Identification of novel candidate compounds for the treatment of lung squamous cell carcinoma by academic drug discovery

• Project/Area Number: 16K15638
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Respiratory surgery
• Research Institution: Kawasaki Medical School
• Principal Investigator: Fukazawa Takuya 川崎医科大学, 医学部, 准教授 (20379845)
• Co-Investigator(Kenkyū-buntansha): 猶本 良夫 川崎医科大学, 医学部, 教授 (00237190) ; 山辻 知樹 川崎医科大学, 医学部, 教授 (40379730) ; 高岡 宗徳 川崎医科大学, 医学部, 講師 (50548568)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2016: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000)
• Keywords: Midkine / 分子標的治療法 / 肺扁平上皮癌

Outline of Final Research Achievements

We have developed a specific inhibitor for cancer-specific growth factor Midkine: iMDK, and reported that the small compound can inhibit PI3Kinase / AKT pathway and induce an antitumor effect in lung cancer. In the present study, by optimizing the structure, we have synthesized derivatives of iMDK as the lead compound and investigated the antitumor properties of these small molecule compounds.
In HCC95 lung squamous cell carcinoma cells, two of the newly synthesized compounds showed antitumor activity at lower concentrations than iMDK. Furthermore, immunoblot revealed that these two compounds suppressed the phosphorylation of AKT at low concentration and induced apoptosis.

Academic Significance and Societal Importance of the Research Achievements

肺扁平上皮癌における有効な分子標的療法は未だ樹立されていない。その中で近年、肺扁平上皮癌の増殖・進展におけるPI3Kinaseの関与が報告され、また米国癌ゲノムアトラス研究ネットワーク（The Cancer Genome Atlas Research Network）から肺扁平上皮癌の多くにPIK3CA変異が認められることが報告されている。検討に用いたHCC95株など、これらの腫瘍においてはしばしば、下流のAKTの活性化が見られる。派生化合物X,Yは当該肺癌細胞株に対し低濃度で抗腫瘍性を示し、臨床化合物として有望と考えられた。

Research Products

• [Presentation] Development of a novel targeted therapy for malignant mesothelioma by a midkine inhibitor. (2017)
  • Author(s): Takuya Fukazawa, Yuitaka Maeda, Tomoki Yamatsuji, Munenori Takaoka, Masakazu Yoshida, Naomasa Ishida, Miki Iwai, Etsuko Yokota, Takuro Yukawa, Minoru Haisa, Noriko Miyake, Tomoko Ikeda, Nagio Takigawa, Jeffery Whitsett, Yoshio Naomoto
  • Organizer: AACR Annual Meeting 2017
  • Place of Presentation: Center, Cincinnati, OH,Washington DC,USA
  • Int'l Joint Research