Peptide mimetic ligands of polo-like kinase 1 polo box domain and methods of use

Patent metadata

Field	Value
Publication number	US-10266565-B2
Application number	US-201214111540-A
Country	US
Kind code	B2
Filing date	Apr 12, 2012
Priority date	Apr 12, 2011
Publication date	Apr 23, 2019
Grant date	Apr 23, 2019

Abstract

Novel compounds are provided that bind to polo-like kinases through the polo-box domain. In certain embodiments, the novel compounds are PEGylated peptides. The PEGylated peptides in accordance with the invention demonstrate high PBD-binding affinity. In certain embodiments, the PEGylated peptides have also achieved activities in whole cell systems. The invention also provides compounds that bind polo-like kinases through the polo-box domain and possess reduced anionic charge. Further provided are methods of design and/or synthesis of the PEGylated peptides and methods of use thereof. The invention provides methods of use of the compounds and methods of synthesis of the compounds.

First claim

We claim:

1. A compound of Formula (a):

wherein
Z is O, CH 2 , or CF 2 ;
R 1 is

B is H, (C 1-6 )alkyl,

or hydrosulfide-(C 1-6 )alkyl-C(O)—NH—(C 1-6 )alkyl, wherein each (C 1-6 )alkyl moiety, independently, is further optionally substituted by an amino or N-Fmoc-amino group;
n′ is an integer selected from 5-20;
R′—X 3 is R′, R′—CH═N—O—, R′—(C 1-6 )alkyl-O—, R′—C(O)—NH—O—, R′—(C 1-6 )alkyl-S—, or R′—(C 1-6 )alkyl;
R′ is H, H 2 NO—, (C 2-6 )alkenyl, phenyl-(C 0-6 )alkyl, furanyl-(C 0-6 )alkyl, thiophenyl-(C 0-6 )alkyl, N-indolyl-(C 1-6 )alkyl, fluorenyl, (C 3-8 )cycloalkyl, imidazolyl, quinolinyl, pyridinyl, pyrimidinyl, dioxo-pyrimidinyl, phenanthrenyl, or bicyclo[2.2.1]hept-2-enyl, wherein R′ is further optionally substituted by one or more substituents selected from the group of halogen, (C 6-10 )aryl, heteroaryl, (C 1-6 )alkyl, (C 1-6 )alkoxy, hydroxyl, hydrosulfide, (C 1-6 )alkoxy-carbonyl, cyano, (C 6-10 )aryl-(C 1-6 )alkoxy, hydroxyl(C 1-6 )alkyl, trifluoromethyl, amino, and nitro; and
G is H, alkenyl-(C 1-20 )alkyl, (C 1-6 )alkoxy-carbonyl-(C 1-20 )alkyl, hydroxyl-carbonyl-(C 1-20 )alkyl, amino(C 1-20 )alkyl, aryl-(C 1-20 )alkyl, (C 1-20 )alkyl, or heretoaryl-(C 1-20 )alkyl, wherein each of alkyl, aryl and heretoaryl moieties is optionally substituted by one or more halogen, hydroxyl or alkoxy groups;
or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof.

2. The compound of claim 1 , wherein
Z is O or CH 2 ;
n′ is an integer between 5 and 20;
B is (C 1-6 )alkyl,

R′—X 3 is R′, R′—CH═N—O—, R′—C(O)—NH—O—, or R′—(CH 2 ) 2 —O—;
R′ is H, H 2 NO—, or phenyl-(C 1-6 )alkyl; and
G is H.

3. The compound of claim 2 , wherein said compound is selected from the group of

wherein n′, each independently, is an integer selected from 5-8; or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof.

4. The compound of claim 2 , wherein said compound is

or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof.

5. The compound of claim 1 , wherein
Z is O or CH 2 ;
n′ is an integer between 5 and 20,
B is (C 1-6 )alkyl, or hydrosulfide-(C 1-6 )alkyl-C(O)—NH—(C 1-6 )alkyl, wherein each (C 1-6 )alkyl moiety, independently, is further optionally substituted by an amino or N-Fmoc-amino group;
R′—X 3 is R′, R′—CH═N—O—, R′—C(O)—NH—O—, or R′—(CH 2 ) 2 —O—;
R′ is H, H 2 NO—, or phenyl-(C 1-6 )alkyl; and
G is alkenyl-(C 1-10 )alkyl, hydroxyl-carbonyl-(C 1-6 )alkyl, amino(C 1-6 )alkyl, aryl-(C 1-10 )alkyl, (C 1-10 )alkyl, or heretoaryl-(C 1-10 )alkyl; wherein each alkyl moiety is further optionally substituted by one or more hydroxyl or amino groups.

6. The compound of claim 5 , wherein Z is O; R′—X 3 is H; and B is methyl,

7. The compound of claim 6 , wherein said compound has one of the following structures:

wherein n′, each independently, is an integer selected from 5-8; or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof.

8. The compound of claim 6 , wherein said compound is

or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof.

9. The compound of claim 5 , wherein Z is O; R′—X 3 is H; and B is hydrosulfide-(C 1-6 )alkyl-C(O)—NH—(C 1-6 )alkyl, wherein the (C 1-6 )alkyl moiety is substituted by amino.

10. The compound of claim 9 , wherein said compound is

or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof.

11. A composition comprising the compound of claim 1 in a pharmaceutically acceptable carrier.

12. A kit comprising at least one compound of claim 1 and instructions for use.

13. A chemical library comprising two or more compounds of claim 1 .

14. The compound of claim 1 , wherein R′ is H, H 2 NO—, (C 2-6 )alkenyl, phenyl-(C 0-6 )alkyl, furanyl-(C 0-6 )alkyl, thiophenyl-(C 0-6 )alkyl, N-indolyl-(C 1-6 )alkyl, fluorenyl, (C 3-8 )cycloalkyl, imidazolyl, quinolinyl, pyridinyl, pyrimidinyl, dioxo-pyrimidinyl, phenanthrenyl, or bicyclo[2.2.1]hept-2-enyl.

Assignees

• Burke Jr Terrence R
• Liu Fa
• Lee Kyung S
• Park Jung Eun
• The Us Secretary Department Of Health & Human Services

Inventors

• Burke Jr Terrence R
• Liu Fa
• Lee Kyung S
• Park Jung-Eun

Classifications

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07K1/006 Primary

  of peptides containing derivatised side chain amino acids · CPC title

• C12Y207/11021

  Polo kinase (2.7.11.21) · CPC title

• C12N9/12

  transferring phosphorus containing groups, e.g. kinases (2.7) · CPC title