title: Preclinical Characterization of G1T28: A Novel CDK4/6 Inhibitor for Reduction of Chemotherapy-Induced Myelosuppression.
abstract: Chemotherapy-induced myelosuppression continues to represent the major dose-limiting toxicity of cytotoxic chemotherapy, which can be manifested as neutropenia, lymphopenia, anemia, and thrombocytopenia. As such, myelosuppression is the source of many of the adverse side effects of cancer treatment including infection, sepsis, bleeding, and fatigue, thus resulting in the need for hospitalizations, hematopoietic growth factor support, and transfusions (red blood cells and/or platelets). Moreover, clinical concerns raised by myelosuppression commonly lead to chemotherapy dose reductions, therefore limiting therapeutic dose intensity, and reducing the antitumor effectiveness of the treatment. Currently, the only course of treatment for myelosuppression is growth factor support which is suboptimal. These treatments are lineage specific, do not protect the bone marrow from the chemotherapy-inducing cytotoxic effects, and the safety and toxicity of each agent is extremely specific. Here, we describe the preclinical development of G1T28, a novel potent and selective CDK4/6 inhibitor that transiently and reversibly regulates the proliferation of murine and canine bone marrow hematopoietic stem and progenitor cells and provides multilineage protection from the hematologic toxicity of chemotherapy. Furthermore, G1T28 does not decrease the efficacy of cytotoxic chemotherapy on RB1-deficient tumors. G1T28 is currently in clinical development for the reduction of chemotherapy-induced myelosuppression in first- and second-line treatment of small-cell lung cancer. Mol Cancer Ther; 15(5); 783-93. ©2016 AACR.
authors.affiliation: G1 Therapeutics, Research Triangle Park, North Carolina.
authors.forename: John E
authors.initials: JE
authors.lastname: Bisi
authors.affiliation: G1 Therapeutics, Research Triangle Park, North Carolina.
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Sorrentino
authors.affiliation: G1 Therapeutics, Research Triangle Park, North Carolina.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Roberts
authors.affiliation: ChemoGenics BioPharma, Research Triangle Park, North Carolina.
authors.forename: Francis X
authors.initials: FX
authors.lastname: Tavares
authors.affiliation: G1 Therapeutics, Research Triangle Park, North Carolina. jcs@g1therapeutics.com.
authors.forename: Jay C
authors.initials: JC
authors.lastname: Strum
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D017209:Apoptosis / Q000187:drug effects; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors*; D051361:Cyclin-Dependent Kinase 6 / Q000037:antagonists & inhibitors*; D004249:DNA Damage; D004195:Disease Models, Animal; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D005260:Female; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D038042:Myelopoiesis / Q000187:drug effects*; D009369:Neoplasms / Q000150:complications / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D020011:Protective Agents / Q000737:chemistry / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D016160:Retinoblastoma Protein / Q000172:deficiency
chemical_list: D000970:Antineoplastic Agents; D020011:Protective Agents; D047428:Protein Kinase Inhibitors; D016160:Retinoblastoma Protein; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6