pan-RAF/MEK molecular glue NST-628

An orally bioavailable non-covalent non-degrading pan-RAF/mitogen-activated protein kinase kinase (MAP2K, MAPK/ERK kinase, or MEK) dual molecular glue, with potential antineoplastic activity. Upon oral administration, pan-RAF/MEK molecular glue NST-628 targets and glues A-RAF, B-RAF and C-RAF protein kinases with unphosphorylated MEK1, forming a stable and inactive RAF-MEK complex. This prevents the phosphorylation and activation of MEK by RAF, inhibits the activity of MEK, thereby preventing the activation of MEK-dependent effector proteins and transcription factors, which may result in the inhibition of growth factor-mediated cell signaling and tumor cell proliferation. Oncogenic mutations in RAF plays a key role in the overactivation of the RAS-mitogen-activated protein kinase (MAPK) pathway and drives tumor cell proliferation and survival. MEK1/2 are dual-specificity threonine/tyrosine kinases that play key roles in the activation of the RAS/RAF/MEK/ERK pathway that regulates cell growth. This pathway is often dysregulated in a variety of tumor cell types through BRAF, KRAS and NRAS mutations. NST-628 is able to cross the blood-brain barrier (BBB).