Development of molecular-targeting prodrug for ENPP1

2019 Fiscal Year Final Research Report

• Project/Area Number: 18K14358
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 37030:Chemical biology-related
• Research Institution: Nagoya City University
• Principal Investigator: Kawaguchi Mitsuyasu 名古屋市立大学, 医薬学総合研究院(薬学), 講師 (10735682)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Keywords: プロドラッグ

Outline of Final Research Achievements

Becuase I found that ENPP1 specifically recognizes and hydrolyzes mGMP groups in living cells, I tried to apply mGMP group to the approved anticancer drug and aimed to develop a compound that shows cytotoxicity in ENPP1 overexpressing cells. However, when we attempted to prodrug SN-38, it was found that the mGMP group was unstable on the synthesis. Considering the background of previous studies, the acidity of the prodrug group is considered to be a key factor in the synthesis of the prodrug. In the result of an investigation of reaction conditions, it was found that coumarin, which is less acidic than TG, is also possible to synthesize Cou-mGMP. By using this reaction condition, I think that I can synthesize various prodrug compounds having mGMP group.

Free Research Field

創薬化学

Academic Significance and Societal Importance of the Research Achievements

本研究ではENPP1 (ecto-nucleotide pyrophosphatase/ phosphodiesterase 1)という細胞外に触媒ドメインを持つ膜タンパク質に着目し、その酵素活性を利用したプロドラッグ技術の開発を目指す。ENPP1は悪性度の高い脳腫瘍や乳がんで発現量が著しく高いことが示され 、がん幹細胞性の獲得・維持に必要であることが報告されているため、ENPP1を標的とすることは「がん幹細胞を標的」とすることとなり、神経膠芽腫やトリプルネガティブ乳がんなど悪性度が高く、有効な治療法の乏しいがんに対して効果的かつ副作用の少ない治療法を提案できると考えられる。