Development of new anti-cancer drug with anti-apoptotic protein MCL-1 selective inhibitory activity

• Project/Area Number: 20K06977
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47010:Pharmaceutical chemistry and drug development sciences-related
• Research Institution: Meiji Pharmaceutical University
• Principal Investigator: YOKOYA MASASHI 明治薬科大学, 薬学部, 准教授 (50338539)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 海洋天然物 / 抗がん剤 / イソキノリンアルカロイド / アポトーシス / Mcl-1 / がん幹細胞 / MCL-1 / イソキノリン / Akt-mTOR / 抗アポトーシス性タンパク質

Outline of Research at the Start

ヒト濾胞性リンパ腫から見いだされたbcl-2ファミリーがん遺伝子の中で、アポトーシス抑制能を有するMCL-1に対して高選択的に阻害活性を発現する新規化学療法剤の創製をめざす。本研究では、独自に見いだした強力な抗がん活性を有する海洋天然物であるレニエラマイシンTを創薬リードとし、外的刺激でがん細胞のアポトーシスを誘導することによりがん細胞を選択的に排除するという、これまでにない作用機序を誘発させ、副作用の少ない抗がん剤の開発につなげる。

Outline of Final Research Achievements

Lung cancer is the most prevalent cause of cancer death, and according to estimates of the global cancer statistics of incidence and mortality of all types of malignancies, its incidence is increasing. Derivatives of the RT right-half analog were used to treat NSCLC cells (H460 and H23) to analyze cell viability. The results revealed that the right half model compound of RT with thiazole ring, named DH-25, shows very potent anticancer activity against NSCLC. The compound was also shown to be effective against cancer stem cells, which have been implicated in cancer recurrence and drug resistance.

Academic Significance and Societal Importance of the Research Achievements

本邦において死因のトップであるがんを新しい作用で治療する医薬品の開発をおこなった。がんの根治が難しい要因として、がん細胞が医薬品に対し抵抗性を示すことが挙げられる。我々が開発した化合物は、この抵抗性に関与しているタンパク質を減少させることで、がん細胞自らを細胞死（アポトーシス）させることができる。

Research Products

• [Int'l Joint Research] Chulalongkorn University(タイ)
• [Int'l Joint Research] チュラロンコーン大学(タイ)
• [Int'l Joint Research] チュラロンコーン大学(タイ)
• [Journal Article] Transformation of Renieramycin M into Renieramycins T and S by Intramolecular Photoredox Reaction of 7-Methoxy-6-methyl-1,2,3,4-tetrahydroisoquinoline-5,8-dione Derivatives (2023)
  • Author(s): Yokoya Masashi、Yamazaki-Nakai Miku、Nakai Keiyo、Sirimangkalakitti Natchanun、Chamni Supakarn、Suwanborirux Khanit、Saito Naoki
  • Journal Title: Journal of Natural Products Volume: 86 Issue: 1 Pages: 222-231
  • DOI: 10.1021/acs.jnatprod.2c00974
  • Peer Reviewed
• [Journal Article] Novel Synthetic Derivative of Renieramycin T Right-Half Analog Induces Apoptosis and Inhibits Cancer Stem Cells via Targeting the Akt Signal in Lung Cancer Cells (2023)
  • Author(s): Petsri Korrakod、Yokoya Masashi、Racha Satapat、Thongsom Sunisa、Thepthanee Chorpaka、Innets Bhurichaya、Ei Zin Zin、Hotta Daiki、Zou Hongbin、Chanvorachote Pithi
  • Journal Title: International Journal of Molecular Sciences Volume: 24 Issue: 6 Pages: 5345-5345
  • DOI: 10.3390/ijms24065345
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] LIPASE-CATALYZED SITE-SELECTIVE DEACETYLATION OF 2METHOXY-3-METHYLNAPHTHALENE-1,4-DIOL DIACETATE FOR CONSTRUCTION OF CHARACTERISTIC SUBSTITUTED 1,2,3,4TETRAHYDROISOQUINOLINE DERIVATIVE OF ECTEINASCIDIN MARINE NATURAL PRODUCT (2022)
  • Author(s): Masashi Yokoya, Ryo Sato, Naoki Saito
  • Journal Title: Heterocycles Volume: 105 Issue: 1 Pages: 511-511
  • DOI: 10.3987/com-21-s(r)1
  • Peer Reviewed
• [Journal Article] Akt/mTOR Targeting Activity of Resveratrol Derivatives in Non-Small Lung Cancer (2022)
  • Author(s): Innets Bhurichaya、Thongsom Sunisa、Petsri Korrakod、Racha Satapat、Yokoya Masashi、Moriue Sohsuke、Chaotham Chatchai、Chanvorachote Pithi
  • Journal Title: Molecules Volume: 27 Issue: 23 Pages: 8268-8268
  • DOI: 10.3390/molecules27238268
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Structure-activity relationships and molecular docking analysis of Mcl-1 targeting renieramycin T analogues in patient-derived lung cancer cells (2020)
  • Author(s): Petsri K., Yokoya M., Tungsukruthai S., Rungrotmongkol T., Nutho B., Vinayanuwattikun C., Saito N., Matsubara T., Sato R, Chanvorachote P.
  • Journal Title: Cancers Volume: 12 (4) Issue: 4 Pages: 875-875
  • DOI: 10.3390/cancers12040875
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 抗腫瘍活性レニエラマイシン海洋天然物を基盤としたMCL-1標的薬の開発 (2022)
  • Author(s): 堀田 大貴、Chanvorachote Pithia、木村 真也、山中 正道、齋藤 直樹、横屋 正志
  • Organizer: 日本薬学会第142年会
• [Presentation] 抗腫瘍活性レニエラマイシン海洋天然物を基盤としたMCL-1標的薬の開発 (2022)
  • Author(s): 堀田 大貴、Chanvorachote Pithi、木村 真也、山中 正道、齋藤 直樹、横屋 正志
  • Organizer: 日本薬学会年会