A novel CDK4/6 inhibitor combined with irradiation demonstrates potent anti-tumor efficacy in diffuse midline glioma

Abstract

Diffuse midline glioma, H3 K27-altered (DMG) is a lethal pediatric brainstem tumor. Despite numerous efforts to improve survival benefits, its prognosis remains poor. This study aimed to design and synthesize a novel CDK4/6 inhibitor YF-PRJ8-1011, which exhibited more potent antitumor activity against a panel of patient-derived DMG tumor cells in vitro and in vivo compared with palbociclib. Patient-derived DMG cells were used to assess the antitumor efficacy of YF-PRJ8-1011 in vitro. The liquid chromatography tandem-mass spectrometry method was used to measure the activity of YF-PRJ8-1011 passing through the blood-brain barrier. DMG patient-derived xenograft models were established to detect the antitumor efficacy of YF-PRJ8-1011. The results showed that YF-PRJ8-1011 could inhibit the growth of DMG cells both in vitro and in vivo. YF-PRJ8-1011 could well penetrate the blood-brain barrier. It also significantly inhibited the growth of DMG tumors and prolonged the overall survival of mice compared with vehicle or palbociclib. Most notably, it exerted potent antitumor efficacy in DMG in vitro and in vivo compared with palbociclib. In addition, we also found that YF-PRJ8-1011 combined with radiotherapy also showed more significant inhibition of DMG xenograft tumor growth than radiotherapy alone. Collectively, YF-PRJ8-1011 is a novel, safe, and selective CDK4/6 inhibitor for DMG treatment.