The Wide World of ASMS, Part 2: Even More Applications of ASMS Screening for Therapeutic Innovation

In last month’s blog post – The Wide World of ASMS – we discussed how affinity selection mass spectrometry (ASMS) can provide powerful support for the discovery and development of RNA- and DNA-targeting drugs, drugs targeting multi-protein (or protein:oligo) complexes, and targeted protein degraders. This month, we’ll continue to explore the diverse applications of ASMS, highlighting its utility in the identification and optimization of molecular glues, radiotherapeutics, and membrane protein-targeting drugs.

What is ASMS?

Affinity selection mass spectrometry (ASMS) is a biophysical assay that leverages the analytic power of mass spectrometry to identify small molecules that bind a target of interest. The approach is solution-based, eliminating the need for target or compound immobilization, as well as label-free; these features ensure that ASMS detects physiologically relevant binders rapidly and effectively. In addition to the efficient high-throughput screening of compound libraries, ASMS can be used at lower throughput for the targeted validation and characterization of leads, including as an orthogonal confirmation assay for hits identified by alternative screening approaches, such as DEL screening and functional screening.

ASMS for Molecular Glues 

Molecular glues are small molecule drugs that induce or enhance protein-protein interactions, typically resulting in a target protein being routed for degradation. A common strategy for molecular glues is to strengthen interactions between a disease-associated target protein and an E3 ligase; however, the technique can be applied to any two protein partners, including both natively interacting partners and novel partners whose interaction is induced by the molecular glue itself. While the first molecular glues were mechanistically elucidated over three decades ago, advances in large-scale screening, chemical biology, and bioengineering have made their discovery and optimization increasing feasible in recent years. However, screening for molecular glues continues to pose unique challenges.

One technology that can accelerate the discovery and development of molecular glues is ASMS screening. To this end, Momentum has developed a paired screening/counterscreening approach intended to facilitate the effective identification of molecular glue candidates. In this approach, complex proteins are screened together to identify all binders (primary screen), while individual targets are screened in parallel to identify binders of each component protein (counterscreen). By eliminating individual component binders from the hits identified in the primary screen, researchers can readily identify promising molecular glue candidates that bind interaction interfaces.

ASMS for Radiotherapeutics

Radiotherapeutics are a potent therapeutic modality (explored in more detail in our previous blog post) combining a radionuclide component with a targeting moiety to enable the specific delivery of radioactivity to a desired cell population. This can be done with the goal of killing targeted cells, as in the treatment of cancer, or to facilitate radio-imaging for diagnostic and theragnostic purposes. Radiotherapeutics have attracted significant interest in recent years, including applications extending beyond cancer treatment to the treatment of neurodegenerative, cardiovascular, and inflammatory diseases.

At Momentum, we have developed a powerful workflow that harnesses the analytic power of mass spectrometry for the discovery and development of radiotherapeutics. First, ASMS is used to identify small molecule ligands that bind a target of interest. Next, secondary ASMS screens are performed to interrogate the binding affinities of preliminary hits and prioritize further development. Target-specific ligands are then linked to lanthanides, which are used as surrogate payloads to support radiotherapeutic development without the safety and regulatory concerns associated with the use of radioactivity. Following treatment with these lanthanide-linked compounds, cell culture samples, biofluids, or tissue/tumor samples are subjected to ICP-MS (Inductively Coupled Plasma Mass Spectrometry), a highly sensitive elemental analysis technique compatible with complex biological matrices. Ultimately, this workflow provides a straightforward, sensitive approach for the identification and preclinical characterization of radiotherapeutics.

ASMS for Membrane Proteins

Membrane proteins represent a clinically valuable class of protein targets. In fact, as many as two-thirds of all currently approved drugs target proteins on the cell surface, with roughly 700 drugs targeting a single family of membrane receptors (the G protein coupled receptors, or GPCRs). However, the effective discovery and development of drugs targeting membrane proteins remains challenging for several reasons. These proteins are typically large, flexible, and contain both hydrophobic and hydrophilic regions, making their successful expression and stabilization difficult to achieve. This, in turn, hinders high-throughput screening efforts, as well as the structural characterization work necessary to support structure-based drug design.

To address these challenges, Momentum has partnered with Cube Biotech, an expert service provider whose innovative NativeMP™ technology enables the effective solubilization and stabilization of membrane proteins without compromising native conformation. By expressing target proteins in a copolymer-based nanodisc, this approach allows otherwise challenging targets to be effectively screened via ASMS. In collaboration with Cube, Momentum has successfully applied this strategy to discover and validate small-molecule binders of the GLP1 receptor, an extremely relevant target in the treatment of obesity and type 2 diabetes.

Why ASMS?

Affinity selection mass spectrometry (ASMS) is a powerful technology that can be leveraged for the discovery and validation of small molecule drug candidates, including for the specialized applications described above. With no labeling requirements, minimal assay development, and superior analytical precision, this approach supports both high-throughput primary screening, secondary confirmation, and orthogonal validation of hits identified in other assays (e.g., DEL and functional screens). ASMS is compatible with challenging or non-traditional targets, such as RNA oligos and membrane proteins, and identified leads can be readily developed into cutting-edge therapeutic modalities, including targeted protein degraders, radiotherapeutics, and more. Thanks to our team’s extensive experience harnessing ASMS to advance a range of drug discovery and development projects, we are well positioned to help accelerate your research efforts with this methodology.

To learn more about how ASMS could advance your drug discovery and development research, start a conversation with our scientific team.

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