4MO Preclinical evaluation of novel CDK4/6 inhibitor GLR2007 in breast and lung cancer models

Abstract

Background: Cyclin-dependent kinases (CDKs) such as CDK4/6 are essential in regulating the cell cycle, which is disrupted in many cancers. Currently marketed CDK4/6 inhibitors abemaciclib, palbociclib, and ribociclib have shown preclinical efficacy in solid tumors including breast cancer and non-small cell lung cancer. GLR2007 is an investigational CDK4/6 inhibitor with potential to treat advanced solid tumors. In vitro and in vivo antitumor effects of GLR2007 were investigated in breast and lung cancer cell line preclinical models.Methods: In vitro proliferation inhibition was evaluated through live cell counts in 7 human and murine breast cancer cell lines and 21 human lung cancer cell lines after culture for 72 h with 0.01e10,000 nM GLR2007 or 1.5e10,000 nM abemaciclib, reported as half maximal inhibitory concentration (IC 50 ). In vivo antitumor efficacy was determined in MCF-7 breast cancer orthotopic xenografts in NOD/SCID mice, and NCI-H1975 and NCI-H2228 lung cancer subcutaneous xenografts in BALB/C nude mice treated with 50 mg/kg GLR2007 by once-daily oral gavage.Results: GLR2007 inhibited proliferation at lower IC 50 values compared to abemaciclib in 5 breast cancer cell lines (IC 50 fold difference range ¼ 0.08e0.92; median ¼ 0.33) and in 20 lung cancer cell lines (IC 50 fold difference range ¼ 0.03e0.99; median ¼ 0.39). In MCF-7 breast cancer orthotopic xenografts, compared to vehicle control, 50 mg/kg GLR2007 induced 49.6% tumor growth inhibition (TGI) (P¼0.001) in mice treated for 21 days, and 81.4% TGI (P¼0.037) on day 25 in mice treated for 28 days. In lung cancer subcutaneous xenograft models, compared to vehicle control, 50 mg/kg GLR2007 induced 68.9% TGI (P<0.001) on day 16 in mice implanted with NCI-H1975 cells and treated for 22 days, and 33.9% TGI (P¼0.003) on day 34 in mice implanted with NCI-H2228 cells and treated for 28 days.Conclusions: In a number of tumor cell lines, GLR2007 inhibited proliferation at lower IC 50 values compared to abemaciclib. GLR2007 demonstrated significant antitumor efficacy in xenograft models compared to vehicle controls. These preclinical studies demonstrate the potential of GLR2007 as a novel CDK4/6 inhibitor for the treatment of breast and lung cancer.

A new perspective on the proper timing of radiotherapy during CDK4/6 inhibitor therapy in patients with “bone-only” metastatic breast cancer

“…Their half-life times are also different: 24-34 h of palbociclib, 30-55 h of ribociclib, and 17-38 h of abemaciclib. Within 3 days, they half, suggesting a 1 week drug-free period before irradiation [12]. optimal schedule through cellular senescence.…”

“…Dalpiciclib, which has good penetration of the blood-brain barrier, based on a DAWNA-1 randomized phase 3 trial [ 11 ], was conducted only in Chinese subjects, so its performance in other populations is still an open question. GLR2007 is also a promising new CDK4/6 inhibitor [ 12 ] that is effective in smaller concentrations compared with abemaciclib, which also has proper blood-brain barrier permeation. This suggests fewer adverse events and more effective treatment in cases of central nervous system metastasis.…”