Peptide and peptide mimetic binding antagonists of polo-like kinase 1 polo box domain and methods of use

Patent metadata

Field	Value
Publication number	US-10047122-B2
Application number	US-201414776512-A
Country	US
Kind code	B2
Filing date	Mar 14, 2014
Priority date	Mar 14, 2013
Publication date	Aug 14, 2018
Grant date	Aug 14, 2018

Abstract

The invention provides novel compounds that may serve as anticancer therapeutics. The compounds of the invention bind to polo-like kinases through the polo-box domain. In certain embodiments, the compounds of the invention are POM-protected peptide derivatives. The use of cationic bis-alkyl his residues in combination with a mono POM-protected phophoryl group results in a peptide possessing an overall neutral charge. The peptide derivatives of the invention have achieved both good efficacy and an enhanced bioavailability. The invention also provides methods of use, compositions, and kits thereof. Further, the invention provides a novel method of design and/or synthesis of phosphoryl-derived peptide derivatives useful as therapeutic agents.

First claim

We claim:

1. A compound of Formula (A′):

wherein
X is O, —(C 1-6 )alkyl-, or —C(Y) 2 —; wherein Y, for each occurrence independently, is F, Cl, or Br;
X 1 is H, (C 1-6 )alkyl-C(O)—, or a polyethylene glycol moiety or a derivative thereof;
R 1 and R 2 , each independently, are selected from the group of H, (C 1-6 )alkyl-C(O)O—(C 1-6 )alkyl-, (C 1-20 )alkyl, aryl-(C 1-20 )alkyl-, heteroaryl-(C 1-20 )alkyl, X 2 O—C(O)—(C 1-6 )alkyl-, and amino(C 1-6 )alkyl, wherein each alkyl moiety that appears at the R 1 and R 2 positions is further optionally substituted by one or more carboxyl, hydroxyl, or alkoxy groups, and wherein R 1 and R 2 cannot both be H;
X 2 is H or (C 1-6 )alkyl; wherein the (C 1-6 )alkyl is optionally substituted by one or more hydroxyl, halo, or alkoxy groups;
R 3 is H, —OH, (C 1-6 )alkyl-C(O)O—, or (C 1-6 )alkoxy;
R 4 is H, acyl, (C 1-6 )alkyl-OC(O)O—, or (C 1-6 )alkyl-O—C(S)—O—;
R 5 and R 6 , each independently, are selected from the group of H, (C 1-6 )alkyl-C(O)—, (C 1-6 )alkoxy-(C 1-6 )alkyl, X 3 ═N—O—(C 1-6 )alkyl, an amino acid, and a glycine moiety;

wherein X 3 is derived from a sugar moiety;
R a is H, aryl-(C 1-20 )alkyl, heteroaryl-(C 1-20 )alkyl, (C 1-20 )alkyl, allyl-(C 1-20 )alkyl, (C 0-20 )alkoxy-C(O)—(C 1-20 )alkyl, or amino(C 1-20 )alkyl; wherein each of the said alkyl, aryl, and heteroaryl moieties is further optionally substituted by one or more same or different subtituents selected from the group of (C 1-6 )alkyl, carboxyl, halo, hydroxyl, amine, and (C 1-6 )alkoxy groups;
R b is a member selected from the group of allyl-(C 1-6 )alkyl, aryl-(C 1-6 )alkyl-, heteroaryl-(C 1-6 )alkyl, and (C 1-6 )alkyl optionally substituted by one or more carboxyl, (C 1-6 )alkoxyl, or hydroxyl groups;
R 7 and R 8 , each independently, are selected from the group of H, (C 1-6 )alkyl, and (C 1-6 )alkyl-C(O)—; and
R 9 is a bond, 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, (C 1-6 )alkyl, halo, amino-O—, (C 1-6 )alkyl-C(O)—, (C 2-6 )alkenyl, cycloalkyl, heterocyclic, aryl-(C 0-6 )alkyl, or heretoaryl-(C 0-6 )alkyl, wherein each of said alkyl, cycloalkyl, heterocyclic, aryl and heteroaryl moieties is optionally substituted by one or more same or different substituents selected from the group of aryl, heteroaryl, hydroxyl, hydrosulfide, alkyl, alkoxy, alkenyl, halogen, nitro, cyano, ester, amine, amide, carboxyl, and alkyl-carbonyl groups;
or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof.

2. The compound of any one of claim 1 , wherein X 1 is CH 3 C(O)—, and R 7 and R 8 are both H.

3. The compound of claim 1 wherein said compound is a compound of Formula (B′):

Wherein
X is O or CH 2 ;
one of R 1 and R 2 is (C 1-6 )alkyl-C(O)O—(C 1-6 )alkyl- or H, and the other is selected from the group of H, (C 1-6 )alkyl, allyl-(C 1-6 )alkyl-, aryl-(C 1-6 )alkyl-, (C 1-6 )alkyl-C(O)O—(C 1-6 )alkyl-, and heteroaryl-(C 1-6 )alkyl-; wherein each alkyl moiety is further optionally substituted by one or more carboxyl, hydroxyl, or (C 1-6 )alkoxy groups, and wherein R 1 and R 2 cannot both be H;
R 3 is H, —OH, (C 1-6 )alkyl, (C 1-6 )alkyl-C(O)O—, or (C 1-6 )alkoxy;
R 4 is H or (C 1-6 )alkyl; and
R a is H, aryl-(C 1-10 )alkyl, aryl-(C 1-10 )alkyl, or heteroaryl-(C 1-10 )alkyl; wherein each of the said alkyl, aryl, and heteroaryl moieties is further optionally substituted by one or more same or different substituents selected from the group of carboxyl, hydroxyl, and (C 1-6 )alkoxy;
R b is a member selected from the group of allyl-(C 1-6 )alkyl, aryl-(C 1-6 )alkyl-, heteroaryl-(C 1-6 )alkyl, and (C 1-6 )alkyl optionally substituted by one or more carboxyl, (C 1-6 )alkoxyl, or hydroxyl groups;

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

4. The compound of claim 3 , wherein one of R 1 and R 2 is (C 1-6 )alkyl-C(O)O—(C 1-6 )alkyl-, and the other is selected from the group of H, (C 1-6 )alkyl-C(O)O—(C 1-6 )alkyl-, aryl-(C 1-6 )alkyl-, and (C 1-6 )alkyl optionally substituted by one or more hydroxyl groups.

5. The compound of claim 4 , wherein one of R 1 and R 2 is t-Bu-C(O)O—CH 2 — (“POM”), and the other is selected from the group of H, t-Bu-C(O)O—CH 2 —, —(CH 2 ) 2 OH, and benzyl.

6. The compound of claim 3 , wherein R 3 is H or —OH.

7. The compound of claim 3 , wherein R a is phenyl-(C 1-10 )alkyl.

8. The compound of claim 3 , wherein R b is (C 1-6 )alkyl optionally substituted by one or more (C 1-6 )alkoxyl or hydroxyl groups.

9. The compound of claim 3 , wherein R 4 is (C 1-6 )alkyl.

10. The compound of claim 3 , wherein said compound is selected from the group consisting of Compound Nos. A10-A12 as provided in Table 1:

TABLE 1

Comp.

No.
X
R 1
R 2
R 3
R a
R b

A10
O
POM
H
OH
Ph(CH 2 ) 8 —

A11
O
POM
H
H
Ph(CH 2 ) 8 —

A12
O
POM
H
OH
H

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

11. The compound o

Assignees

• The Us Secretary Department Of Health & Human Services

Inventors

• Qian Wenjian
• Park Jung Eun
• Lai Christopher C
• Kelley James A
• Lee Kyung S
• Burke Jr Terrence R

Classifications

• C12N9/1205

  Phosphotransferases with an alcohol group as acceptor (2.7.1), e.g. protein kinases · CPC title

• C07K2319/50

  containing protease site · CPC title

• C07K7/06 Primary

  having 5 to 11 amino acids · CPC title

• C07K1/061

  using protecting groups · CPC title

• C07K2319/21

  containing a His-tag · CPC title