JP2015531747A - チエノトリアゾロジアゼピン化合物を使用するリンパ腫の治療方法 - Google Patents
チエノトリアゾロジアゼピン化合物を使用するリンパ腫の治療方法 Download PDFInfo
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Abstract
Description
22個のびまん性大細胞型B細胞リンパ腫(DLBCL)、8個の未分化大T細胞リンパ腫(ALCL)、4個のマントル細胞リンパ腫(MCL)、および3個の脾臓周辺帯リンパ腫(SMZL)樹立ヒト細胞系において、式2の抗増殖活性を評価した。10% ウシ胎児血清、1% L−グルタミンおよびペニシリン−ストレプトマイシン−ネオマイシン(〜5,000単位のペニシリン、5mg/mLのストレプトマイシン、10mg/mLのネオマイシン)で補足されたRPMI−1640(GIBCO Invitrogen,Basel,Switzerland)またはDMEM(GIBCO Invitrogen,Basel,Switzerland)培地内で細胞系を培養した。
米国特許出願公開第20100286127号(その全体を参照により本明細書に組み入れることとする)に開示されているとおり、式2の化合物はBETブロモドメインタンパク質2、3および4(BRD2、BRD3、BRD4)の競合的インヒビターであることが既に示されている。BRD4の阻害はc−MYC癌遺伝子のダウンレギュレーションを引き起こすことが示されている[Delmore JE,Issa GC,LemieuxMEら:BET bromodomain inhibition as a therapeutic strategy to target c−Myc.Cell 2011;146:1−14]。したがって、BRD2、BRD3およびBRD4のmRNAおよびタンパク質の基底レベル、ならびにc−MYCのmRNAおよびタンパク質レベルに対する式2の化合物の効果を、選択されたDLBCLおよびALCL細胞系において評価した。
式2の化合物は、米国特許出願公開第20100286127号に開示されているとおり、BETブロモドメインタンパク質2、3および4(BRD2、BRD3、BRD4)の競合的インヒビターであることが既に示されており、BRD4は、ある状況において腫瘍抑制因子として作用しうる転写因子NFκBの調節に関与すると報告されている[Huang B,Yang XD,Zhou MM,Ozato K,Chen LF:Brd4 coactivates transcriptional activation of NF−κB via specific binding to acetylated RelA.Mol Cell Biol 2009;29:1375−1387]。したがって、NFκB標的(IRF4、A20、BIRC3)のmRNA発現に対する式2の化合物の効果を5個のDLBCL(DoHH2、Karpas 422、SU−DHL−2、SU−DHL−6、U2932)細胞系において評価した。結果は、式2の化合物がNFκB標的のダウンレギュレーションを誘導することを示した。代表的な結果を図9に示す。
Claims (11)
- 式1:
- 患者がヒトである、請求項1記載の方法。
- 該B細胞悪性疾患がびまん性大細胞型B細胞リンパ腫である、請求項1記載の方法。
- 該B細胞悪性癌が脾臓周辺帯リンパ腫である、請求項1記載の方法。
- 該T細胞悪性癌が未分化大T細胞リンパ腫である、請求項1記載の方法。
- 式1により表されるチエノトリアゾロジアゼピン化合物が、独立して、(i)(S)−2−[4−(4−クロロフェニル)−2,3,9−トリメチル−6H−チエノ[3,2−f][1,2,4]トリアゾロ−[4,3−a][1,4]ジアゼピン−6−イル]−N−(4−ヒドロキシフェニル)アセトアミドまたはその二水和物、(ii)メチル(S)−{4−(3’−シアノビフェニル−4−イル)−2,3,9−トリメチル−6H−チエノ[3,2−f][1,2,4]トリアゾロ[4,3−a][1,4]ジアゼピン−6−イル}アセタート、(iii)メチル(S)−{2,3,9−トリメチル−4−(4−フェニルアミノフェニル)−6H−チエノ[3,2−f][1,2,4]トリアゾロ[4,3−a][1,4]ジアゼピン−6−イル}アセタート、および(iv)メチル(S)−{2,3,9−トリメチル−4−[4−(3−フェニルプロピオニルアミノ)フェニル]−6H−チエノ[3,2−f−][1,2,4]トリアゾロ[4,3−a][1,4]ジアゼピン−6−イル}アセタートから選択される、請求項1記載の方法。
- 患者がヒトである、請求項7記載の方法。
- 該B細胞悪性疾患がびまん性大細胞型B細胞リンパ腫である、請求項7記載の方法。
- 該B細胞悪性癌が脾臓周辺帯リンパ腫である、請求項7記載の方法。
- 該T細胞悪性癌が未分化大T細胞リンパ腫である、請求項7記載の方法。
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