A novel brain penetrant PDGFRα inhibitor HY-008 is effective against glioblastoma

Abstract: Background: Glioblastoma multiforme (GBM) is the most common primary intracranial malignant tumor in adults, with poor prognosis and high recurrence. Routine treatments of GBM show unsatisfactory efficiency in improving patient survival because of limited area of surgical resection and drug resistance. New therapeutic agents are needed to improve GBM treatment efficiency, but the blood-brain barrier (BBB) permeability is a major hurdle. Here, we report HY-008 as a promising therapeutic drug targeting PDGFR-alpha signaling with high BBB permeability and efficient inhibiting effects both in vitro and in vivo. Methods: Through structural modification and medicinal chemistry efforts, HY-007 and HY-008 were developed. The brain and plasma pharmacokinetic profiles of these two compounds were assessed. The inhibitory efficiency of HY-007 and HY-008 on GBM cell survival and PDGFR-alpha signaling were evaluated. The efficacy of HY-007 and HY-008 as a single agent or HY-008 in combination with temozolomide (TMZ) was investigated using transformed mouse astrocyte and glioma stem-like cell (GSC) orthotopic xenograft models. Results: HY-007 and HY-008 both had good brain permeability and desirable PK profiles with mild hERG inhibition, while HY-008 is more brain permeable than HY-007. In vitro, HY-007 and HY-008 both significantly inhibited viability of the established GBM cells with PDGF-A overexpression and transformed mouse astrocytes with PDGF-A/PDGFR; overexpression by targeting the PDGFR-alpha signaling activated Erk1/2 and Akt. In vivo, HY-007 and HY-008 both effectively inhibited orthotopic GBM tumor xenograft growth and prolonged the survival of mice, and HY-008 showed less toxicity and better therapeutic effect. In addition, HY-008 increased sensitivity of TMZ, exhibited treatment efficiency both as a single agent and in combination with TMZ, providing significant survival benefits for GBM tumor xenograft-bearing mice. Conclusions: Our data demonstrate that HY-008 is a promising therapeutic agent in GBM treatment and a combination HY-008 with TMZ could serves as a potential efficient therapeutic option for improving GBM clinical treatment.