Pyrazolo[1,5-a]pyrimidin-7(4H)-one, 5-(4-cyclohexylphenyl)-3-[[3-(fluoromethyl)-1-azetidinyl]carbonyl]-2-(3-methyl-2-pyrazinyl)-

GNE-7883 is a pan-TEAD inhibitor that blocks the association of YAP/TAZ with TEAD. GNE-7883 effectively reduces chromatin accessibility at TEAD motifs, inhibits cell proliferation in multiple cell line models, and achieves strong anti-tumor efficacy in vivo. In addition, GNE-7883 effectively overcomes intrinsic and acquired resistance to KRAS (Kirsten rat sarcoma viral oncogene homolog) G12C inhibitors in multiple preclinical models by inhibiting YAP/TAZ activation[1][2][3].

YAP/TAZ-TEAD

[1] Hagenbeek TJ, et al. An allosteric pan-TEAD inhibitor blocks oncogenic YAP/TAZ signaling and overcomes KRAS G12C inhibitor resistance. Nat Cancer. 2023 Jun;4(6):812-828. DOI:10.1038/s43018-023-00577-0
[2] McGee L E. YAP Signaling Promotes Resistance to MEK Inhibition in NF1-Related MPNSTs[M]. Van Andel Research Institute, 2023.
[3] Barry E R, et al. Recent therapeutic approaches to modulate the Hippo pathway in oncology and regenerative medicine[J]. Cells, 2021, 10(10): 2715. DOI:10.3390/cells10102715