When Georg Halder (VIB & KU Leuven) identified a series of fruit fly mutants exhibiting markedly enlarged head structures reminiscent of a hippopotamus, he named the mutant gene Hippo. Together with collaborators, he went on to elucidate the core components of what is now known as the conserved growth control Hippo signaling pathway. In humans, Hippo signaling serves to restrain oncogenic YAP/TEAD transcription, and loss-of-function mutations in Hippo components (such as NF2 or LATS1/2) are associated with highly aggressive tumors, such as mesothelioma.

Based on these insights, Georg proposed to CD3 to take on YAP/TEAD as a drug target. Unlike enzymatic components of cell signaling pathways, such as kinases, effectively inhibiting a transcriptional complex such as YAP/TEAD was, at the time, unprecedented.

Building a First-in-Class Drug Discovery Program

In less than five years, CD3 and the Halder Lab jointly:

• Developed a rational strategy to target YAP/TEAD transcription through engaging the palmitoylation pocket of all four TEAD isoforms
• Established assays to measure small-molecule binding to the TEAD palmitoylation pocket, along with a full assay cascade to quantify YAP/TEAD inhibition in cancer cells and in tumors in vivo.
• Screened and rationally designed novel small-molecule TEAD binders
• Optimized those binders with iterative drug discovery cycles towards potent, selective and orally bioavailable drug-like pan-TEAD inhibitors
• Demonstrated selective impairment of growth of Hippo-mutant cancers in vitro and in vivo with selected examples of proprietary chemical series of TEAD inhibitors

Clinical translation: Licensing by SpringWorks Therapeutics

Recognizing the strong therapeutic potential, SpringWorks Therapeutics licensed the TEAD inhibitor program in 2021. CD3 and the Halder Lab continued to work closely with the SpringWorks team to ensure a smooth transition from discovery to clinical development.

Into the Clinic: SW-682

Today, thanks to the combined efforts of the Halder Lab, CD3, and SpringWorks Therapeutics, the TEAD inhibitor SW-682 has advanced into Phase 1 clinical development in cancer patients. This marks a significant milestone for an idea originating at VIB/KU Leuven, and underscores how strong partnerships between academia and CD3 can accelerate the transition of groundbreaking science into real therapeutic opportunities for patients.