Date

Monday 13 Oct 2025

Time

15:15 - 15:45

Location

BW029

Supervisor

Sylvestre Bonnet

2nd reviewer

Hermen Overkleeft

Jury

Remus Dame

Proteasome inhibitors, such as bortezomib and carfilzomib have successfully been used to treat human multiple myeloma. Yet, they have failed to treat solid tumors due to side effects, and resistance. Coordinating these highly potent inhibitors to photoactivated ruthenium-based complexes allows to reach high treatment dosage with accurate spatio-temporal control, minimizing side effects and circumventing resistance. Carfilzomib derivatives containing a 4-pyridyl-L-alanine at position P2 (L1) and a methionine at position P3 (L2), together with bortezomib, were caged with [Ru(baptpy)], forming far-red light-activatable chemotherapeutics. In this thesis, these three complexes were assessed on inhibitory potency with activity-based protein profiling, and on photocytotoxicity with MTT assays on human malignant melanoma A375 cells. Free inhibitors L1 and L2 without cage were nearly as potent as carfilzomib. Caged bortezomib, although partly degraded, still exhibited a promising photoindex. Caged L1 exhibited promising in vitro inhibition, but was still highly potent in caged formation according to ABPP. The caged L2 inhibitor revealed instability in the dark in ABPP assay-mimicking conditions, and resulted in high photoindexes in ABPP assays.