Small Molecule Inhibitors Selective For Polo-Like Kinase Proteins
Disclosed are small molecule PLK inhibitors that can target the polo box domain (PBD). Inhibitors can have an atomic mass of about 1000 Da or less and a general structure of For instance, the inhibitors can include an alkyl benzamido benzoic acid core structure.
1 . A small molecule PLK inhibitor having the general structure:
wherein
R 1 comprises an alkyl, —O-alkyl, —S-alkyl, or —NH-alkyl, and optionally includes a terminal aryl;
R 8 and R 9 are independently hydrogen, alkyl, OH, NH 2 , SH, —S-alkyl, —O-alkyl, —NH-alkyl, —CONH-alkyl, halogen, or —CN;
X is an amide, —C1 to C4 alkyl-NH—, —NH—, —SNH—, —SONH—, or —SO 2 N—;
R 7 is selected from the following structures:
in which
R 2 through R 6 are independently selected from hydrogen, carboxyl, alkyl, alkyl ester, hydroxyl, methoxy, halogen, sulfonamide, phosphate, nitro, methylamine, or boronic acid, and
R 10 is C or N, and R 3 is relevant only when R 10 is C;
2 . The small molecule PLK inhibitor of claim 1 , wherein the small molecule inhibitor is selective for PLK1.
3 . The small molecule PLK inhibitor of claim 1 , wherein R 1 is a C3 to C8 alkyl group, R 8 and R 9 are hydrogen, R 7 is a), R 2 is carboxyl, R 3 through R 6 are independently selected from hydrogen, hydroxyl, methoxy, halogen, nitro, or alkyl, R 10 is C, and X is an amide linkage.
4 . The small molecule PLK inhibitor of claim 1 , wherein at least one of R 2 through R 6 is a C3 to C8 alkyl group.
5 . The small molecule PLK inhibitor of claim 4 , wherein R 4 is a methyl group.
6 . The small molecule PLK inhibitor of claim 1 , wherein the small molecule inhibitor is selective for PLK3.
7 . The small molecule PLK inhibitor of claim 6 , wherein R 1 comprises a C6 to C12 alkyl, R 8 and R 9 are hydrogen, R 7 is a), R 2 is hydrogen or carboxyl, R 3 through R 6 are independently selected from hydrogen, carboxyl, methyl, or hydroxyl, R 10 is C, and X an amide linkage.
8 . The small molecule PLK inhibitor of claim 7 , wherein R 1 comprises a C10 to C12 alkyl.
9 . The small molecule PLK inhibitor of claim 1 , wherein the inhibitor has an atomic mass of about 1000 Daltons or less.
10 . The small molecule PLK inhibitor of claim 1 , wherein the inhibitor has an atomic mass of about 500 Daltons or less.
11 . The small molecule PLK inhibitor of claim 1 , wherein the inhibitor has a polar surface area of about 200 Å or less.
12 . The small molecule PLK inhibitor of claim 1 , wherein the inhibitor has a polar surface area of about 100 Å or less.
13 . The small molecule PLK inhibitor of claim 1 , wherein the inhibitor induces apoptosis.
14 . The small molecule PLK inhibitor of claim 1 , wherein the inhibitor has the following structure:
wherein
R 1 comprises an alkyl, —O-alkyl, —S-alkyl, or —NH-alkyl, and optionally includes a terminal aryl;
R 2 through R 6 are independently selected from hydrogen, carboxyl, alkyl, alkyl ester, hydroxyl, methoxy, halogen, sulfonamide, phosphate, nitro, methylamine or boronic acid; and
X is an amide, —C1 to C4 alkyl-NH—, —NH—, —SNH—, —SONH—, or —SO 2 N—.
15 . The small molecule PLK inhibitor of claim 14 , wherein R 1 is C3 to C8 alkyl and X is an amide.
16 . The small molecule PLK inhibitor of claim 1 , wherein the inhibitor has the following structure:
wherein
R 1 comprises an alkyl, —O-alkyl, —S-alkyl, or —NH-alkyl, and optionally includes a terminal aryl;
R 7 is selected from: