Optimization of TEAD P‑Site Binding Fragment
Hit into In Vivo Active Lead MSC-4106
Posted on 2022-06-28 - 17:34
The dysregulated Hippo pathway and,
consequently, hyperactivity
of the transcriptional YAP/TAZ-TEAD complexes is associated with diseases
such as cancer. Prevention of YAP/TAZ-TEAD triggered gene transcription
is an attractive strategy for therapeutic intervention. The deeply
buried and conserved lipidation pocket (P-site) of the TEAD transcription
factors is druggable. The discovery and optimization of a P-site binding
fragment (1) are described. Utilizing structure-based
design, enhancement in target potency was engineered into the hit,
capitalizing on the established X-ray structure of TEAD1. The efforts
culminated in the optimized in vivo tool MSC-4106, which
exhibited desirable potency, mouse pharmacokinetic properties, and
in vivo efficacy. In close correlation to compound exposure, the time-
and dose-dependent downregulation of a proximal biomarker could be
shown.
CITE THIS COLLECTION
DataCite
3 Biotech
3D Printing in Medicine
3D Research
3D-Printed Materials and Systems
4OR
AAPG Bulletin
AAPS Open
AAPS PharmSciTech
Abhandlungen aus dem Mathematischen Seminar der Universität Hamburg
ABI Technik (German)
Academic Medicine
Academic Pediatrics
Academic Psychiatry
Academic Questions
Academy of Management Discoveries
Academy of Management Journal
Academy of Management Learning and Education
Academy of Management Perspectives
Academy of Management Proceedings
Academy of Management Review
Heinrich, Timo; Peterson, Carl; Schneider, Richard; Garg, Sakshi; Schwarz, Daniel; Gunera, Jakub; et al. (2022). Optimization of TEAD P‑Site Binding Fragment
Hit into In Vivo Active Lead MSC-4106. ACS Publications. Collection. https://doi.org/10.1021/acs.jmedchem.2c00403
or
Select your citation style and then place your mouse over the citation text to select it.
SHARE
Usage metrics
Read the peer-reviewed publication
AUTHORS (28)
TH
Timo Heinrich
CP
Carl Peterson
RS
Richard Schneider
SG
Sakshi Garg
DS
Daniel Schwarz
JG
Jakub Gunera
AS
Anita Seshire
LK
Lisa Kötzner
SS
Sarah Schlesiger
DM
Djordje Musil
HS
Heike Schilke
BD
Benjamin Doerfel
PD
Patrizia Diehl
PB
Pia Böpple
AL
Ana R. Lemos
PS
Pedro M. F. Sousa
FF
Filipe Freire
TB
Tiago M. Bandeiras
EC
Emma Carswell
NP
Nicholas Pearson
KEYWORDS
proximal biomarker couldmouse pharmacokinetic propertiesdysregulated hippo pathwayconserved lipidation pockettead transcription factorsexhibited desirable potencyvivo active lead4106 btead complexestarget potencyvivo toolvivo efficacyutilizing structuretherapeutic interventionray structureestablished xefforts culminateddependent downregulationdeeply buriedcompound exposureclose correlationbased designattractive strategy