Evading growth supressors
beyond MM, opportunity for histology-
agnostic trials in biomarker selected
enabled by structure
based drug design and optimization
Aberrant YAP TEAD transcriptional activity is responsible for primary tumor growth or resistance to targeted therapies
The Hippo pathway regulates cell proliferation and apoptosis during normal development. In approximately 10% of all human cancers, dysregulation of this pathway promotes tumor growth, metastasis, and resistance to therapies. Inactivation of upstream negative regulators in the Hippo pathway results in binding of the transcription co-activator YAP to TEAD transcription factors in the nucleus, consequently activating a pro-growth and anti-apoptotic transcriptional program.
Mutations in the neurofibromatosis 2 (NF2) gene inactivate the upstream regulator, Merlin. NF2 mutations are prevalent in approximately 40% of malignant mesotheliomas and could serve as a biomarker for sensitivity to YAP-TEAD inhibition.
Opna’s small molecule program inhibits TEAD
TEAD proteins control the ultimate transcriptional output of the Hippo pathway and are more amenable to small molecule inhibition than YAP proteins or the YAP-TEAD interaction interface. Directly inhibiting TEAD function using Opna’s proprietary small molecules is a compelling strategy in combating cancers driven by dysregulated Hippo signaling.