Discovery of specific inhibitor of MGMT against glioblastoma using in silico screening method

2016 Fiscal Year Final Research Report

• Project/Area Number: 26670648
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Neurosurgery
• Research Institution: Jikei University School of Medicine
• Principal Investigator: Arai Takao 東京慈恵会医科大学, 医学部, 講師 (40307400)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Keywords: in silico創薬 / drug repositioning / 神経膠芽腫 / MGMT特異的阻害剤

Outline of Final Research Achievements

An alkylating agent, temozolomide (TMZ), is a standard chemotherapeutic drug against malignant gliomas. Epigenetic silencing of the O6-methylguanine-DNA methyltransferase (MGMT) gene promoter in tumor tissue from patients with malignant glioma is associated with improved survival after treatment with TMZ. A specific inhibitor of MGMT, therefore may improve prognosis of patients with malignant glioma. We extracted several MGMT inhibitory candidates from compound libraries by using an in silico screening method. Based on the results of a cell-based screening assay using a MGMT-positive human glioblastoma cell line “T98G”, we selected a papaverine hydrochloride (PH) as an object for this study. The results of WST and colony formation assays indicated that PH had an antitumor effect against not only T98G but also a MGMT-negative cell line “U87MG”. A study using a subcutaneous tumor model of nude mouse indicated that a PH had an antitumor effect against U87MG in vivo.

Free Research Field

脳神経外科