Development of GZ38-1, a Novel Protectant of Chemotherapy-Induced Myelosuppressio

DESCRIPTION provided by applicant Myelosuppression continues to represent the major dose limiting toxicity of cancer chemotherapy resulting in considerable morbidity and mortality along with frequent reductions in chemotherapy dose intensity which may compromise disease control and survival G Zero Therapeutics with operations in the Research Triangle Park of North Carolina has developed a novel approach to attenuate the hematologic toxicity of chemotherapy This approach relies on the administration of novel small molecule kinase inhibitors around the time of chemotherapy administration These compounds in turn induce a cell cycle arrest of the early hematopoietic stem and progenitor cells HSPC through the inhibition of cyclin dependent kinases and CDK that govern the G S transition of the cell cycle of HSPC We have termed this arrest andquot pharmacological quiescenceandquot or PQ throughout which is protective as non cycling cells are resistant to DNA damaging agents Specifically PQ enhances the per cell survival of HSPC by augmenting the repair of DNA damage following exposure to chemotherapy 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 protect all hematopoietic cell lineages including red cells platelets granulocytes and lymphocytes from chemotherapy induced DNA damage G Zero has licensed from the University of North Carolina the broad intellectual property developed in Dr Sharplessandapos lab at UNC surrounding the use of PQ for chemoprotection In addition G Zero is developing its own proprietary series of CDK drug candidates from which we have identified GZ as our lead candidate In this proposal we seek to extend our proof of concept results using our own proprietary CDK inhibitors by demonstrating in vivo efficacy and safety of GZ In Phase I we will determine the efficacy of novel chemotherapeutic regimens incorporating GZ and standard SCLC chemotherapeutic agents in Small Cell Lung Cancer xenograft models In Phase II we will pursue pharmaceutical chemistry development of GZ for future IND enabling GLP studies We believe work described in this proposal will lead to a commercially valuable approach to prevent chemotherapy induced myelosuppression that is protected by G Zeroandapos s broad intellectual property a simple and non toxic therapeutic that will provide protectio of all hematopoietic cell lineages following exposure to chemotherapeutic DNA damaging agents PUBLIC HEALTH RELEVANCE Myelosuppression continues to represent the major dose limiting toxicity of cancer chemotherapy resulting in considerable morbidity and mortality along with frequent reductions in chemotherapy dose intensity which may compromise disease control and survival G Zero Therapeutics is developing a novel approach and proprietary CDK series to attenuate the hematologic toxicity of chemotherapy and protect all hematopoietic cell lineages red cells platelets granulocytes and lymphocytes from chemotherapy induced DNA damage