Hematologic toxicity is a principal cause of morbidity and mortality after exposure to ionizing radiation (IR). G-Zero Therapeutics, with operations in the Research Triangle Park, North Carolina, has developed a novel approach to mitigating the hematologic toxicity of total body irradiation (TBI). This approach relies on the administration of novel, orally bioavailable small molecule kinase inhibitors around the time of exposure to TBI. These compounds in turn induce pharmacological quiescence (PQ) of the early hematopoietic stem and progenitor cells (HSPC) through the inhibition of cyclin dependent kinases (CDK's) which govern the G1-S transition of the cell cycle. As quiescent cells are resistant to IR, PQ enhances the per cell survival of HSPC by augmenting the repair of DNA damage post-TBI. This enhanced survival of HSPC in turn translates into markedly reduced acute hematologic toxicity. G-Zero has shown in mice that the PQ approach can significantly boost the tolerated dose of IR when administered at the time of TBI (dose modifying factor > 1.3). Additionally, CDK inhibitor administered 20 hours after TBI still affords significant radioprotection with enhanced animal survival, and we anticipate that time of administration can be extended to more than 24 hours post exposure. As little as a single oral dose of kinase inhibitor affords radioprotection, enhancing survival and protecting all blood lineages including red cells, platelets, granulocytes and lymphocytes. G-Zero has licensed broad intellectual property surrounding the use of PQ for radioprotection. In this proposal, we seek to extend these results in three specific aims. In aim 1, we will test several additional CDK small molecule inhibitors with differing pharmacokinetics in vitro and in vivo to identify the optimal dosing schedule for maximal radioprotection. In aim 2, we will perform extensive characterization in rodents of the pharmacology and toxicology of the most promising CDK inhibitors identified in aim 1. In aim 3, we will additionally determine the ability of PQ to afford protection against the long-term sequelae of peri-lethal doses of IR. We believe these Phase I studies will position G-Zero to begin primate studies of CDK inhibitors in Phase II. It is our expectation that this work will lead to a simple and non-toxic pill that will enhance survival when taken up to 24 hours after a peri-lethal IR exposure that could occur as a result of nuclear accident or radiological attack.
Public Health Relevance: Exposure to radiation from terrorist attack and resulting toxicity is an imminent threat to the American public and military. Hematological toxicity through radiation-induced DNA damage of blood-producing cells of the bone marrow is a severe lethal consequence of radiation exposure of humans. G-Zero Therapeutics is developing drugs which can be stockpiled and easily administered following such an attack to protect the bone marrow from the damaging effects of radiation.
Public Health Relevance Statement: Exposure to radiation from terrorist attack and resulting toxicity is an imminent threat to the American public and military. Hematological toxicity through radiation-induced DNA damage of blood-producing cells of the bone marrow is a severe lethal consequence of radiation exposure of humans. G-Zero Therapeutics is developing drugs which can be stockpiled and easily administered following such an attack to protect the bone marrow from the damaging effects of radiation.
Project Terms: Acute; American; Animals; Apoptotic; Armed Forces Personnel; Attenuated; Bioavailable; Bizzozero's corpuscle/cell; Blood; Blood Platelets; Blood Precursor Cell; Blood erythrocyte; Blood granulocytic cell; Blood normocyte; Bone Marrow; Bone Marrow Blood-Deriving Cell; Bone Marrow Blood-Forming Cell; Bone Marrow Cells; CDK; CDK Inhibitor Protein; CDK4 Protein; CDKI Protein; Cell Cycle; Cell Cycle Arrest; Cell Division Cycle; Cell Division Protein Kinase 4; Cell Survival; Cell Viability; Cells; Chronic; Clinical Trials, Phase I; Cyclin Kinase Inhibitor; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase Inhibitor; Cyclin-Dependent Kinases; Cyclin-Dependent Protein Kinases; DNA Damage; DNA Damage Repair; DNA Injury; DNA Repair; Deetjeen's body; Dose; Drug Kinetics; Drugs; Early-Stage Clinical Trials; Effects of radiation; Electromagnetic Radiation, Ionizing; Erythrocytes; Erythrocytic; Exposure to; GFAC; Genotoxicity, Radiation Induced; Granular Leukocytes; Granulocytic cell; Growth Agents; Growth Factor; Growth Factors, Proteins; Growth Substances; Hayem's elementary corpuscle; Hematopoiesis; Hematopoietic; Hematopoietic Cellular Control Mechanisms; Hematopoietic stem cells; Hour; In Vitro; Intellectual Property; Ionizing radiation; Lead; Letters; Licensing; Lymphocyte; Lymphocytic; Mammals, Mice; Mammals, Primates; Mammals, Rodents; Marrow erythrocyte; Marrow platelet; Medication; Mice; Military; Military Personnel; Morbidity; Morbidity - disease rate; Mortality; Mortality Vital Statistics; Mother Cells; Murine; Mus; North Carolina; Nuclear Accidents; Operation; Operative Procedures; Operative Surgical Procedures; Oral; Organ; PSK-J3 kinase; Pb element; Pharmaceutic Preparations; Pharmaceutical Agent; Pharmaceutical Preparations; Pharmaceuticals; Pharmacokinetics; Pharmacologic Substance; Pharmacological Substance; Pharmacology; Pharmacology and Toxicology; Phase; Phase 1 Clinical Trials; Phase I Clinical Trials; Phase I Study; Pill; Platelets; Position; Positioning Attribute; Primates; Progenitor Cells; Progenitor Cells, Hematopoietic; Radiation; Radiation Induced DNA Damage; Radiation Toxicity; Radiation, Whole-Body; Radiation-Ionizing Total; Radioprotection; Red Blood Cells; Red Cell; Red blood corpuscule; Red cell of marrow; Research; Resistance; Reticuloendothelial System, Blood; Reticuloendothelial System, Bone Marrow; Reticuloendothelial System, Erythrocytes; Reticuloendothelial System, Platelets; Rodent; Rodentia; Rodentias; SCHED; Schedule; Series; Stem cells; Surgical; Surgical Interventions; Surgical Procedure; Testing; Therapeutic; Thrombocytes; Time; Total Body Irradiation; Toxic effect; Toxicities; Toxicology; Translating; Translatings; Universities; Unscheduled DNA Synthesis; Whole-Body Irradiation; Work; blood corpuscles; cdk Proteins; cdk4 cyclin-dependent kinase; cyclin D-dependent kinase CDK4; drug candidate; drug/agent; effect, adverse, radiation; expectation; exposed human population; granulocyte; heavy metal Pb; heavy metal lead; human exposure; in vitro testing; in vivo; inhibitor; inhibitor/antagonist; kinase inhibitor; language translation; lymph cell; new approaches; novel; novel approaches; novel strategies; novel strategy; p34(cdk4); p34PSK-J3 kinase; p34PSK-J3-CDK4 kinase; phase 1 study; phase 1 trial; phase I trial; pill (pharmacologic); protocol, phase I; public health relevance; radiation damage to DNA; radiation effect; ray (radiation); reconstitute; reconstitution; resistant; small molecule; stem; surgery; thrombocyte/platelet
