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.
Highlights
The cell cycle is a highly conserved and regulated process by which genomic integrity and replicative capacity must be maintained for proper cell maintenance and proliferation
Biochemical profiling was completed against CDK4/ cyclin D1 and CDK6/cyclin D3
Compounds with 100-fold or greater selectivity for CDK4/ cyclin D1 versus CDK2/cyclin E were profiled in cell-based screens to look for G1 arrest in normal HS68 fibroblast cells, with a functioning RB pathway
Summary
The cell cycle is a highly conserved and regulated process by which genomic integrity and replicative capacity must be maintained for proper cell maintenance and proliferation. The cell cycle consists of four distinct phases: G1 or Gap phase where cells grow and synthesize proteins in preparation for DNA synthesis; S-phase, where DNA synthesis occurs; G2 or Gap phase postsynthesis where cells continue to synthesize proteins to increase mass in preparation for mitosis; and M-phase in which the DNA divides and the parent cell undergoes cytokinesis to produce two daughter cells [1]. Regulation of this process is maintained by a series of highly conserved proteins referred to as cyclins, and their catalytic binding partners, cyclindependent kinases (CDK). Throughout G1, expression of the Dtype cyclins (D1, D2, D3) increases until active complexes with
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