Cullin-ring e3 ubiquitin ligase 4 inhibitor compounds and methods of their use
AssigneeIcahn School of Medicine at Mount Sinai
InventorsRobert J. DEVITA, Zhen-Qiang PAN, Khoi Q. HUYNH, Moses MOUSTAKIM, Kenneth WU, Chalada SUEBSUWONG, Benjamin D. HOPKINS, Peng-Jen CHEN, Michael Block LAZARUS
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Abstract
Disclosed herein are compounds that inhibit cullin-RING E3 ubiquitin ligase 4, a method of inhibiting the catalytic activity of a Cullin-RING E3 Ubiquitin (Ub) Ligase (CRL) in a cell, compositions comprising the inhibitor compounds, a method of treating a tumor, and a method of treating a subject for cancer.
Claims47
A compound of formula (I) having the following structure:
- or a stereoisomer, pharmaceutically acceptable salt, oxide, or solvate thereof, wherein
- R1 is H,
- R2 is H or CF3;
- R3, R4, R5, and R6 are each independently selected from the group consisting of H, OH, OAc, alkoxy, OTf, and ONa;
- R7, R8, and R9 are each independently selected from H, C1-C6 alkyl, pyridine, or
- wherein the benzene ring of
- is optionally substituted one or more times with C1-C6 alkyl, NH2, CF3, halogen, CN, C(O)NH2, and alkoxy;
- and
- n is 0 or 1;
- with the proviso that when R3 and R4 are H, R5 and R6 are OH, and R2 is CF3, R1 is not
A method of inhibiting the catalytic activity of a Cullin-RING E3 Ubiquitin (Ub) Ligase (CRL) in a cell, said method comprising:
- contacting a cell with a compound of formula (II) having the following structure:
- or a stereoisomer, pharmaceutically acceptable salt, oxide, or solvate thereof, wherein
- R1 and R2 are each independently H, CF3,
- wherein the benzene ring of
- is optionally substituted with NO2 or halogen;
- R3, R4, R5, and R6 are each independently selected from the group consisting of H, halogen, OH, C1-C6 alkyl, OAc, NaO, OTf, and alkoxy, wherein two adjacent alkoxy groups may be taken together to form a heterocycle;
- R7, R8, and R9 are each independently selected from H, C1-C6 alkyl, pyridine, or
- wherein the benzene ring of
- is optionally substituted one or more times with C1-C6 alkyl, NH2, CF3, halogen, CN, C(O)NH2, and alkoxy;
- X is either present or absent, and when present is CH2 or O;
- and
- n is 0 or 1;
- under conditions effective to inhibit activity of the CRL in the cell.
A method of treating a subject for cancer, said method comprising:
- administering to a subject in need of treatment for cancer a compound of formula (II) having the following structure:
- or a stereoisomer, pharmaceutically acceptable salt, oxide, or solvate thereof, wherein
- R1 and R2 are each independently H, CF3,
- wherein the benzene ring of
- is optionally substituted with NO2 or halogen;
- R3, R4, R5, and R6 are each independently selected from the group consisting of H, halogen, OH, C1-C6 alkyl, OAc, NaO, OTf, and alkoxy, wherein two adjacent alkoxy groups may be taken together to form a heterocycle;
- R7, R8, and R9 are each independently selected from H, C1-C6 alkyl, pyridine, or
- wherein the benzene ring of
- is optionally substituted one or more times with C1-C6 alkyl, NH2, CF3, halogen, CN, C(O)NH2, and alkoxy;
- X is either present or absent, and when present is C or O;
- and
- n is 0 or 1;
- under conditions effective to treat the subject for cancer.
A compound having a structure selected from the group consisting of
A method of inhibiting the catalytic activity of a Cullin-RING E3 Ubiquitin (Ub) Ligase (CRL) in a cell, said method comprising:
- contacting a cell with a compound selected from the group consisting of
- under conditions effective to inhibit activity of the CRL in the cell.
A method of treating a subject for cancer, said method comprising:
- administering to a subject in need of treatment for cancer a compound selected from the group consisting of
- under conditions effective to treat the subject for cancer.
Dependencies are inferred from the claim text.