Development of Alkylating PI polyamides targeting oncogenic driver gene mutations

2016 Fiscal Year Final Research Report

• Project/Area Number: 26290060
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Tumor therapeutics
• Research Institution: Chiba Cancer Center (Research Institute)
• Principal Investigator: Nagase Hiroki 千葉県がんセンター(研究所), がん遺伝創薬研究室, 研究所長 (90322073)
• Co-Investigator(Kenkyū-buntansha): 渡部 隆義 千葉県がんセンター(研究所), がん遺伝創薬研究室, 研究員 (60526060) ; 越川 信子 千葉県がんセンター(研究所), がん遺伝創薬研究室, 研究員 (90260249)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Keywords: がん / ドライバー遺伝子 / 遺伝子変異 / DNA副溝結合化合物 / ピロールイミダゾールポリアミド / アルキル化剤 / 抗癌治療薬

Outline of Final Research Achievements

Critical driver oncogenic proteins, such as RAS and MYC, are difficult therapeutic targets due to the smooth 3D surface. A new approach that directly target driver genes is needed.
Pyrrole-Imidazole polyamide (PIP) specifically recognizes DNA minor groove in a sequence dependent manner. We synthesized a series of PIP-drug conjugates targeting cancer driver genes. PIP conjugates targeting the cancer genome often showed reasonable anti-cancer effect and target gene modification as expected. It is also confirmed the anti-cancer efficacy in mouse models of human cancer with little or no adverse event. Intriguingly, pharmacokinetic studies suggested PIP conjugates showed the enhanced permeability and retention (EPR) like effect, which may take additional advantage of restricted local effects of PI-polyamide conjugates only in tumor and tumor environments for cancer therapeutics.
Thus, PI-polyamide conjugates targeting the mutated cancer genome is a promising strategy for cancer therapeutics.

Free Research Field

がん遺伝学