INTRACELLULAR KINASE INHIBITORS
Intracellular kinase inhibitors and their therapeutic uses for patients with T cell malignancies, B cell malignancies, autoimmune disorders, and transplanted organs.
1 . A protein kinase inhibitor which has a structural formula selected from the group consisting of:
(a)
wherein R 3 , R 4 , R 5 , and R 6 are independently hydrogen or optionally substituted C 1 -C 6 alkyl, wherein R 22 is selected from hydrogen, C 1 -C 4 alkyl, —NR′R″, —COH, —COOH, —CNR′R″, and —CONHR′, and wherein R′ and R″ are independently selected from hydrogen and C 1 -C 4 alkyl;
(b)
wherein R 3 , R 4 , R 5 , and R 6 are as defined above and wherein R 24 is
(c)
wherein L is
and wherein R 3 , R 4 , R 5 , and R 6 are as defined above;
(d)
wherein T, U, V, and W independently are selected from hydrogen; halogen; —O; C 1 -C 3 alkyl; and C 1 -C 3 alkyloxy; and wherein R 25 is hydrogen or C 1 -C 3 alkyl;
(e)
wherein T, U, V, and W independently are selected from hydrogen; halogen; —O; C 1 -C 3 alkyl; and C 1 -C 3 alkyloxy; and wherein R 8 is hydrogen or C 1 -C 3 alkyl;
(f)
wherein T, U, V, and W independently are selected from hydrogen; halogen; —O; C 1 -C 3 alkyl; and C 1 -C 3 alkyloxy; and wherein R 8 is hydrogen or C 1 -C 3 alkyl;
(g)
wherein D is S, O, or NH;
(h)
wherein D is as defined above; and
(i)
wherein G′ is NH or CH,
or a pharmaceutically acceptable salt thereof.
2 . The protein kinase inhibitor of claim 1 , which is a compound of formula (X).
3 . The protein kinase inhibitor of claim 1 , which is a compound of formula (XII).
4 . The protein kinase inhibitor of claim 1 , which is a compound of formula (XIII).
5 . The protein kinase inhibitor of claim 1 , which is a compound of formula (XIV).
6 . The protein kinase inhibitor of claim 1 , which is a compound of formula (XV).
7 . The protein kinase inhibitor of claim 1 , which is a compound of formula (XVI).
8 . The protein kinase inhibitor of claim 1 , which is a compound of formula (XVII).
9 . The protein kinase inhibitor of claim 1 , which is a compound of formula (XVIII).
10 . The protein kinase inhibitor of claim 1 , which is a compound of formula (XIX).
11 . A composition, comprising:
(a) a pharmaceutically acceptable vehicle; and
(b) the protein kinase inhibitor of claim 1 .
12 . An adduct formed between (a) the protein kinase inhibitor of claim 1 ; and (b) a DKC triad kinase domain.
13 . The adduct of claim 12 , wherein the DKC triad kinase comprises ITK.
14 . A complex, comprising the protein kinase inhibitor of claim 1 which is bound to a DKC triad kinase.
15 . The complex of claim 14 , wherein the DKC triad kinase comprises ITK.
16 . A method of inhibiting kinase activity, comprising contacting a DKC triad kinase with the protein kinase inhibitor of claim 1 or a pharmaceutically acceptable salt thereof, whereby kinase activity of the DKC triad kinase is inhibited.
17 . The method of claim 16 , wherein the DKC triad kinase comprises ITK.
18 . The method of claim 16 , wherein the contacting occurs in a cell-free system.
19 . The method of claim 16 , wherein the contacting occurs in a cell.
20 . The method of claim 19 , wherein the cell is in vitro.
21 . The method of claim 19 , wherein the cell is in a patient.
22 . The method of claim 21 , wherein patient has an organ transplant, an autoimmune disease, or a blood cell malignancy.
23 . The method of claim 22 , wherein the patient has a blood cell malignancy and the blood cell malignancy is selected from the group consisting of a B cell malignancy and a T cell malignancy.
24 . The method of claim 16 , wherein the DKC triad kinase comprises ITK.