Expanding the Chemical Space of Transforming Growth Factor-β (TGFβ) Receptor Type II Degraders with 3,4-Disubstituted Indole Derivatives

TL;DR

This study expands the chemical space of TGFβ receptor type II degraders by identifying new indole-based compounds that effectively inhibit TGFβ signaling in cancer cells.

Contribution

The paper introduces two novel 3,4-disubstituted indole chemotypes as potent TβRII degraders.

Findings

Compounds 2r and 3n selectively degrade TβRII without affecting TβRI.

The new degraders block endothelial-to-mesenchymal transition and cell migration in cancer cells.

They do not disrupt the microtubule network, indicating good selectivity.

Abstract

The TGFβ type II receptor (TβRII) is a central
player
in all TGFβ signaling downstream events, has
been linked to cancer progression, and thus, has emerged as an auspicious
anti-TGFβ strategy. Especially its targeted degradation presents
an excellent goal for effective TGFβ pathway inhibition. Here,
cellular structure–activity relationship (SAR) data from the
TβRII degrader chemotype 1 was successfully transformed
into predictive ligand-based pharmacophore models that allowed scaffold
hopping. Two distinct 3,4-disubstituted indoles were identified from
virtual screening: tetrahydro-4-oxo-indole 2 and indole-3-acetate 3. Design, synthesis, and screening of focused amide libraries
confirmed 2r and 3n as potent TGFβ
inhibitors. They were validated to fully recapitulate the ability
of 1 to selectively degrade TβRII, without affecting
TβRI. Consequently, 2r and 3n efficiently
blocked endothelial-to-mesenchymal transition and cell migration in
different cancer cell lines while not perturbing the microtubule network.
Hence, 2 and 3 present novel TβRII
degrader chemotypes that will (1) aid target deconvolution efforts
and (2) accelerate proof-of-concept studies for small-molecule-driven
TβRII degradation in vivo.

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