T細胞悪性腫瘍に対する新しい分子標的薬
国立がん研究センター、東京大学、第一三共
新規分子標的薬を共同開発 悪性リンパ腫(成人T細胞白血病リンパ腫含む)に対する第Ⅰ相試験開始
国立研究開発法人国立がん研究センター(理事長:堀田知光)と国立大学法人東京大学(総長:五神 真)及び第一三共株式会社(代表取締役社長:中山讓治)は、血液がんに対する新規分子標的薬としてヒストンメチル化酵素EZH1とEZH2の二重阻害剤(DS-3201b)を共同開発し、
この度、成人T細胞白血病リンパ腫(adult T-cell leukemia-lymphoma, ATL )を含む悪性リンパ腫患者に対し、世界で初めて人へ投与するファースト・イン・ヒューマン試験として第Ⅰ相試験*1を開始しました。
悪性リンパ腫の予後が悪い一因は、がん細胞を再生する能力をもつ「がん幹細胞*2」が治療後も残存するためと考えられています。そのため、「がん幹細胞」を根絶することが血液がんの根治には重要であるといえます。
国立がん研究センター研究所の造血器腫瘍研究分野 北林一生研究分野長の研究グループは、がん幹細胞の維持に必須な酵素としてEZH1/2を発見し、ふたつの酵素を共に阻害することで、「がん幹細胞」を根絶、治療抵抗性を打破し、再発を抑制することを示唆する研究成果を得ました。これまでの実験動物等を用いた非臨床試験で急性骨髄性白血病や非ホジキンリンパ腫に有効であることが示唆されています。
ATLについては、東京大学大学院新領域創成科学研究科の渡邉俊樹教授、山岸誠特任助教を中心とする研究グループが、ATLの発症及び進展にEZH1/2に依存的なエピゲノム異常*3があることを発見しました。さらに、正常細胞に比べ、ATL細胞はEZH1/2によるエピゲノム変化に強く依存した細胞であるため、EZH1/2二重阻害は非常に高感度かつ特異的にATL細胞の生存能を低下させることがわかりました。また、ATLの原因となるヒトT細胞白血病ウイルスI型(HTLV-1)キャリアの血液細胞にこの阻害剤を処理することにより、感染細胞が選択的に除去されることを見出しました。
Adult T-cell leukemia/lymphoma (ATL) is a malignancy of mature CD4+ T cells caused by human T-cell lymphotropic virus type 1 (HTLV-1)-induced T-cell transformation. After infection with HTLV-1, it takes several decades for HTLV-1 carriers to develop ATL. The prognosis of ATL remains poor despite several new agents being approved in the last few years. Recently, it has been noted that epigenetic abnormalities, both DNA methylation and trimethylation at histone H3Lys27 (H3K27me3), contribute to ATL leukemogenesis. Here, we investigated the effect of combination treatment with DNA demethylating agents (azacitidine [AZA], decitabine (DAC), and OR-2100 (OR21), which is a silylated derivative of DAC) and inhibitors of enhancer of zeste homolog 2 (EZH2) (EPZ-6438 and DS-3201b), which catalyze trimethylation of H3K27, in ATL. The combination of DAC and OR21 but not AZA with EZH inhibitors exhibited synergistic anti-ATL effects in vitro and in vivo, concomitant with DNA demethylation and reduction of H3K27me3. The combination induced gene expression reprogramming. Dual-specificity phosphatase 5 (DUSP5), an extracellular signal-regulated kinase (ERK)-specific phosphatase, was identified as a key molecule that mediated the inhibitory effect of combination treatment by inactivating the ERK signaling pathway. DUSP5 was downregulated by DNA methylation and H3K27me3 accumulation in the promoter region in HTLV-1-infected cells from patients with ATL during ATL leukemogenesis. The present results demonstrate that dual targeting of aberrant DNA and histone methylation synergistically suppresses tumor cell growth by restoring DUSP5, and that dual targeting of aberrant DNA and histone methylation is a feasible therapeutic approach for ATL.
Structure of the primary oncogenic mutant Y641N Hs/AcPRC2 in complex with a pyridone inhibitor
- PDB DOI: https://doi.org/10.2210/pdb5IJ8/pdb
- Classification: transferase/transferase inhibitor
- Organism(s): Anolis carolinensis, Homo sapiens
- Expression System: Spodoptera frugiperda
- Mutation(s): Yes
- Deposited: 2016-03-01 Released: 2016-05-04
Experimental Data Snapshot
- Method: X-RAY DIFFRACTION
- Resolution: 2.99 Å
- R-Value Free: 0.240
- R-Value Work: 0.188
- R-Value Observed: 0.191
wwPDB Validation 3D Report Full Report
Ligand Structure Quality Assessment
Polycomb repressive complex 2 structure with inhibitor reveals a mechanism of activation and drug resistance.
Brooun, A., Gajiwala, K.S., Deng, Y.L., Liu, W., Bolanos, B., Bingham, P., He, Y.A., Diehl, W., Grable, N., Kung, P.P., Sutton, S., Maegley, K.A., Yu, X., Stewart, A.E.(2016) Nat Commun 7: 11384-11384
- PubMed: 27122193
- DOI: https://doi.org/10.1038/ncomms11384
- Primary Citation of Related Structures:
5IJ7, 5IJ8
- PubMed Abstract:
Polycomb repressive complex 2 (PRC2) mediates gene silencing through chromatin reorganization by methylation of histone H3 lysine 27 (H3K27). Overexpression of the complex and point mutations in the individual subunits of PRC2 have been shown to contribute to tumorigenesis. Several inhibitors of the PRC2 activity have shown efficacy in EZH2-mutated lymphomas and are currently in clinical development, although the molecular basis of inhibitor recognition remains unknown. Here we report the crystal structures of the inhibitor-bound wild-type and Y641N PRC2. The structures illuminate an important role played by a stretch of 17 residues in the N-terminal region of EZH2, we call the activation loop, in the stimulation of the enzyme activity, inhibitor recognition and the potential development of the mutation-mediated drug resistance. The work presented here provides new avenues for the design and development of next-generation PRC2 inhibitors through establishment of a structure-based drug design platform.
2024年11月2日 | カテゴリー:AUTODOCK VINA , 各種治療学, 各種病因学, 癌の病態生理と治療学 |