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US 9,175,038 B2Granted
Peptide mimetic ligands of polo-like kinase 1 polo box domain and methods of use
AssigneeThe United States of America, as represented by the Secretary, Department of Health and Human Services
InventorsTerrence R. Burke, Jr., Fa Liu, Kyung S. Lee, Jung-Eun Park
Life of this patent
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Abstract
Found in various eukaryotic organisms, polo-like kinases (collectively, Plks) are a conserved subfamily of Ser/Thr protein kinases that play critical roles in cell proliferation. Provided herein are compounds that specifically inhibit the activity of Plks, specifically Plk1. Further provided herein are methods for use of the compounds for the treatment of hyperproliferative disorders, particularly cancer. Also provided are uses of the compounds for the preparation of a medicament.
Claims21
A compound comprising the structure:
- wherein
- Z is selected from the group consisting of:
- O, CH2, and CF2;
- R1X is selected from the group consisting of:
- R1—CH═N—O—;
- R1—CH2—CH2—O—;
- R1—C(O)—NH—O—;
- R1—CH2—CH2—CH2—;
- and R1—CH2—CH2—S—;
- R1 is selected from the group consisting of:
- Y is a group selected from the group consisting of:
- aryl, heteroaryl, lower alkyl, higher alkyl, lower alkene, higher alkene, halogen, amine, amide, carboxyl, olefin, and carbonyl;
- or any pharmaceutically acceptable salt thereof.
10 more elements
A compound comprising the structure:
- wherein:
- Z is selected from the group consisting of:
- O, CH2, and CF2;
- R1X is selected from the group consisting of:
- R1—CH2—CH2—CH2—;
- R1—CH2—CH2—CH2—CH2—;
- R1—CH2—CH2—S—;
- R1—CH═N—O—;
- R1—CH2—CH2—O—;
- and R1—C(O)—NH—O—;
- R1 is selected from the group consisting of:
- Y is a group selected from the group consisting of:
- aryl, heteroaryl, lower alkyl, higher alkyl, lower alkene, higher alkene, halogen, amine, amide, carboxyl, olefin, and carbonyl;
- or any pharmaceutically acceptable salt thereof.
11 more elements
A compound comprising the structure:
- wherein Z is selected from the group consisting of O, CH2, and CF2;
- R2 is a group selected from the group consisting of:
- wherein n=8, 1, 2, 3, 4, 5, 6, 7, 9, or 10;
- and
- Y is a group selected from the group consisting of:
- aryl, heteroaryl, lower alkyl, higher alkyl, lower alkene, higher alkene, halogen, amine, amide, carboxyl, olefin, and carbonyl;
- or any pharmaceutically acceptable salt thereof.
4 more elements
A compound comprising the structure:
- wherein Z is selected from the group consisting of O, CH2, and CF2;
- R1X is selected from the group consisting of R1—CH═N—O—;
- R1—CH2—CH2—O—;
- R1—C(O)—NH—O—;
- R1—CH2—CH2—CH2—;
- R1—CH2—CH2—S—;
- and
- R1 is a group selected from the group consisting of:
- and any compound A-1, A-2, A-3, A-4, A-5, A-6, A-7, A-8, A-9, A-10, A-11, A-12, A-13, A-14, A-15, A-16, A-17, A-18, A-19, A-20, A-21, A-22, A-23, A-24, A-25, A-26, A-27, A-28, A-29, A-30, A-31, A-31, A-33, A-34, A-35, A-36, A-37, A-38, A-39, A-40, and A-41 from Table A;
- and
- Y is a group selected from the group consisting of:
- aryl, heteroaryl, lower alkyl, higher alkyl, lower alkene, higher alkene, halogen, amine, amide, carboxyl, olefin, and carbonyl;
- or any pharmaceutically acceptable salt thereof.
10 more elements
A compound comprising the structure
- wherein Z is selected from the group consisting of O, CH2, and CF2;
- R1X is selected from the group consisting of R1—CH═N—O—;
- R1—CH2—CH2—O—;
- R1—C(O)—NH—O—;
- R1—CH2—CH2—CH2—;
- R1—CH2—CH2—S—
- R1 is a group selected from the group consisting of:
- and any compound A-1, A-2, A-3, A-4, A-5, A-6, A-7, A-8, A-9, A-10, A-11, A-12, A-13, A-14, A-15, A-16, A-17, A-18, A-19, A-20, A-21, A-22, A-23, A-24, A-25, A-26, A-27, A-28, A-29, A-30, A-31, A-31, A-33, A-34, A-35, A-36, A-37, A-38, A-39, A-40, and A-41 from Table A;
- and
- Y is a group selected from the group consisting of:
- aryl, heteroaryl, lower alkyl, higher alkyl, lower alkene, higher alkene, halogen, amine, amide, carboxyl, olefin, and carbonyl;
- or any pharmaceutically acceptable salt thereof.
9 more elements
A compound comprising the structure:
- wherein R1 is selected from the group consisting of
- and any compound A-1, A-2, A-3, A-4, A-5, A-6, A-7, A-8, A-9, A-10, A-11, A-12, A-13, A-14, A-15, A-16, A-17, A-18, A-19, A-20, A-21, A-22, A-23, A-24, A-25, A-26, A-27, A-28, A-29, A-30, A-31, A-31, A-33, A-34, A-35, A-36, A-37, A-38, A-39, A-40, and A-41;
- Y is a group selected from the group consisting of:
- aryl, heteroaryl, lower alkyl, higher alkyl, lower alkene, higher alkene, halogen, amine, amide, carboxyl, olefin, and carbonyl;
- R1—X is selected from the group consisting of R1—CH═N—O—;
- R1—CH2—CH2—O—;
- R1—C(O)—NH—O—;
- R1—CH2—CH2—CH2—;
- R1—CH2—CH2—S—;
- R1-lower alkyl chain;
- R1-higher alkyl chain;
- and R1-lower heteroalkyl or R1-higher heteroalkyl wherein said heteroalkyl comprises a group selected from the group consisting of:
- alkenyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, amide, ester, oxime, ether or thioether;
- AA1 is an amino acid selected from the group consisting of Cys, Asp, Glu, Phe, Gly, His, Ile, Lys, Leu, Met, Asn, Pro, Gln, Arg, Ser, Thr, Val, Trp, and Tyr;
- AA2 is an amino acid selected from the group consisting of His, Gln, Ala, Cys, Glu, Phe, Ile, Met, Asn, Ser, Thr, Val, and Tyr;
- Z is selected from the group consisting of O, CH2, and CF2;
- R3 is selected from the group consisting of —CH3 and —H;
- and
- R5 is selected from the group consisting of —H or Gly;
- or any pharmaceutically acceptable salt thereof.
17 more elements
A compound comprising the structure:
- R1—X is selected from the group consisting of R1—CH═N—O—;
- R1—CH2—CH2—O—;
- R1—C(O)—NH—O—;
- R1—CH2—CH2—CH2—;
- R1—CH2—CH2—S—;
- R1-lower alkyl chain;
- R1-higher alkyl chain;
- and R1-lower heteroalkyl or R1-higher heteroalkyl wherein said heteroalkyl comprises a group selected from the group consisting of:
- alkenyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, amide, ester, oxime, ether or thioether;
- R1 is selected from the group consisting of
- and any compound A-1, A-2, A-3, A-4, A-5, A-6, A-7, A-8, A-9, A-10, A-11, A-12, A-13, A-14, A-15, A-16, A-17, A-18, A-19, A-20, A-21, A-22, A-23, A-24, A-25, A-26, A-27, A-28, A-29, A-30, A-31, A-31, A-33, A-34, A-35, A-36, A-37, A-38, A-39, A-40, and A-41;
- Y is a group selected from the group consisting of:
- aryl, heteroaryl, lower alkyl, higher alkyl, lower alkene, higher alkene, halogen, amine, amide, carboxyl, olefin, and carbonyl;
- R3 is H or any acyl group;
- Z is O, CH2, and CF2;
- AA1 is a natural amino acid selected from the group consisting of Cys, Asp, Glu, Phe, Gly, His, Ile, Lys, Leu, Met, Asn, Pro, Gln, Arg, Ser, Thr, Val, Trp, and Tyr;
- and any non-natural amino acid except alanine analogs;
- AA2 is an amino acid selected from the group consisting of His, Gln, Ala, Cys, Glu, Phe, Ile, Met, Asn, Ser, Thr, Val, and Tyr;
- and
- R5 is selected from the group consisting of —H or Gly;
- or any pharmaceutically acceptable salt thereof.
18 more elements
A compound comprising the structure:
- wherein R1—X is selected from the group consisting of R1—CH═N—O—;
- R1—CH2—CH2—O—;
- R1—C(O)—NH—O—;
- R1—CH2—CH2—CH2—;
- R1—CH2—CH2—S—;
- R1-lower alkyl chain;
- R1-higher alkyl chain;
- and R1-lower heteroalkyl or R1-higher heteroalkyl wherein said heteroalkyl comprises a group selected from the group consisting of:
- alkenyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, amide, ester, oxime, ether or thioether;
- R1 is selected from the group consisting of:
- and any compound A-1, A-2, A-3, A-4, A-5, A-6, A-7, A-8, A-9, A-10, A-11, A-12, A-13, A-14, A-15, A-16, A-17, A-18, A-19, A-20, A-21, A-22, A-23, A-24, A-25, A-26, A-27, A-28, A-29, A-30, A-31, A-31, A-33, A-34, A-35, A-36, A-37, A-38, A-39, A-40, and A-41;
- Y is a group selected from the group consisting of:
- aryl, heteroaryl, lower alkyl, higher alkyl, lower alkene, higher alkene, halogen, amine, amide, carboxyl, olefin, and carbonyl
- Z is selected from the group consisting of O, CH2, and CF2;
- AA1 is a natural amino acid selected from the group consisting of Cys, Asp, Glu, Phe, Gly, His, Ile, Lys, Leu, Met, Asn, Pro, Gln, Arg, Ser, Thr, Val, Trp, and Tyr;
- and any non-natural amino acid except alanine analogs;
- AA2 is an amino acid selected from the group consisting of His, Gln, Ala, Cys, Glu, Phe, Ile, Met, Asn, Ser, Thr, Val, and Tyr;
- R3 is selected from the group consisting of —H and CH3;
- and
- R5 is H or glycine;
- or any pharmaceutically acceptable salt thereof.
18 more elements
A compound selected from the group consisting of:
- Z is selected from the group consisting of O, CH2, and CF2;
- or a pharmaceutically acceptable salt thereof, or
- A compound comprising
- wherein R7 is selected from the group consisting of:
- or a pharmaceutically acceptable salt thereof, or
- A compound comprising a compound selected from the group consisting of:
- n is 7 or 8;
- Z is selected from the group consisting of O, CH2, and CF2;
- or a pharmaceutically acceptable salt thereof, or
- A compound comprising a compound selected from the group consisting of:
- n is 2-10;
- Z is selected from the group consisting of O, CH2, and CF2;
- or a pharmaceutically acceptable salt thereof, or
- A compound comprising the structure:
- or a pharmaceutically acceptable salt thereof, or
- A compound comprising the structure:
- wherein R1 is selected from the group consisting of:
- and an R1 group derived from any aldehyde provided herein;
- or any pharmaceutically acceptable salt thereof, or
- A compound comprising structure:
- R9 is H or acetyl;
- and R8 is selected from the group consisting of:
- or any pharmaceutically acceptable salt thereof, or
- A compound selected from the group consisting of:
- wherein R10 comprises —(CH2)n-Ph wherein n=2, 3, 4, 5, 6, or 7;
- or any pharmaceutically acceptable salt thereof, or
- A compound selected from the group consisting of:
- or any pharmaceutically acceptable salt thereof, or
- A compound comprising a structure of any of the compounds in a table selected from the group consisting of
26 more elements
Dependencies are inferred from the claim text.