Peptide mimetic ligands of polo-like kinase 1 polo box domain and methods of use
View Patent ↗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.
1. A compound comprising the structure:
wherein
Z is selected from the group consisting of: O, CH 2 , and CF 2 ;
R 1 X is selected from the group consisting of: R 1 —CH═N—O—; R 1 —CH 2 —CH 2 —O—; R 1 —C(O)—NH—O—; R 1 —CH 2 —CH 2 —CH 2 —; and R 1 —CH 2 —CH 2 —S—;
R 1 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.
2. The compound of claim 1 , wherein
Z is O; and
R 1 is selected from the group consisting of a-1, a-2, a-3, a-4, a-5, a-6, and a-7;
or any pharmaceutically acceptable salt thereof.
3. The compound of claim 1 , wherein the compound is selected from the group consisting of
and any pharmaceutically acceptable salt thereof.
4. A compound comprising the structure:
wherein:
Z is selected from the group consisting of: O, CH 2 , and CF 2 ;
R 1 X is selected from the group consisting of: R 1 —CH 2 —CH 2 —CH 2 —; R 1 —CH 2 —CH 2 —CH 2 —CH 2 —; R 1 —CH 2 —CH 2 —S—; R 1 —CH═N—O—; R 1 —CH 2 —CH 2 —O—; and R 1 —C(O)—NH—O—;
R 1 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.
5. The compound of claim 4 , wherein
Z is O; and
R 1 is selected from the group consisting of a-1, a-2, a-3, a-4, a-5, a-6, and a-7;
or any pharmaceutically acceptable salt thereof.
6. The compound of claim 4 , wherein:
Z is O;
R 1 X is selected from the group consisting of R 1 —CH 2 —CH 2 —CH 2 — or R 1 —CH 2 —CH 2 — CH 2 —CH 2 —;
and R 1 is a-1, wherein the compound has the structure of
or any pharmaceutically acceptable salt thereof.
7. A compound comprising the structure:
wherein Z is selected from the group consisting of O, CH 2 , and CF 2 ;
R 2 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.
8. The compound of claim 7 , wherein Z is O; or any pharmaceutically acceptable salt thereof.
9. The compound of claim 7 , wherein Z is O, R 2 is a-1, and n=8, wherein the compound has the structure of
or any pharmaceutically acceptable salt thereof.
10. A compound comprising the structure:
wherein Z is selected from the group consisting of O, CH 2 , and CF 2 ;
R 1 X is selected from the group consisting of R 1 —CH═N—O—; R 1 —CH 2 —CH 2 —O—; R 1 —C(O)—NH—O—; R 1 —CH 2 —CH 2 —CH 2 —; R 1 —CH 2 —CH 2 —S—; and
R 1 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.
11. The compound of claim 10 ,
wherein Z is O; and
R 1 is a group selected from the group consisting of a-1, a-2, a-3, a-4, a-5, a-6, and a-7;
or any pharmaceutically acceptable salt thereof.
12. A compound comprising the structure
wherein Z is selected from the group consisting of O, CH 2 , and CF 2 ;
R 1 X is selected from the group consisting of R 1 —CH═N—O—; R 1 —CH 2 —CH 2 —O—; R 1 —C(O)—NH—O—; R 1 —CH 2 —CH 2 —CH 2 —; R 1 —CH 2 —CH 2 —S—
R 1 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.
13. The compound of claim 12 ,
wherein Z is O; and
R 1 is a group selected from the group consisting of a-1, a-2, a-3, a-4, a-5, a-6, and a-7;
or any pharmaceutically acceptable salt thereof.
14. A compound comprising the structure:
wherein R 1 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;
R 1 —X is selected from the group consisting of R 1 —CH═N—O—; R 1 —CH 2 —CH 2 —O—; R 1 —C(O)—NH—O—; R 1 —CH 2 —CH 2 —CH 2 —; R 1 —CH 2 —CH 2 —S—; R 1 -lower alkyl chain; R 1 -higher alkyl chain; and R 1 -lower heteroalkyl or R 1 -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;
AA 1 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;
AA 2 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, CH 2 , and CF 2 ;
R 3 is selected from the group consisting of —CH 3 and —H; and
R 5 is selected from the group consisting of —H or Gly;
or any pharmaceutically acceptable salt thereof.
15. A compound comprising the structure:
R 1 —X is selected from the group consisting of R 1 —CH═N—O—; R 1 —CH 2 —CH 2 —O—; R 1 —C(O)—NH—O—; R 1 —CH 2 —CH 2 —CH 2 —; R 1 —CH 2 —CH 2 —S—; R 1 -lower alkyl chain; R 1 -higher alkyl chain; and R 1 -lower heteroalkyl or R 1 -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;
R 1 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;
R 3 is H or any acyl group;
Z is O, CH 2 , and CF 2 ;
AA 1 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;
AA 2 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
R 5 is selected from the group consisting of —H or Gly;
or any pharmaceutically acceptable salt thereof.
16. A compound comprising the structure:
wherein R 1 —X is selected from the group consisting of R 1 —CH═N—O—; R 1 —CH 2 —CH 2 —O—; R 1 —C(O)—NH—O—; R 1 —CH 2 —CH 2 —CH 2 —; R 1 —CH 2 —CH 2 —S—; R 1 -lower alkyl chain; R 1 -higher alkyl chain; and R 1 -lower heteroalkyl or R 1 -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;
R 1 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, CH 2 , and CF 2 ;
AA 1 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;
AA 2 is an amino acid selected from the group consisting of His, Gln, Ala, Cys, Glu, Phe, Ile, Met, Asn, Ser, Thr, Val, and Tyr;
R 3 is selected from the group consisting of —H and CH 3 ; and
R 5 is H or glycine;
or any pharmaceutically acceptable salt thereof.
17. A compound selected from the group consisting of:
Z is selected from the group consisting of O, CH 2 , and CF 2 ;
or a pharmaceutically acceptable salt thereof, or
A compound comprising
wherein R 7 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, CH 2 , and CF 2 ;
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, CH 2 , and CF 2 ;
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 R 1 is selected from the group consisting of:
and an R 1 group derived from any aldehyde provided herein;
or any pharmaceutically acceptable salt thereof, or
A compound comprising structure:
R 9 is H or acetyl;
and R 8 is selected from the group consisting of:
or any pharmaceutically acceptable salt thereof, or
A compound selected from the group consisting of:
wherein R 10 comprises —(CH 2 ) 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
18. A composition comprising a compound of claim 1 in a pharmaceutically acceptable carrier.
19. A method for inhibiting Plk1 polo-box domain function in a cell comprising contacting the cell with a composition comprising any of the compounds of claim 1 .
20. A kit comprising at least one compound of claim 1 and instructions for use.
21. A chemical library including two or more compounds of claim 1 .