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.

Preclinical development of G1T38: A novel, potent and selective inhibitor of cyclin dependent kinases 4/6 for use as an oral antineoplastic in patients with CDK4/6 sensitive tumors

“…We have previously reported on a novel kinase inhibitor scaffold and the discovery of trilaciclib (G1T28), an IV, short-acting, potent and selective inhibitor of CDK4/6 currently in clinical development to preserve HSPC and immune system function during chemotherapy [27]. Further development of the tricyclic lactam scaffold has produced a number of oral, potent and selective CDK4/6 inhibitors with excellent drug like properties.…”

Transient CDK4/6 inhibition protects hematopoietic stem cells from chemotherapy-induced exhaustion

“…G1T28 (trilaciclib) is a small-molecule CDK4/6i developed for reducing chemotherapy-induced myelosuppression (18). This molecule affords excellent in vivo protection against DNA-damaging agents in rodent models and has favorable potency, selectivity, and pharmacological properties for this purpose (18).…”

Safety and efficacy profile of cyclin‐dependent kinases 4/6 inhibitor palbociclib in cancer therapy: A meta‐analysis of clinical trials

“…Serious adverse effect due to poor specificity usually restricts potential therapeutic value in oncology . Our results suggested there were more adverse effects in the group that used palbociclib‐containing regimen but all remained within expected parameters, at the same time, toxicities were relatively manageable.…”