Protection of renal tissues from ischemia through inhibition of the proliferative kinases CDK4 and CDK6
The presently disclosed subject matter relates to methods and compositions for protecting cells and or tissues from damage due to ischemia. In particular, the presently disclosed subject matter relates to the protective action of cyclin dependent kinase 4/6 (CDK4/6) inhibitors administered to subjects that have been exposed to, or that are at risk of, ischemia.
1. A method of mitigating injury in a cell that proliferates in response to ischemia in a subject in need of treatment, the method comprising administering to the subject a pharmaceutically effective amount of a compound that inhibits cyclin dependent kinase 4 (CDK4) and cyclin dependent kinase 6 (CDK6), wherein the compound has a 50% inhibitory concentration (IC 50 ) for CDK4 that is at least 6 times lower than the compound's IC 50 for cyclin dependent kinase 2 (CDK2), wherein the cell proliferation is CDK4/6 dependent, and wherein the cell that proliferates in response to ischemia is a renal cell.
2. The method of claim 1 , wherein the compound is administered to the subject prior to the subject being exposed to the ischemia-inducing event.
3. The method of claim 1 , wherein the compound is administered at the same time the subject is being exposed to the ischemia-inducing event.
4. The method of claim 1 , wherein the compound is administered after exposure of the subject to the ischemia-inducing event.
5. The method of 4 , wherein the compound is administered to the subject between about 24 and about 48 hours after exposure of the subject to the ischemia-inducing event.
6. The method of claim 1 , wherein the compound is administered to the subject such that therapeutic levels are maintained until conditions inducing renal injury have been reversed.
7. The method of claim 1 , wherein the compound is administered to the subject such that therapeutic levels are maintained for between 12 and 72 hours following exposure to the ischemia.
8. The method of claim 2 , wherein the compound is administered to the subject such that plasma levels of the compound are peaking at the time of the ischemia.
9. The method of claim 2 , wherein the compound is administered to the subject 24 to 20 hours prior to the subject being exposed to the ischemia.
10. The method of claim 1 , wherein the compound has an IC 50 for CDK4 that is at least 50 times lower than the IC 50 for CDK2.
11. The method of claim 1 , wherein the compound has an IC 50 for CDK4 that is at least 100 times lower than the IC 50 for CDK2.
12. The method of claim 1 , wherein the compound has an IC 50 for CDK4 that is at least 1000 times lower than the IC 50 for CDK2.
13. The method of claim 1 , wherein the compound is substantially free of off-target effects other than inhibition of CDK6.
14. The method of claim 1 , wherein the ischemia-inducing event is cardiac surgery, or other surgery associated with hypotensive episodes.
15. The method of claim 1 , wherein the ischemia-inducing event is the administration of radio-contrast agents.
16. The method of claim 1 , where the ischemia-inducing event is trauma associated with a period of hypovolemia and/or hypotension.
17. The method of claim 1 , where the ischemia-inducing event is administration of a medicine or agent that decreases renal blood flow.
18. The method claim 1 , where the ischemia-inducing event is acute tissue ischemia or infarction as caused by arterial embolus or in situ arterial or venous thrombosis.
19. The method of claim 1 , where the ischemia-inducing event is torsion of a volvulus or other transient anatomic disruption of organ blood flow.
20. The method of claim 1 , where the ischemia-inducing event is kidney harvesting and/or transportation prior to implantation in a kidney transplant recipient.
21. The method of claim 1 , wherein the inhibitor compound is selected from the group consisting of a pyrido[2,3-d]pyrimidine, a triaminopyrimidine, an aryl[a]pyrrolo[3,4-c]carbazole, a nitrogen-containing heteroaryl-substituted urea, a 5-pyrimidinyl-2-aminothiazole, a benzothiadiazine, and an acridinethione.