Turning eltrombopag into DCL1191, an oral inhibitor of the 'undruggable' TFEB
- TFEB, a transcription factor long seen as undruggable, was approached starting from eltrombopag, which has weak TFEB inhibitory activity alongside its Tpo-R agonism.
- SAR optimisation gave DCL1191, which binds TFEB, disrupts TFEB–DNA binding and shows reduced Tpo-R and MITF activity; modelling and mutagenesis support the binding mode.
- It represses TFEB target genes, blocks autophagic flux and is orally bioavailable, with activity in autophagy-hyperactivated glioblastoma cells.
💡 Points
Starting from a marketed drug with a known off-target is a smart way into a transcription factor, because you inherit drug-like properties. The real test is the MITF/TFE3 family: if selectivity over close paralogues holds, this is a genuine tool compound rather than another autophagy-flavoured cytotoxin.