The induction of potent anti-tumor efficacy in diffuse intrinsic pontine glioma by YF-PRJ8-1011 of a novel cyclin-dependent kinase 4/6 inhibitor

Abstract

Abstract Objective Diffuse intrinsic pontine glioma (DIPG) 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 DIPG tumor cells in vitro and in vivo compared with palbociclib. Methods Patient-derived DIPG cells were used to assess the antitumor efficacy of YF-PRJ8-1011 in vitro. The Liquid chromatography tandem-mass spectrometry (LC-MS/MS) method was used to measure the activity of YF-PRJ8-1011 passing through the blood-brain barrier. DIPG patient-derived xenograft models were established to detect the antitumor efficacy of YF-PRJ8-1011. Results The results showed that YF-PRJ8-1011 could inhibit the growth of DIPG cells both in vitro and in vivo. YF-PRJ8-1011 could well penetrate the blood-brain barrier. It also significantly inhibited the growth of DIPG tumors and prolonged the overall survival of mice compared with vehicle or palbociclib. Most notably, it exerted potent antitumor efficacy in DIPG 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 DIPG xenograft tumor growth than radiotherapy alone. Conclusion Collectively, YF-PRJ8-1011 is a novel, safe, and selective CDK4/6 inhibitor for DIPG treatment.