TY - JOUR
T1 - TEAD–YAP Interaction Inhibitors and MDM2 Binders from DNA-Encoded Indole-Focused Ugi Peptidomimetics
AU - Kunig, Verena B.K.
AU - Potowski, Marco
AU - Akbarzadeh, Mohammad
AU - Klika Škopić, Mateja
AU - dos Santos Smith, Denise
AU - Arendt, Lukas
AU - Dormuth, Ina
AU - Adihou, Hélène
AU - Andlovic, Blaž
AU - Karatas, Hacer
AU - Shaabani, Shabnam
AU - Zarganes-Tzitzikas, Tryfon
AU - Neochoritis, Constantinos G.
AU - Zhang, Ran
AU - Groves, Matthew
AU - Guéret, Stéphanie M.
AU - Ottmann, Christian
AU - Rahnenführer, Jörg
AU - Fried, Roland
AU - Dömling, Alexander
AU - Brunschweiger, Andreas
PY - 2020/11/9
Y1 - 2020/11/9
N2 - DNA-encoded combinatorial synthesis provides efficient and dense coverage of chemical space around privileged molecular structures. The indole side chain of tryptophan plays a prominent role in key, or “hot spot”, regions of protein–protein interactions. A DNA-encoded combinatorial peptoid library was designed based on the Ugi four-component reaction by employing tryptophan-mimetic indole side chains to probe the surface of target proteins. Several peptoids were synthesized on a chemically stable hexathymidine adapter oligonucleotide “hexT”, encoded by DNA sequences, and substituted by azide-alkyne cycloaddition to yield a library of 8112 molecules. Selection experiments for the tumor-relevant proteins MDM2 and TEAD4 yielded MDM2 binders and a novel class of TEAD-YAP interaction inhibitors that perturbed the expression of a gene under the control of these Hippo pathway effectors.
AB - DNA-encoded combinatorial synthesis provides efficient and dense coverage of chemical space around privileged molecular structures. The indole side chain of tryptophan plays a prominent role in key, or “hot spot”, regions of protein–protein interactions. A DNA-encoded combinatorial peptoid library was designed based on the Ugi four-component reaction by employing tryptophan-mimetic indole side chains to probe the surface of target proteins. Several peptoids were synthesized on a chemically stable hexathymidine adapter oligonucleotide “hexT”, encoded by DNA sequences, and substituted by azide-alkyne cycloaddition to yield a library of 8112 molecules. Selection experiments for the tumor-relevant proteins MDM2 and TEAD4 yielded MDM2 binders and a novel class of TEAD-YAP interaction inhibitors that perturbed the expression of a gene under the control of these Hippo pathway effectors.
KW - combinatorial chemistry
KW - DNA-encoded library
KW - peptidomimetics
KW - protein–protein interaction inhibition
KW - Ugi reaction
UR - http://www.scopus.com/inward/record.url?scp=85087906122&partnerID=8YFLogxK
U2 - 10.1002/anie.202006280
DO - 10.1002/anie.202006280
M3 - Article
C2 - 32537835
AN - SCOPUS:85087906122
SN - 1433-7851
VL - 59
SP - 20338
EP - 20342
JO - Angewandte Chemie - International Edition
JF - Angewandte Chemie - International Edition
IS - 46
ER -