Cyclin dependent kinase inhibitors and methods of use

Abstract

The presently disclosed subject matter relates to methods and compositions for protecting healthy cells from damage due to DNA damaging agents. In particular, the presently disclosed subject matter relates to the protective action of selective cyclin dependent kinase 4/6 (CDK4/6) inhibitors administered to subjects that have been exposed to or that are at risk of exposure to DNA damage.

1 . A method of increasing the efficacy of a toxicity reducing agent in a subject in need of treatment thereof, the method comprising:
 providing a subject that has been exposed to, is being exposed to, or is at risk of being exposed to a DNA damaging agent or event;   administering to said subject a toxicity reducing agent; and   administering to said subject a pharmaceutically effective amount of a compound that selectively inhibits cyclin dependent kinase 4 (CDK4) and/or cyclin dependent kinase 6 (CDK6).   
     
     
         2 . The method of  claim 1 , wherein said toxicity reducing agent is a chemotherapy toxicity reducing agent. 
     
     
         3 . The method of  claim 1 , wherein said toxicity reducing agent is a radiation toxicity reducing agent. 
     
     
         4 . The method of  claim 1 , wherein said toxicity reducing agent comprises one or more agents selected from the group consisting of a growth factor, a granulocyte colony-stimulating factor (G-CSF), a pegylated G-CSF, granulocyte-macrophage colony stimulating factor (GM-CSF), thrombopoietin, erythropoietin, pegylated erythropoietin, interleukin (IL)-12, steel factor, a keratinocyte growth factor, or derivatives thereof. 
     
     
         5 . The method of  claim 1 , wherein the compound that selectively inhibits CDK4 and/or CDK6 induces pharmacologic quiescence in one or more cells within the subject. 
     
     
         6 . The method of  claim 5 , wherein the one or more cells are each selected from the group consisting of a hematologic cell, a hematologic stem cell, and a hematologic precursor cell. 
     
     
         7 . The method of  claim 1 , wherein the compound that selectively inhibits CDK4 and/or CDK6 is administered to the subject prior to the subject being exposed to the DNA damaging agent or event, at the same time the subject is being exposed to the DNA damaging agent or event, or after exposure of the subject to the DNA damaging agent or event. 
     
     
         8 . The method of  claim 1 , wherein the compound that selectively inhibits CDK4 and/or CDK6 is administered to the subject between about 24 and about 48 hours after exposure of the subject to the DNA damaging agent or event. 
     
     
         9 . A method of mitigating DNA damage in a non-hematologic cell or tissue in a subject in need of treatment thereof prior to or following exposure of the cell or tissue to a DNA damaging agent or event, the method comprising administering to the subject a pharmaceutically effective amount of a compound that selectively inhibits cyclin dependent kinase 4 (CDK4) and/or cyclin dependent kinase 6 (CDK6). 
     
     
         10 . The method of  claim 9 , wherein the non-hematologic cell or tissue is comprises a cell or tissue from one of the group consisting of kidney, gut, heart, liver, brain, thyroid, skin, intestinal mucosa, auditory system, lung, bladder, ovaries, uterus, testicles, adrenals, gallbladder, pancreas, pancreatic islets, stomach, blood vessels, bone, and combinations thereof. 
     
     
         11 . A method of reducing or inhibiting memory T cell proliferation in a subject in need of treatment thereof, the method comprising administering to the subject a pharmaceutically effective amount of a compound that selectively inhibits cyclin dependent kinase 4 (CDK4) and/or cyclin dependent kinase 6 (CDK6) to the subject. 
     
     
         12 . The method of  claim 11 , wherein the subject has or is at risk of developing an autoimmune or allergic disease. 
     
     
         13 . The method of  claim 12 , wherein the autoimmune or allergic disease is selected from the group consisting of systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), autoimmune arthritis, scleroderma, hemolytic anemia, autoimmune aplastic anemia, autoimmune granulocytopenia, type I diabetes, thrombotic thrombocytopenic purpura (TTP), psoriasis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, contact dermatitis, polymyalgia rheumatica, uveitis, immune pneumonitis, autoimmune hepatitis, immune nephritis, immune glomerulonephritis, multiple sclerosis, autoimmune neuropathy, vitiligo, discoid lupus, Wegener's Granulomatosis, Henoch-Schoelein Purpura, sclerosing cholangitis, autoimmune thyroiditis, autoimmune myocarditis, autoimmune vasculitis, dermatomyositis, extrinsic and intrinsic reactive airways disease (asthma), myasthenia gravis, autoimmune ovarian failure, pernicious anemia, Addison's disease, autoimmune hypoparathyroidism and other syndromes of inappropriate cellular immune response. 
     
     
         14 . A method of reducing or inhibiting B cell progenitor proliferation in a subject in need of treatment thereof, the method comprising administering to the subject a pharmaceutically effective amount of a compound that selectively inhibits cyclin dependent kinase 4 (CDK4) and/or cyclin dependent kinase 6 (CDK6) to the subject. 
     
     
         15 . The method of  claim 14 , wherein the subject has or is at risk of developing an autoimmune or allergic disease. 
     
     
         16 . The method of  claim 15 , wherein the autoimmune or allergic disease is selected from the group consisting of systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), scleroderma, hemolytic anemia, idiopathic thrombocytopenic purpura (ITP), acquired inhibitors in hemophilia, thrombotic thrombocytopenic purpura (TTP), Goodpasture's syndrome, cold and warm agglutin diseases, cryoglobulinemia, and syndromes of inappropriate antibody production. 
     
     
         17 . A method for mitigating an autoimmune or allergic disease in a subject in need of treatment thereof, the method comprising administering to the subject a pharmaceutically effective amount of a compound that selectively inhibits cyclin-dependent kinase 4 (CDK4) and/or cyclin dependent kinase 6 (CDK6), wherein said compound reduces or inhibits memory T cell proliferation, B cell progenitor proliferation, or both memory T cell proliferation and B cell progenitor proliferation. 
     
     
         18 . The method of  claim 17 , wherein the autoimmune or allergic disease is selected from the group consisting of systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), autoimmune arthritis, scleroderma, hemolytic anemia, autoimmune aplastic anemia, autoimmune granulocytopenia, type I diabetes, thrombotic thrombocytopenic purpura (TTP), psoriasis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, contact dermatitis, polymyalgia rheumatica, uveitis, immune pneumonitis, autoimmune hepatitis, immune nephritis, immune glomerulonephritis, multiple sclerosis, autoimmune neuropathy, vitiligo, discoid lupus, Wegener's Granulomatosis, Henoch-Schoelein Purpura, sclerosing cholangitis, autoimmune thyroiditis, autoimmune myocarditis, autoimmune vasculitis, dermatomyositis, extrinsic and intrinsic reactive airways disease (asthma), myasthenia gravis, autoimmune ovarian failure, pernicious anemia, Addison's disease, autoimmune hypoparathyroidism, other syndromes of an inappropriate cellular immune response, Goodpasture's syndrome, cold and warm agglutin diseases, cryoglobulinemia, and syndromes of inappropriate antibody production. 
     
     
         19 . A method of treating cancer in a subject in need of treatment thereof, wherein the cancer is characterized by an increased level of cyclin dependent kinase 2 (CDK2) activity or by reduced expression of retinoblastoma tumor suppressor protein or a retinoblastoma family member protein, the method comprising administering to the subject a pharmaceutically effective amount of a compound that selectively inhibits cyclin dependent kinase 4 (CDK4) and/or cyclin dependent kinase 6 (CDK6). 
     
     
         20 . The method of  claim 19 , wherein the compound that selectively inhibits CDK4 and/or CDK6 does not induce pharmacologic quiescence in cancer cells. 
     
     
         21 . The method of  claim 19 , wherein the compound that selectively inhibits CDK4 and/or CDK6 increases the sensitivity of cancer cells to DNA damaging agents. 
     
     
         22 . The method of  claim 21 , wherein the increase in sensitivity increases cancer cell death. 
     
     
         23 . The method of  claim 19 , wherein the increased level of CDK2 activity is associated with MYC protooncogene amplification or overexpression. 
     
     
         24 . The method of  claim 19 , wherein the increased level of CDK2 activity is associated with overexpression of Cyclin E1, Cyclin E2, or Cyclin A. 
     
     
         25 . The method of  claim 19 , wherein administration of the compound that selectively inhibits CDK4 and/or CDK6 mitigates hematologic toxicity associated with exposure to a DNA damaging agent or event. 
     
     
         26 . The method of  claim 25 , wherein the compound that selectively inhibits CDK4 and/or CDK6 is administered to the subject prior to the subject being exposed to the DNA damaging agent or event, at the same time the subject is being exposed to the DNA damaging agent or event, or after exposure of the subject to the DNA damaging agent or event 
     
     
         27 . The method of  claim 25 , wherein the compound that selectively inhibits CDK4 and/or CDK6 is administered to the subject between about 24 and about 48 hours after exposure of the subject to the DNA damaging agent or event. 
     
     
         28 . A method of mitigating chemotherapy-induced or radiotherapy-induced secondary malignancies of hematological or non-hematological origin in a subject, the method comprising administering to the subject a pharmacologically effective amount of a compound that selectively inhibits cyclin dependent kinase 4 (CDK4) and/or cyclin dependent kinase 6 (CDK6). 
     
     
         29 . The method of  claim 28 , wherein the compound that selectively inhibits CDK4 and/or CDK6 is administered to the subject prior to or during the same time period that the subject is undergoing chemotherapy or radiation-based therapy to treat a primary malignancy.