Drug developers are creating a new class of compounds that disrupt a protein-protein interaction in the Hippo pathway that goes awry in cancers and fibrotic diseases. At least two programs are poised to enter the clinic next year, and the companies are honing their patient selection strategies.
The aim is to block the interaction between transcriptional activator YAP1 and transcription factor TEAD, which constitutes the most downstream event in the Hippo signaling pathway and drives transcription of proliferation and survival genes.
Activation of YAP1 in adult tissues is usually a bad sign. The Hippo pathway’s major function is developmental. It controls organ size by driving proliferation until the cells have reached a certain density, at which point other signals turn it off (see Figure: “Hippo: Development to Disease”).
Activated YAP1 is present in 85% of uveal melanomas, 70% of mesotheliomas and in subsets of patients across a wide array of cancer types. Overactivation can drive pediatric tumors, and FDA listed the four TEAD family members, TEAD1-4, in its October guidelines on pediatric cancer targets (see "FDA's Pediatric Target Picks").
Fibrotic diseases also stand to benefit from modulating the pathway, particularly non-alcoholic steatohepatitis (NASH) where companies are testing anti-proliferative agents (see "New Partners for NASH").
Inhibiting YAP1 directly is difficult because it has no targetable pockets, and no companies have active programs with YAP1 inhibitors, according to BioCentury’s BCIQ database.
“There has been a lot of interest in this pathway from academics