent binders, either from Momentum’s in-house 5.7K covalent fragment library or from client/third-party libraries. By partnering with Momentum Biotechnologies as a CRO, research teams can accelerate the discovery and development of powerful covalent TPD therapeutics.

ProteomeScout™-HT Phenotypic Screening for Molecular Glues & Degraders

Phenotypic screening is a powerful approach to drug discovery in which promising candidates are identified by their functional effect on a cellular phenotype, rather than by the direct assessment of target binding. For targeted protein degraders and degradation-inducing molecular glues, the relevant phenotype is a reduction of target protein levels (ideally in the absence of significant off-target activity). To facilitate this type of screening workflow, Momentum offers ProteomeScout™-HT, a high-throughput proteomic profiling technology.

ProteomeScout™-HT incorporates triple SILAC labeling, automated sample handling, and cutting-edge mass spectrometry instrumentation to enable high-throughput degrader screening with comprehensive proteome coverage. Thousands of compounds can be assessed per month, and complementary non-mulitplexed workflows are available for small-scale screens and targeted follow-up studies. This approach is well-suited for the systematic discovery and prioritization of targeted protein degraders and molecular glues. As a CRO partner, Momentum Biotechnologies has well-established workflows – including sample processing, analysis, and bioinformatics – to facilitate phenotypic screening experiments and ensure that research teams get the data they need to accelerate their therapeutic programs, especially for targets that have been historically challenging.

CHIPP Target Engagement Profiling for Molecular Glue & Degrader Discovery

In a target identification or deconvolution study, a compound of interest is exposed to the cellular proteome, and proteins that interact with that compound can be identified. Momentum Biotechnologies offers a unique technology for target identification, deconvolution, and selectivity analysis known as CHIPP, or Chaotrope-Induced Protein Precipitation & Proteome Profiling. In this approach, isothermal, reversible chemical denaturation is leveraged to enable sensitive drug target identification under near-physiological conditions with proteome-wide readout. The assay is performed in 96-well-plate format, meaning that it can be readily used as a front-line validation assay to systematically screen hundreds of primary screening hits.  In addition to assessing binding activity between a drug and its target, CHIPP reveals off-target interactions, de-risking drug discovery and development efforts. CHIPP also has specific applications in the degrader space, as it can be used to analyze and monitor ternary complex formation. Momentum Biotechnologies has experience performing CHIPP on a range of scales and with diverse drug classes to provide valuable program-advancing data to research teams.

 

To learn more about these technologies and how they can accelerate the discovery and development of targeted protein degraders, molecular glues, and more, connect with Momentum Biotechnologies’ scientific team.

 

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