Development of a Quantitative High-Throughput Kinase Panel to Assess Degrader Selectivity

Degradation selectivity is an essential criterion in targeted protein degradation (TPD) to determine which compounds progress during drug development. To assess degradation selectivity, mass spectrometry-based methods can be used to quantitatively monitor protein abundance. Multiple reaction monitoring (MRM) targeted proteomics is commonly used to detect multiple peptides—often simultaneously—within a single method, enabling quantitative readouts for a diverse set of proteins in a single assay. The ability to multiplex these measurements allows for the design of highly curated protein panels, that can quantitate collections of proteins to determine degrader selectivity. Additionally, the robust and reproducible nature of MRM triple quadrupole mass spectrometry (QqQ) makes it ideal for high-throughput screening for degrader optimization.

Nurix Therapeutics developed a quantitative kinase panel with over 45 unique proteins for degrader screening and analysis using an Agilent 6495 series QqQ LCMS. Our data demonstrates the ability to quantify kinase abundance across multiple cell matrices, an essential step in determining matrix sensitivity and on-target selectivity in TPD molecule development.

Presenter: Paul Auger (Director of Early Discovery Mass Spectrometry, Nurix Therapeutics)

Paul is currently the Director of Early Discovery Mass Spectrometry at Nurix Therapeutics where he guides programs through the early stages of research to help identify potential drug candidates as they move towards the clinic. He has been working in the field of mass spectrometry for more than 25 years and received his BA from St. Mary’s College of Maryland and his MS from Johns Hopkins University. His career has spanned more than two decades with stops at Denali, creating and building out a proficient proteomics team to lead all facets of the R&D pipeline in targeted and untargeted proteomics; Genentech, building quantitative proteomic assays for therapeutic candidates in the neuro and ophthalmology therapeutic areas; and Amgen, where he honed his skills in both targeted and untargeted mass spectrometry for biomarker discovery and assay development.