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

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.

Transcription Factors in Cancer Development and Therapy

“…palbociclib, ribociclib, and abemaciclib are the small molecule CDK4/6 inhibitors currently approved for breast cancer treatment and are under clinical investigation for other solid tumors. A next-generation CDK4/6 inhibitor, G1T38, was developed to minimize the side effects of Palbociclib, which causes severe neutropenia [161], and was recently entered into phase I and II trials.…”

G1T48, an oral selective estrogen receptor degrader, and the CDK4/6 inhibitor lerociclib inhibit tumor growth in animal models of endocrine-resistant breast cancer

“…The increased efficacy observed for the combination of G1T48 and lerociclib, as compared to monotherapy administration, in multiple in vivo breast cancer models sensitive or refractory to endocrine therapy treatment supports the potential utility of this regimen as an intervention in multiple stages of breast cancer treatment. Furthermore, lerociclib has been shown to promote less myelosuppression than palbociclib [25,26]. Collectively, these data indicate that G1T48 has the potential to be an efficacious oral antineoplastic agent in ER+ breast cancer.…”

“…G1T48 was found to robustly inhibit ER activity in multiple in vitro models of endocrine therapy resistance, including those harboring ER mutations or growth factor activation. Importantly, G1T48 demonstrated robust antitumor activity in an animal model of early stage estrogen-dependent breast cancer and suppressed the growth of tamoxifen-and estrogen deprivation-resistant xenograft tumors with increased efficacy observed for the combination of G1T48 and lerociclib, a newly developed CDK4/6 inhibitor [25,26].…”

Recent advances with cyclin-dependent kinase inhibitors: therapeutic agents for breast cancer and their role in immuno-oncology

“…Secondly, the side effects of bone marrow suppression, as a limiting toxicity, warrant the development of additional CDK inhibitors with distinct toxicity profiles. In preliminary preclinical studies, GiT38 appears to have less neutropenia [214]. Thirdly, it will be important to develop efficient predictors of response to CDKs inhibitors with ctDNA appearing promising.…”