Phenotypic Hit Identification and Optimization of Novel Pan-TEAD and Subtype-Selective Inhibitors

Aiming to identify novel inhibitors of YAP-TEAD-dependent
transcription,
we conducted a TEAD-reporter-based cellular screen, which yielded
a 5-azaindole hit that significantly stabilized TEAD subtypes 2 and
4 in a thermal shift assay. During optimization, derivatives with
diverse TEAD selectivity profiles were obtained, including pan-TEAD
and TEAD3-sparing inhibitors. Atropisomers with stabilized binding
conformations surprisingly resulted in TEAD2 selective inhibitors.
Cellular potency in reporter and viability assays was enhanced through
targeted structural modifications. The physicochemical and pharmacokinetic
properties were improved by the introduction of heteroatoms and the
reduction of aromaticity. Structure-based considerations inspired
the generation of a pyrrolo-pyridinone scaffold with further optimized
properties. In lung cancer xenograft studies, representatives from
both substance classes demonstrated monotherapeutic antitumor activity.
For one selected example, the combination effect with the KRASG12C inhibitor sotorasib was demonstrated in vivo.