YAP1 inhibitors that target the interaction of YAP1 with OCT4
AssigneeH. Lee Moffitt Cancer Center and Research Institute, Inc.
InventorsSrikumar Chellappan, Nicholas J. Lawrence, Sujeewa Ranatunga Mahanthe Mudiyanselage
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Abstract
Binding of the transcriptional co-activator, YAP1, to the transcription factor Oct4, induces Sox2, which is a transcription actor necessary for the self-renewal of stem-like cells from non-small cell lung cancer. The WW domain of YAP1 binds to the PPxY motif of Oct4 to induce Sox2. Delivering a peptide corresponding to the WW domain could prevent the induction of Sox2 and sternness. Similarly, peptides and mimetics of the PPxY motif would be able to inhibit sternness. Disclosed are compounds that affect the Yap1:Oct4 interaction.
Claims29
A compound of Formula I,
- wherein,
- the dash line is a bond that is present or absent;
- n is 0, 1, or 2;
- Ar is phenyl, pyridinyl, pyrimidinyl, or pyrazinyl;
- R1 is C1-C8 alkyl, C3-C6 cycloalkyl, or C6 aryl, and of which is optionally substituted with one or more groups chosen from halo, hydroxyl, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxyl, C1-C6 haloalkoxyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, C6 aryl, heteroaryl, OCH2-C6 aryl, or O—CH2-heteroaryl;
- R2 is halo, OH, C1-C8 alkyl, C1-C8 alkoxyl, C6 aryl, O—C6 aryl, heteroaryl, O-heteroaryl, O—CH2-C6 aryl, or O—CH2-heteroaryl;
- and
- R3 is CH2OH, CO2H, CO2-C1-C6 alkyl, CO2-C3-C6 cycloalkyl, or CO2-C1-C6 heteroalkyl,
- or a pharmaceutically acceptable salt thereof.
Dependencies are inferred from the claim text.