DYR684 is a potent, and selective PROTAC degrader of DYRK1 with KD of 6.3/16 nM for DYRK1A/DYRK1B, DC50 value of 12.3 nM for DYRK1A in HEK293 cells.
The maximum percentage of degradation (Dmax) is ∼90% for DYRK1A and ∼50% for DYRK1B.
DYR684 does not alter the cellular levels of DCAF7 (a.k.a. WDR68), an adaptor protein that forms stoichiometric complexes with DYRK1A and DYRK1B.
DYRK1B-p65 is resistant to DYR684-induced degradation.
DYR684 induces proteasomal degradation of DYRK1 via CRBN-mediated ubiquitination.
DYR684 (0-100 nM) inhibits downstream target of DYRK1A/B, phosphorylation of SF3B1 on Thr434 in HEK293 cells.
