Methods and compositions for inhibition of the transitional endoplasmic reticulum ATPase
Compounds of Formulas I-XLIII are identified as direct inhibitors of p97 ATPase or of the degradation of a p97-dependent ubiquitin-proteasome system (UPS) substrate. Methods and compositions are disclosed for inhibiting p97 ATPase and the degradation of a p97-dependent UPS substrate, and for identifying inhibitors thereof.
1. A composition suitable for decreasing p97 ATPase activity and/or degradation of a p97 dependent ubiquitin-proteasome substrate, comprising: a compound of Formula VII, IX, XII, XX, XXI or XLIII, or a pegylated analog of the compound, a pharmaceutically acceptable salt of the compound or the analog, or any regioisomer or stereoisomer of the compound:
Wherein, for Formula VII, R 1 , n, X, and Y are selected from the group consisting of combinations listed in Table 7:
TABLE 7
Cpd #
R1
n
X
Y
VII-3
H
1
O
H, H
VII-4
H
1
NH
H, H
VII-5
8-OMe
1
NH
H, H
VII-6
8-OMe
1
O
H, H
VII-7
8-OH
1
O
H, H
VII-8
8-Ph
1
O
H, H
VII-9
8-OCH 2 CH 2 OH
1
O
H, H
VII-10
8OCH 2 CH 2 NEt 2
1
O
H, H
VII-11
8-p-OMePh
1
O
H, H
VII-12
8-OMe
1
NMe
H, H
VII-13
8-OMe
1
NCOMe
H, H
VII-14
8-OCH 2 CH 2 OMe
1
O
H, H
VII-16
8-OMe
0
NH
NH
VII-17
8-OMe
0
O
Y,Y together form
one O as oxygen of
carbonyl incorporating
both Y's
VII-15
8-n-Butyl
1
O
H, H
Wherein, for Formula XII, R 4 is selected from the group consisting of the moieties listed in Table 10:
TABLE 10.1
Cpd #
R4
Cpd #
R4
XII-4
XII-8
XII-7
XII-10
XII-2
XII-11
XII-9
Wherein for Formula XXI, R 1 is 5,6-dimethyl;
2. A composition of claim 1 , further comprising a pharmaceutically acceptable carrier.
3. A composition of claim 1 , wherein the isomer is a regioisomer or stereoisomer.
4. A composition of claim 1 , wherein the compound is represented by Formula VII or XXI.
5. A composition of claim 4 wherein the compound is represented by Formula VII.
6. A composition suitable for decreasing p97 ATPase activity and/or degradation of a p97 dependent ubiquitin-proteasome substrate, comprising: a compound of Formula LII, LVII, LVIII, LIX, LX, LXI, LXII or a pegylated analog of the compound, a pharmaceutically acceptable salt of the compound or the analog, or any regioisomer or stereoisomer of the compound:
Formula LII wherein N is 0, 1 or 2;
Formula LVII wherein X is oxygen or N—R′
wherein R′ is methyl, ethyl or phenyl; n is −1,
0, 1 or 2; m is 1, 2, 3 or 4; R 1 and R 2 are
independently selected from the group
consisting of hydrogen, methyl, fluoro, Chloro,
bromo and methoxy;
Formula LVIII wherein X is O, NR′ wherein
Formula LIX wherein R 1 , R 2 , R 3 are
R′ is methyl, ethyl or phenyl; n is −1, 0, 1 or 2;
independently selected from the group
m is 1, 2, 3 or 4; R 1 is hydrogen, methyl fluoro,
consisting of hydrogen, A(CH 2 ) n CH 3 and
chloro, bromo or methoxy
A(CH 2 ) n X wherein n is 0, 1, 2, 3, 4 or 5; A is
O, S or NH; and X is heteroaryl, O-alkyl, S-
alkyl, (O-alkyl) 2 or (S-alkyl) 2
Formula LX wherein, A 1 is O, S, Se, N, NH,
Formula LXI wherein R 1 , R 2 , R 3 are
CH, CH 2 , CHalkyl, or Calkyl; n is 1 or 2; A 2 is
independently selected from the group
N, NH, CH, or Calkyl; and R 1 is selected from
consisting of alkyl, alkoxyalkyl and
the group consisting of H, A(CH 2 ) m CH 3 , and
aminoalkyl
A(CH 2 ) n X, wherein A is O, S or NH and X is
heteroaryl, O(alkyl), S(alkyl), (O-alkyl) 2 , or (S-
alkyl) 2 ; and m is 0, 1, 2, 3, 4, or 5
Formula LXII wherein n is −1, 0, 1 or 2; m is
0, 1 or 2; and X is CH 2 , O or NR′; and R′ is
methyl, ethyl or phenyl.
7. A composition of claim 6 , further comprising a pharmaceutically acceptable carrier.
8. A composition of claim 6 , wherein the isomer is a regioisomer or stereoisomer.
9. A composition of claim 6 , wherein the compound is represented by Formula LII, LVII, LVIII or LXII.
10. A composition of claim 6 wherein the compound is represented by Formula LVII, LVIII or LXII.
11. A composition of claim 6 wherein the compound has formula LIX-A
12. A composition suitable for decreasing p97 ATPase activity and/or degradation of a p97 dependent ubiquitin-proteasome substrate, comprising: a compound of Formula VIII or a pegylated analog of the compound, a pharmaceutically acceptable salt of the compound or the analog, or any regioisomer or stereoisomer of the compound:
13. A composition of claim 1 wherein the compound of Formula VII, IX, XII, XX, XXI or XLIII is labeled with a fluorescent label selected from the group consisting of 4-chloro-7-nitor-2,1,3-benzoxadiaxole, R—NCO wherein the R group is a stable organic fluorescent group and R—NCS wherein the R group is a stable organic fluorescent group.
14. A composition of claim 1 wherein the compound of Formula VII, IX, XII, XX, XXI or XLIII is biotinylated with a biotin derivative selected from the group consisting of ester-biotin, amin-biotin, amide-biotin and hydroxyl-biotin.
15. A composition of claim 6 wherein the compound of Formula LII, LVII, LVIII, LIX, LX, LXI, LXII is labeled with a fluorescent label selected from the group consisting of 4-chloro-7-nitor-2,1,3-benzoxadiaxole, R—NCO wherein the R group is a stable organic fluorescent group and R—NCS wherein the R group is a stable organic fluorescent group.
16. A composition of claim 6 wherein the compound of Formula LII, LVII, LVIII, LIX, LX, LXI, LXII is biotinylated with a biotin derivative selected from the group consisting of ester-biotin, amine-biotin, amide-biotin and hydroxyl-biotin.
17. A composition of claim 12 wherein the compound of Formula VIII is labeled with a fluorescent label selected from the group consisting of 4-chloro-7-nitor-2,1,3-benzoxadiaxole, R—NCO wherein the R group is a stable organic fluorescent group and R—NCS wherein the R group is a stable organic fluorescent group.
18. A composition of claim 12 wherein the compound of Formula VIII is biotinylated with a biotin derivative selected from the group consisting of ester-biotin, amin-biotin, amide-biotin and hydroxyl-biotin.