TY  - JOUR
A1  - Schwalm, Martin P.
A1  - Berger, Lena Marie
A1  - Meuter, Maximilian N.
A1  - Vasta, James D.
A1  - Corona, Cesear R.
A1  - Röhm, Sandra
A1  - Berger, Benedict-Tilman
A1  - Farges, Frederic
A1  - Beinert, Sebastian M.
A1  - Preuß, Franziska Friederike
A1  - Morasch, Viktoria
A1  - Rogov, Vladimir V.
A1  - Mathea, Sebastian
A1  - Saxena, Krishna
A1  - Robers, Matthew B.
A1  - Müller, Susanne
A1  - Knapp, Stefan
T1  - A toolbox for the generation of chemical probes for Baculovirus IAP Repeat containing proteins
T2  - Frontiers in cell and developmental biology
N2  - E3 ligases constitute a large and diverse family of proteins that play a central role in regulating protein homeostasis by recruiting substrate proteins via recruitment domains to the proteasomal degradation machinery. Small molecules can either inhibit, modulate or hijack E3 function. The latter class of small molecules led to the development of selective protein degraders, such as PROTACs (PROteolysis TArgeting Chimeras), that recruit protein targets to the ubiquitin system leading to a new class of pharmacologically active drugs and to new therapeutic options. Recent efforts have focused on the E3 family of Baculovirus IAP Repeat (BIR) domains that comprise a structurally conserved but diverse 70 amino acid long protein interaction domain. In the human proteome, 16 BIR domains have been identified, among them promising drug targets such as the Inhibitors of Apoptosis (IAP) family, that typically contain three BIR domains (BIR1, BIR2, and BIR3). To date, this target area lacks assay tools that would allow comprehensive evaluation of inhibitor selectivity. As a consequence, the selectivity of current BIR domain targeting inhibitors is unknown. To this end, we developed assays that allow determination of inhibitor selectivity in vitro as well as in cellulo. Using this toolbox, we have characterized available BIR domain inhibitors. The characterized chemical starting points and selectivity data will be the basis for the generation of new chemical probes for IAP proteins with well-characterized mode of action and provide the basis for future drug discovery efforts and the development of PROTACs and molecular glues.
KW  - IAP
KW  - E3 Ligase
KW  - PROTAC
KW  - Ubiquitin
KW  - NanoBRET
Y1  - 2022
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/71735
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-717359
SN  - 2296-634X
VL  - 10
IS  - art. 886537
SP  - 1
EP  - 13
PB  - Frontiers Media
CY  - Lausanne
ER  -