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
Life of this patent
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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 stemness. Similarly, peptides and mimetics of the PPxY motif would be able to inhibit sternness. Disclosed are compounds that affect the Yap1:Oct4 interaction.
Claims18
A compound having Formula I
- R1 is C1-C8 alkyl, C1-C8 alkenyl, C1-C8 alkynyl, C1-C8 alkoxyl, C1-C8 heteroalkyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, aryl, or heteroaryl, any of which is optionally substituted with one or more carbonyl (C=O), C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxyl, amino, —NR6R7, —C(O)NR6R7, C1-C6 alkylhydroxy, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, aryl, heteroaryl, halo, hydroxyl, thiol, cyano, nitro, or radiolabeled isotope;
- R2 is amino, hydroxyl, C1-C8 alkyl, C1-C8 alkenyl, C1-C8 alkynyl, C1-C8 alkoxyl, C1-C8 heteroalkyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, aryl, or heteroaryl, any of which is optionally substituted with one or more carbonyl (C=O), carboxyl (—CO2-), ester (CO2R6), C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxyl, amino, —NR6R7, —C(O)NR6R7, C1-C6 alkylC3-6cycloalkyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, aryl, heteroaryl, C1-6 alkylaryl, halo, hydroxyl, thiol, cyano, nitro, or radiolabeled isotope;
- each R3 is, independently, hydrogen, halogen, OH, C1-C8 alkyl, C1-C8 alkoxyl, aryl, O-aryl, heteroaryl, O-heteroaryl, O-CH2aryl, or O-CH2heteroaryl;
- and
- R6 and R7 are independently selected from hydrogen, C1-C8 alkyl, C1-C8 alkenyl, C1-C8 alkynyl, C1-C8 alkoxide, C1-C8 carboxylate, C1-C8 haloalkyl, C1-C8 haloalkenyl, C1-C8 haloalkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, aryl, C1-C3 alkylheteroaryl, or heteroaryl;
- any of which is optionally substituted with a halogen;
- and n is 1-5.
Dependencies are inferred from the claim text.