Is your protein degrader effectively driving the biology you desire?
Confirming target engagement with either the POI or the E3 ligase using CETSA® Navigate HT
CETSA® Navigate HT leverages on homogeneous bead-based approaches, such as AlphaLISA®, for protein detection and allows for primary screening in high throughput to identify binders to either the POI or the E3 ligase. With the AlphaLISA® protein detection kits, one can also, in the same cells, monitor the compound-mediated degradation of the POI and identify the optimal concentration to achieve effective degradation, thus assessing the relevant pharmacology.
Selectivity profiling and MoA studies using CETSA® Explore
it is possible to simultaneously identify direct binding events to both the POI and the E3 ligase and potential off-targets, or to observe downstream effects from direct binding interactions as well as from the removal of the POI by PROTAC®-mediated degradation [1]. The proteome effects of BSJ-03-204 in K562 cells were further investigated with CETSA® Explore in both intact and lysed K562 cells, by incubating these matrices with up to 30 μM of the PROTAC® for 60 and 15 minutes, respectively.
Pelago Bioscience is your partner to increase the likelihood for drug success
- The prevention of failure at later stages of clinical development is of paramount importance in early drug discovery.
- Morgan et al. [2] have laid the ground for three pillars of survival for a successful program when reaching Phase II: (1) exposure at target site of action (cell penetration), (2) binding to the pharmacological target (target engagement and selectivity), and (3) expression of pharmacology.
- Later, Bunnage et al. [3] expanded the concept to other chemical probes like PROTACs® with the addition of a fourth pillar: expression of relevant phenotype.
- Pelago Bioscience is set to be your drug discovery research partner and offers a range of assays to support all these pillars, building trust and assuring the efficacy of your molecules from the early stages of development.
How can I measure degradation efficiency? Download our protein degradation application note.
Publications
- Chernobrovkin, Alexey L. et al. SLAS discovery : advancing life sciences R & D vol. 26,4 (2021): 534-546. doi:10.1177/2472555220984372
- Morgan, Paul et al. Drug discovery today vol. 17,9-10 (2012): 419-24. doi:10.1016/j. drudis.2011.12.020
- Bunnage, Mark E et al. Nature chemical biology vol. 9,4 (2013): 195-9. doi:10.1038/ nchembio.1197