Membrane proteins are without a doubt an important drug target: about 60% of all confirmed drug targets are located on the cell surface. However, studying these proteins in vitro has long been challenging due to…
SMR Meeting: Molecular Glues
In person Molecular glues and targeted protein degraders are revolutionizing the field of drug discovery, offering promising solutions for a range of diseases, including cancer, infectious, inflammatory, and neurodegenerative diseases. These innovative therapies are particularly beneficial for targeting previously “undruggable” pathogenic proteins. The recent emergence of the ‘molecular glue’ class of protein degraders is paving…
PRMT5: Capturing Out-of-Range Target Engagement Kinetics for an Advanceable Clinical Candidate
Challenge
Our client requested characterization of the oncology clinical candidate MRTX1719’s interaction with two forms of Protein Arginine Methyl Transferase 5 (PRMT5), bound to either SAM (PRMT5•SAM) or MTA (PRMT5•MTA).
SPR (Surface Plasmon Resonance) direct measurement was not feasible due to the slow dissociation rate (koff) of MRTX1719 from both PRMT5 complexes. The dissociation rate was too slow, causing minimal dissociation during single-cycle kinetics, which prevented accurate koff determination.
Achievements
To overcome this problem an adapted SPR chaser assay was implemented. This strategy indirectly measured the dissociation rate constant (koff) and allowed for the determination of the affinity of MRTX1719 for both complexes.
Tackling the Hard-to-Drug Frontier: The Power of Complementary Screening Modalities
Developing small-molecule drugs for hard-to-drug targets remains one of the toughest challenges in modern drug discovery. Targets like cytokines, transcription factors, and scaffolding proteins often lack well-defined…