Investigation of novel oral/ intraveneous PCA-1 inhibitors of for cancer

• Project/Area Number: 17K08378
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Drug development chemistry
• Research Institution: Hyogo University of Health Sciences
• Principal Investigator: Tanaka Akito 兵庫医療大学, 薬学部, 教授 (30454789)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2019: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2018: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2017: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
• Keywords: 前立腺がん / 創薬化学 / 抗がん剤 / PCA-1 / 前立腺癌 / 癌 / 創薬

Outline of Final Research Achievements

Some compounds which were superior to HUHS015, a seed compound were found in inhibition of PCA-1 activity and DU145 cell proliferation. Then, we investigated metabolism of the compounds by S9 mix, and oral absorption. Next, the compounds of 10, 32 mg/kg were subcutaneously administered to mice xenograft model, and supressed the growth of tumor with statistical significance. Furthermore, oral treatment combined with Docetaxel（2.5 mg/kg、s.c.、once/week）, first-choice drug for hormone independent prostate cancer, were more effective than Docetaxel alone.

Academic Significance and Societal Importance of the Research Achievements

前立腺がんは我が国においても重要な社会問題となりつつある。特に、前立腺がんは疾患の進行に伴いホルモン非依存性に変化するとその予後が著しく悪化することから、ホルモン非依存性前立腺がんに有効な薬物開発が求められている。辻川らは前立腺がんの予後に強く相関する臨床予後因子としてDNA/RNAの脱メチル化酵素PCA-1を発見した。我々はその阻害薬の創出に成功し、有効性を報告してきたが、さらに代謝安定性も視野に入れた創薬研究を行い、経口投与でも有効な選択的 PCA-1 阻害剤を創出し、アカデミア発創薬実現を目指した。これらの化合物は前立腺がん、肺がん、すい臓がんなど広範な癌治療への効果も期待される。