Abstract
Inhibition of the p16INK4a/cyclin D/CDK4/6/RB pathway is an effective therapeutic strategy for the treatment of estrogen receptor positive (ER+) breast cancer. Although efficacious, current treatment regimens require a dosing holiday due to severe neutropenia potentially leading to an increased risk of infections, as well as tumor regrowth and emergence of drug resistance. Therefore, a next generation CDK4/6 inhibitor that can inhibit proliferation of CDK4/6-dependent tumors while minimizing neutropenia could reduce both the need for treatment holidays and the risk of inducing drug resistance.Here, we describe the preclinical characterization and development of G1T38; a novel, potent, selective, and orally bioavailable CDK4/6 inhibitor. In vitro, G1T38 decreased RB1 (RB) phosphorylation, caused a precise G1 arrest, and inhibited cell proliferation in a variety of CDK4/6-dependent tumorigenic cell lines including breast, melanoma, leukemia, and lymphoma cells. In vivo, G1T38 treatment led to equivalent or improved tumor efficacy compared to the first-in-class CDK4/6 inhibitor, palbociclib, in an ER+ breast cancer xenograft model. Furthermore, G1T38 accumulated in mouse xenograft tumors but not plasma, resulting in less inhibition of mouse myeloid progenitors than after palbociclib treatment. In larger mammals, this difference in pharmacokinetics allowed for 28 day continuous dosing of G1T38 in beagle dogs without producing severe neutropenia. These data demonstrate G1T38 has unique pharmacokinetic and pharmacodynamic properties, which result in high efficacy against CDK4/6 dependent tumors while minimizing the undesirable on-target bone marrow activity, thus potentially allowing G1T38 to be used as a continuous, daily oral antineoplastic agent.
Highlights
In normal cells, the cyclin D/CDK4/6/p16INK4a/ RB pathway allows for the orderly control of cell cycle progression for cell growth and proliferation
The therapeutic importance of CDK4/6 as a target has been established by palbociclib (IBRANCE®), a firstin-class CDK4/6 inhibitor, which is approved for the treatment of hormone receptor (HR)-positive and human epidermal receptor 2 (HER2)-negative breast cancer in combination with the aromatase inhibitor, letrozole, or the selective estrogen receptor degrader (SERD), fulvestrant [35]
Palbociclib-induced neutropenia may lead to an increased risk of infections and the treatment holiday may lead to tumor outgrowth and emergence of drug resistance
Summary
The cyclin D/CDK4/6/p16INK4a/ RB pathway allows for the orderly control of cell cycle progression for cell growth and proliferation. While the cyclin D/CDK4/6/p16INK4a/RB pathway is frequently disrupted in cancer, the majority of human neoplasms maintain functional RB but have aberrations that increase the activity of CDK4/6, which hyper-phosphorylates RB and allows cell proliferation [1, 2]. CDK4/6 appears to be a key enzyme necessary for the proliferation of human cancers that have functional RB. In the absence of a growth signal, RB inhibits the activation of genes required for S phase transition [1, 2]. Growth signals activate CDK4/6, which phosphorylates and deactivates RB, activating S phase-specific genes that stimulate cell cycle progression from the G1 phase to the S phase [3]. Inhibiting CDK4/6 activity has the potential to be therapeutically beneficial in a wide variety of tumors with functional RB
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
