JP2021504371A - Yeats阻害剤およびその使用方法 - Google Patents
Yeats阻害剤およびその使用方法 Download PDFInfo
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- JP2021504371A JP2021504371A JP2020528873A JP2020528873A JP2021504371A JP 2021504371 A JP2021504371 A JP 2021504371A JP 2020528873 A JP2020528873 A JP 2020528873A JP 2020528873 A JP2020528873 A JP 2020528873A JP 2021504371 A JP2021504371 A JP 2021504371A
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Abstract
Description
開示する発明は、一般に官能化オリゴマーの分野、特に官能化ペプチドおよびペプチド阻害剤の分野に属する。
白血病は、通常、骨髄で始まる、異常な完全に発達していない白血球を多数発生させる癌のグループである。白血病とリンパ腫はどちらも、血液、骨髄、リンパ系に影響を与える腫瘍のより広いグループに属しており、造血組織とリンパ組織の腫瘍として知られている。急性白血病は、未熟な血液細胞の数の急速な増加を特徴とする。そのような細胞から生じる過密状態により、骨髄は健康な血液細胞を産生できなくなる。急性白血病は、悪性細胞が急速に発達し蓄積し、その後、血流に溢れて身体の他の臓器に拡がるため、即時の治療を必要とする。急性型の白血病は、子供の最も一般的な白血病の型である。慢性白血病は、比較的成熟しているが異常な白血球の過剰な蓄積を特徴とする。通常は進行に数か月または数年かかるが、細胞は、通常よりもはるかに高い速度で生成され、その結果多くの異常な白血球が生じる。急性白血病は直ちに治療しなければならないのに対し、慢性型は治療の最大の効果を確実にするために治療前にしばらくモニターされることがある。慢性白血病は主に高齢者に発生するが、あらゆる年齢層に発生する可能性がある。
本明細書に開示されるのは、YEATSタンパク質ドメインにおけるπ−π−πスタッキングを阻害することにより急性白血病を治療するのに適した組成物および方法である。YEATSタンパク質ドメインは、通常、さまざまなクロマチン修飾分子複合体に見られる。これらのドメインの芳香環間の非共有的相互作用は、通常、πスタッキング(あるいはパイスタッキング)相互作用と呼ばれる。YEATSドメインは、ヒストンのリジンクロトン化マークを特異的に認識し、アミノ酸残基を含む2つの保存された芳香環を使用してπ−π−πスタッキングを形成することにより、クロトニル基を収容する。
で定義され得る。ある形態では、m又はnの少なくとも一方は0ではない。ある形態では、mまたはnはいずれも0ではない。
で定義され得る。ある形態では、R8及びR9はアミノ酸の側鎖であり、アミノ酸Lys、Gln、Thr、Ala、Arg、Ser、Leu、Trp、及びGlyの側鎖から独立して選択され得る。
開示される方法および組成物は、以下の特定の実施形態の詳細な説明およびそこに含まれる実施例、ならびに図面およびそれらの上記および下記の説明を参照することにより、より容易に理解され得る。
ここで使用される「アルキル基」という用語は、1〜24炭素原子の分岐または非分岐の飽和炭化水素基(例えば、メチル、エチル、n−プロピル、n−イソプロピル、n−ブチル、イソブチル、t−ブチル、ペンチル、ヘキシル、ヘプチル、オクチル、デシル、テトラデシル、ヘキサデシル、エイコシル、テトラコシルなど)である。「低級アルキル」基は、1〜6個の炭素原子を含むアルキル基である。
本明細書では、ベースペプチドおよび側鎖を含む化合物、ならびにそれらの薬学的に許容される形態が開示される。本明細書で使用される「側鎖」という用語は、分子の主要部分またはベースペプチドに結合された原子群を指す。最も好ましい実施形態では、化合物は線状ペプチドである。ある形態では、化合物は環状ペプチドである。線状ペプチドまたは環状ペプチドを含む医薬組成物は、化合物および医薬的に許容される添加剤を含むタンパク質である。そのような医薬組成物は、場合により、1以上の追加の生物活性物質を含んでもよい。本開示の目的のために、語句「活性成分」は、一般に、線状または環状化合物を指す。
ペプチドの合成は、最初に、アミノ酸およびアミノ酸類似体の、所望の配列と数が選択される。当業者が理解するように、選択されるアミノ酸構造(天然または非天然)の数、立体化学、およびタイプは、調製されるペプチドのサイズ、所望の構造モチーフ(例えば、αヘリックス)を生成する特定のアミノ酸の能力、および標的またはエフェクター生体分子に効果的に結合するタンパク質ドメインを模倣することが望ましい任意の特定のモチーフに依存する。ある形態では、ペプチドはらせん状である。ある形態では、ペプチドはらせん状ではない。したがって、ペプチド配列は、既知のペプチドまたはタンパク質の配列または部分配列に対応し、その中の既存のαヘリックスまたは他のアミノ酸モチーフの安定性または他の特性を改善することができる。さらにあるいは別法として、ペプチド配列を既知のペプチドまたはタンパク質に付加して、以前は存在しなかったαヘリックスまたは他のアミノ酸モチーフを追加することができる。
H2N−Lys−Gln−Thr−Ala−Arg−Lys−Ser−Thr−Gly−Gly−CONH2(配列番号1);
H2N−Gln−Thr−Ala−Arg−Lys−CONH2(配列番号2);
H2N−Lys−Gln−Thr−Ala−Arg−Lys−CONH2(配列番号3);又は
CbzHN−Gln−Thr−Ala−Arg−Lys−CONH2(配列番号4)
Cbzはカルボキシベンジルを意味する。
急性白血病を有する対象を治療するための組成物および方法が開示される。一般に、組成物は、ベースオリゴマーおよび側鎖を含む線状または環状オリゴマーを含む。側鎖は一般に、共役/非局在化基を含むように設計または選択される。オリゴマーは一般に、共役/非局在化基を介してYEATSタンパク質ドメインと相互作用し得る。この相互作用は、YEATSタンパク質ドメインにおけるπ−π−πスタッキング相互作用を妨害または阻害し、これが所望のYEATS阻害効果を有すると考えられる。YEATSドメインは、ヒストンのリジンクロトン化マークを特異的に認識し、アミノ酸残基を含む2つの保存された芳香環を使用してπ−π−πスタッキングを形成することにより、クロトニル基を提供する。
AはCR2又はNであり得;
B1及びB2はそれぞれ独立して選択された二価の連結単位であり得、
該連結単位は、アミド、エステル、チオエステル、チオアミド、イミダート、イミド、スルホネート、又はスルホンアミド結合で頭−尾方向に連結し;
D1は、H又は置換されていない又は置換されたヒドロカルビル、カルボシクリル又はヘテロシクリルであり得;
D2はH、NH2、NHR15、NR16R17、OH、OR18、又は置換されていない又は置換されたヒドロカルビル、カルボシクリル又はヘテロシクリルであり得;
Xは置換されていない又は置換されたC1−10アルキル、C1−10アルケニル、C1−10アルキニル、C1−10カルボシクリル、C1−10ヘテロアルキル、C1−10ヘテロアルケニル、C1−10ヘテロアルキニル、又はC1−10ヘテロシクリルであり得:
YはNR3、O、又はSであり得:
Zは−CO−、−CS−、−CNR4−、−SO−、又は−SO2−であり得;
R15、R16、R17およびR18は、H又はアルキル、アルケニル、アルキニル、置換されたアルキル、置換されたアルケニル、置換されたアルキニル、アルコキシ、アルキルアミノ、ジアルキルアミノ、ヒドロキシ、アリール、置換されたアリール、ヘテロアリール、置換されたヘテロアリール、置換されたアルコキシ、カルボキシル、置換されたカルボキシル、アミノ、置換されたアミノ、アミド、置換されたアミド、C3−C20環、置換されたC3−C20環、ヘテロ環、又は置換されたヘテロ環であり得;
R2、R3、R4は、独立して、H又はC1−10ヒドロカルビル、C1−10カルボシクリル、又はC1−10ヘテロシクリルであり得;
R1は共役/非局在化基であり得る]。ある形態では、共役/非局在化基は置換された又は置換されていない、ヘテロ環又は炭素環、芳香環(例えば、単環、二環、三環、四環の)又は置換されていない又は置換されたアルケニル又はアルキニルであり、共役/非局在化基は、π電子が非局在化することを可能にするオーバーラップするp軌道を含み;ここで、mおよびnはそれぞれ独立して0〜10の整数であって、m又はnの少なくとも一方は0ではない。ある形態では、m又はnの少なくとも一方は0ではない。ある形態では、mまたはnはいずれも0ではない。
0〜20、1〜20、2〜20、3〜20、4〜20、5〜20、6〜20、7〜20、8〜20、9〜20、10〜20、11〜20、12〜20、13〜20、14〜20、15〜20、16〜20、17〜20、18〜20、19〜20、0〜19、1〜19、2〜19、3〜19、4〜19、5〜19、6〜19、7〜19、8〜19、9〜19、10〜19、11〜19、12〜19、13〜19、14〜19、15〜19、16〜19、17〜19、18〜19、0〜18、1〜18、2〜18、3〜18、4〜18、5〜18、6〜18、7〜18、8〜18、9〜18、10〜18、11〜18、12〜18、13〜18、14〜18、15〜18、16〜18、17〜18、0〜17、1〜17、2〜17、3〜17、4〜17、5〜17、6〜17、7〜17、8〜17、9〜17、10〜17、11〜17、12〜17、13〜17、14〜17、15〜17、16〜17、0〜16、1〜16、2〜16、3〜16、4〜16、5〜16、6〜16、7〜16、8〜16、9〜16、10〜16、11〜16、12〜16、13〜16、14〜16、15〜16、0〜15、1〜15、2〜15、3〜15、4〜15、5〜15、6〜15、7〜15、8〜15、9〜15、10〜15、11〜15、12〜15、13〜15、14〜15、0〜14、1〜14、2〜14、3〜14、4〜14、5〜14、6〜14、7〜14、8〜14、9〜14、10〜14、11〜14、12〜14、13〜14、0〜13、1〜13、2〜13、3〜13、4〜13、5〜13、6〜13、7〜13、8〜13、9〜13、10〜13、11〜13、12〜13、0〜12、1〜12、2〜12、3〜12、4〜12、5〜12、6〜12、7〜12、8〜12、9〜12、10〜12、11〜12、0〜11、1〜11、2〜11、3〜11、4〜11、5〜11、6〜11、7〜11、8〜11、9〜11、10〜11、0〜10、1〜10、2〜10、3〜10、4〜10、5〜10、6〜10、7〜10、8〜10、9〜10、0〜9、1〜9、2〜9、3〜9、4〜9、5〜9、6〜9、7〜9、8〜9、0〜8、1〜8、2〜8、3〜8、4〜8、5〜8、6〜8、7〜8、0〜7、1〜7、2〜7、3〜7、4〜7、5〜7、6〜7、0〜6、1〜6、2〜6、3〜6、4〜6、5〜6、0〜5、1〜5、2〜5、3〜5、4〜5、0〜4、1〜4、2〜4、3〜4、0〜3、1〜3、2〜3、0〜2、1〜2、及び0〜1。ある形態では、m+nは0、1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、又は20であり得る。
開示される化合物は、それを必要とする対象を治療するために使用することができる。この目的のために、本化合物を医薬組成物に配合することが有用である。そのような医薬組成物は、開示された線状または環状ペプチド化合物の1つ以上および医薬的に許容される添加剤を含む。
A.条件
疾患、障害、または病気と診断された、または疾患、障害、または病気に対して感受性を有する対象に、治療的に有効な量のペプチド阻害剤を投与することによって、疾患、障害または病気を治療する方法が提供される。本明細書に記載のペプチド阻害剤化合物は、そのような二次構造モチーフが、例えば治療薬または研究ツールとして有利であれば有用であり得る。ある形態では、化合物は、π−π−πスタッキング相互作用の阻害剤として機能し得る。特定の形態では、化合物は、YEATSドメインにおけるπ−π−πスタッキング相互作用の阻害剤として機能し得る。一般的に言えば、化合物はタンパク質−タンパク質、タンパク質−リガンド、またはタンパク質−受容体結合相互作用のモジュレーターであり得る。ある形態では、これらの化合物は、クロマチン修飾またはリモデリングを特徴とする任意の状態の治療に有用である。ある形態では、これらの化合物は急性白血病の治療に有用である。特定の形態では、これらの化合物は混合系統型白血病の治療に有用である。
本明細書に記載される化合物の投与量は、送達が行われる方法において所望の効果を生み出すのに十分な量である。投与量は、望ましくない交差反応、アナフィラキシー反応などの有害な副作用を引き起こすほど多くすべきではない。一般に、投与量は、対象の年齢、状態、性別および疾患の程度によって異なり、当業者が決定することができる。投与量は、関与する対象の臨床状態に基づいて、個々の医師によって調整され得る。用量、投与のスケジュール、および投与経路は変更することができる。
本発明の医薬組成物は、任意の経路で投与することができる。ある形態では、本発明の医薬組成物は、経口、静脈内、筋肉内、動脈内、髄内、くも膜下腔内、皮下、脳室内、経皮、皮内、直腸、膣内、腹腔内、局所(粉末剤、軟膏、クリーム、および/またはドロップなどによる)、粘膜、鼻腔、バッカル、経腸、舌下;気管内注入、気管支注入、および/または吸入;および/または経口スプレー、鼻スプレー、および/またはエアロゾルを含む、様々な経路で投与される。具体的に考えられる経路は、全身静脈内注射、血液および/またはリンパ液供給を介した局所投与、および/または罹患部位への直接投与である。一般的に、最も適切な投与経路は、薬剤の性質(例えば、胃腸管の環境におけるその安定性)、対象の状態(例えば、対象が耐えられるかどうか)を含む様々な要因に依存する。現在、経口および/または経鼻スプレーおよび/またはエアロゾル経路が、肺および/または呼吸器系に治療薬を直接送達するために最も一般的に使用されている。但し、本発明は、薬物送達の科学における可能性のある進歩を考慮して、任意の適切な経路による医薬組成物の送達を包含する。
試薬と器具
特に明記しない限り、化学試薬はすべてSigma Aldrichから購入した。FmocまたはCbz保護アミノ酸、固相ペプチド合成用の樹脂、およびカップリング試薬はすべてGL Biochemから購入した。溶液中の反応は、メルクのTLCシリカゲル60 F254によってモニターした。フラッシュカラムクロマトグラフィーは、Graceから購入したシリカゲルを用いて行った。
プラスミドHis AF9(1 138)、His SUMO ENL(1 138)、His SUMO YEATS2(201 332)、His Gas41(15 159)およびタンパク質すべて、以下の参考文献に記載されている方法で発現させ、精製した:Y. Li, et al., AF9 YEATS domain links histone acetylation to DOT1L-mediated H3K79 methylation, Cell, 2014, 159(3), 558-571;Y. Li, et al., Molecular Coupling of Histone Crotonylation and Active Transcription by AF9 YEATS Domain, Molecular Cell, 2016, 62(2), 181-193;and YEATS2 is a selective histone crotonylation reader, Cell Research (2016) 26:629-632。タンパク質は大腸菌ロゼッタ細胞で発現させた。発現を誘導するため、IPTGをO.D.600が0.6のときの最終濃度0.4mMに添加し、培養物を16℃でさらに16時間培養した。細胞を回収し、溶解バッファー(50mM Tris HCl、pH 7.5、500mM NaCl、1mM TCEP、20mMイミダゾール、1mM PMSFおよびRoche EDTAを含まないプロテアーゼ阻害剤を新たに添加)に再懸濁した。超音波処理と遠心分離に続いて、溶解バッファーであらかじめ平衡化したNiカラムに上清をロードした。カラムを5カラム容量の洗浄バッファー(50mM Tris HCl、pH 7.5、500mM NaCl、20mMイミダゾール)で洗浄した後、標的タンパク質を溶出バッファー(50mM Tris HCl、pH 7.5、500mM NaCl、250mMイミダゾール)で溶出した。タンパク質をさらにHighload 26/60 Superdex 200ゲルろ過カラム(GE Healthcare Life Sciences)にロードし、溶出バッファー(500mM NaCl、50mM HEPES、1mM TCEP、pH 7.5)で溶出した。濃縮後、標的タンパク質を凍結し、後で使用するために80℃で保存した。
2−フランカルボン酸(1.5当量)とN−ヒドロキシスクシンイミド(NHS、1.4当量)を乾燥テトラヒドロフラン(THF)に溶解した。乾燥THF中のジシクロヘキシルカルボジイミド(DCC、1.4当量)を上記の溶液に加え、室温で一晩撹拌した。反応混合物を濾過し、濾液にN,N−イソプロピルエチルアミン(DIEA、3当量)と共にFmoc Lys OH・HCl(1当量)を加えた。得られた反応混合物を室温でさらに4〜6時間撹拌した。混合物のpHを1M HClで7に調整した。溶媒を真空下で留去した。残留物をジクロロメタンおよび1M HClで抽出した。有機層をブラインで洗浄し、Na2SO4で乾燥させた。溶媒を除去した後、粗製物をシリカゲルカラムクロマトグラフィーによって精製して、白色の固体を得た(収率74%)。1H NMR(DMSO d6、400MHz)δ8.37 (t,1H,J=5.41),7.89 (d,2H,J=7.48),7.79 (s,1H),7.72 (d,2H,J=7.44),7.65 (d,1H,J=7.90),7.41 (t,2H,J=7.39),7.32 (t,2H,J=7.42),7.06 (d,1H,J=3.29),6.60 (d,1H,J=1.43),4.29-4.20 (m,3H),3.95-3.89 (m,1H),3.20 (q,2H,J=6.29),1.73-1.58 (m,2H),1.52-1.42 (m,2H),1.38-1.32 (m,2H)。13C-NMR (DMSO-d6,100MHz)δ174.07、157.75、156.23、148.14、144.80、143.84、140.77、127.70、127.12、125.35、120.17、113.11、111.82、65.65、53.85、46.70、38.26、30.49、28.84、23.84
HRMS(ESI)[M+Na]+ m/z計算値485.1683、実測値485.1681。
ペプチドは、Rink Amide MBHA樹脂で合成した後、標準的なFmocベースの固相ペプチド合成プロトコルを行った。すべてのアミノ酸が結合した後、樹脂を95%トリフルオロ酢酸、2.5%トリイソプロピルシラン、1.5%H2O、および1%チオアニソールを含む切断カクテルと2時間インキュベートすることにより、保護基と樹脂からのペプチドの切断を行った。ペプチドは、XBridge Prep OBDTM C18カラム(30mm×250mm、10μm、Waters)を用いた分取HPLCで精製した。使用した移動相は、0.1%トリフルオロ酢酸を含む水(バッファーA)および0.1%トリフルオロ酢酸を含む水中の90%アセトニトリル(バッファーB)である。ペプチドの純度(>95%)と同一性はLC−MSによって確認した。阻害剤の阻害活性は、光架橋に基づく競合アッセイによって決定した。
示した濃度の異なる阻害剤を含むプローブ4.1または4.2(2μM)を、結合バッファー(50mM HEPES、150mM NaCl、2mM MgCl2、0.1%Tween 20、20%グリセロール、pH7.5、50ng/μL BSAありまたはなし))中でYEATSドメインタンパク質(5または20ng/μL)と、4℃で10分間インキュベートした。次に、サンプルを、氷上の96ウェルプレート内でUVランプを使用して365nmで20分間照射した。
調製した光架橋サンプルに、100μM Rho−N3(DMSO中の10mMストック)を加え、1mM TCEP(H2O中で新たに調製した50mMストック)、100μM TBTA(DMSO中の10mMストック)を加え、最後に1mM CuSO4(H2O中で新しく調製した50mMストック)を添加して反応を開始した。反応液を室温で1時間インキュベートした。5容量の氷冷アセトンを加えて反応を停止させ、−20℃で一晩置いてタンパク質を沈殿させた。
タンパク質沈殿後、サンプルを6000×gで5分間、4℃で遠心分離した。上澄みを捨て、ペレットを氷冷メタノールで2回洗浄し、10分間風乾した。タンパク質を、50mM DTTを含む1XLDSサンプルローディングバッファー(Invitrogen)に再懸濁し、80℃で8分間加熱した。次に、サンプルをSDS−PAGEで分析した。Typhoon 9410可変モードイメージャー(励起532nm、エミッションフィルター580nm)でゲルをスキャンして、標識されたタンパク質を可視化した。
リジンアセチル化(以下に示すKac)を認識するブロモドメイン(BrD)は、阻害剤の開発のために広く研究されているエピジェネティックリーダーの1つである。配列は種々異なるが、BrDは同様の構造を共有する疎水性ポケットでアセチルリジンを収容する。アセチル基は主に、結合ポケット内の保存されたアスパラギンと水素結合を形成することによって固定される。報告されたBrD阻害剤の主要なクラスは、アセチルリジン模倣体であり、BrDに結合したときに特徴的な水素結合を保持する。BrDの阻害は、癌、ウイルス感染、炎症、および神経疾患の治療の効果的な方法として実証されている。
「H3R8−D103」相互作用の有意性を調べるため、アルギニン残基をリジン、シトルリンおよびグルタミンを含む他の3つのアミノ酸に変更した(図46)。Lysへの変異では正電荷が維持され、CitとGlnでは正電荷がブロックまたは負電荷に変換された。0.3μMで、ペプチド対照、競合阻害物質のR8−K、R8−Cit、およびR8−Qのシグナル強度を比較することにより、阻害剤の活性を予備的に推定できる。サンプルR8−K、R8−Cit、およびR8−Qの強い蛍光シグナル強度は、AF9の比較的小さい部分が競合阻害物質に結合することを示した。従来の阻害剤(ペプチド対照)との比較では、これら3つの競合阻害物質がAF9 YEATSドメインと弱く相互作用することを示している。
生理学的pHでは、スレオニンの側鎖は極性であり、荷電していない。この残基をVal、Ala、Leu、Ser、HoFなどの他の中性残基に変更すると、結合が失われた。
この試験では、光架橋ベースの方法を使用して阻害活性を推定した(図28)。この方法は、光親和性プローブを使用する必要がある。プローブ(プローブ1、下記参照)は、タンパク質のリガンドであるクロトニル化ペプチドに由来し、光クロスリンカーと、生体直交型(bioorthogonal)の末端アルキンを有している。
さらに、光架橋ベースの競合アッセイから得られた結果の信頼性を検証するために、等温滴定熱量測定(ITC)を行い、AF9 YEATSドメインに対する阻害剤の直接の結合親和性を測定した。得られた解離定数は、ネイティブのクロトニル基(Kd=14.8μM)を2−フランカルボニル(XL−07、Kd=3.3μM)および5−オキサゾールカルボニル(XL−13、Kd=1.0μM)で置換することで、それぞれ4.5倍、14.8倍、結合が増強したことを示した(図27A〜CおよびTable 3)。ITCの測定値はIC50データと一致しており、光架橋ベースの競合アッセイから得られた結果の信頼性を示している。
対照の競合阻害物質のLC−MS分析は、質量電荷比(m/z)830.43(M+H+)、計算値m/z 830.41(M+H+)を示した。競合阻害物質R8−KのLC−MS分析は、m/z 824.47(M+Na+)、計算値m/z 824.39(M+Na+)、m/z 802.40(M+H+)、計算値m/z 802.40(M+H+);m/z 401.67(M+2H+)、計算値m/z 401.70(M+2H+)を示した。競合阻害物質R8−citのLC−MS分析は、m/z 831.39、計算値m/z 831.30(M+H+)を示した。競合阻害物質R8−QのLC−MS分析は、m/z 802.24(M+H+)、計算値m/z 802.37(M+H+)を示した。競合阻害物質A7−GのLC−MS分析は、m/z 816.47(M+H+)、計算値m/z 816.39(M+H+)、m/z 408.67(M+2H+)、計算値m/z 408.70(M+2H+)を示した。
次に、AF9 YEATS阻害の最適な配列を見い出そうとした。AF9 YEATS H3K9cr複合体では、R8残基がAF9のD103と電荷が安定化した水素結合を形成し、これにより、π−π−πスタッキングの他に、認識における別の重要な接触が提供される。YEATS阻害に対する隣接する残基の寄与を調べるために、阻害剤XL−07のRK特徴モチーフを抽出し、他の残基を1つずつ追加して、元のK4−G13デカマーとは配列の長さが異なる、更なる9つの阻害剤(XL−07a〜XL−07i、以下の構造とTable 5を参照)を作製した。
次に、阻害剤が他のYEATSドメインを標的にできるかどうかを調べた。ENL YEATSドメインに対する競合アッセイは、2つの最も強力な化合物、XL−07jとXL−13aがENLをそれぞれ1.3μMと0.71μMのIC50値で阻害したことを示した(図30〜32)。AF9とENLの間の類似性が高いことを考えると、AF9に活性な阻害剤が、同様にENLと密接に相互作用することが予測できた。しかし、XL−07jとXL−13aは、AF9と比較してENLに対し、それぞれ5倍、2.9倍の活性が低かったことも興味深い。AF9およびENLのYEATSドメインの芳香族「サンドイッチ」ケージは互いにほぼ同一であるため、阻害剤の活性の変化は、他の隣接残基によってもたらされる相互作用の違いに起因する可能性が高かった。この観察結果は、さまざまな配列が2つのYEATSドメインに対する阻害剤の選択性を逆転させる可能性の追求を触発した。報告されているように、ENL YEATSドメインは、H3K9よりもH3K27でのアシル化に対してわずかに高い親和性を示した。したがって、ENL選択的阻害剤を検索するためにH3K27配列に焦点を当てた。5−オキサゾールカルボニル側鎖をK27位置に組み込み、RKモチーフの隣接残基を変更し、これらを、上記のとおり、ENLに対する活性について大まかにスクリーニングすることで14個の阻害剤(XL−13bからXL−13o、以下の構造とTable 6を参照)を得た。
次に、セルラーサーマルシフトアッセイ(CETSA)を適用して、XL−13mが細胞透過性であり、生きている細胞のENLを標的にできるかどうかを調べた。MOLM−13(FLAG−ENL)をXL−13mで12時間処理した後、異なる温度で加熱してタンパク質を変性および沈殿させた。ENLが阻害剤と相互作用すると、熱安定性が向上し、高温で沈殿する。可溶性タンパク質を凍結融解サイクルによって抽出し、ウエスタンブロッティング分析にかけた。FLAG−タグとENLに対する抗体を使用して、XL−13m処理されたMOLM−13細胞中に可溶性ENLタンパク質が豊富に存在することが高い温度(55℃、57℃、59℃)で検出された。また、この阻害剤を別の白血病細胞株MV4−11とインキュベートしても同じ結果が得られ、XL−13mが細胞内に入り内因性ENLを標的にできることを示した。
MOLM13(FLAG−ENL)細胞を、50μMの化合物XL−13mの存在下または非存在下で24時間培養し、細胞を50μMでさらに24時間処理した。細胞をXL−13mで処理すると、c−Myc発現のJQ1誘導減少の感受性が増加した(図49A)。c−Mycの発現はqPCRによって定量化した。
MOLM13(FLAG−ENL)細胞を、50μMの化合物の存在下または非存在下で16時間インキュベートし、既に記載したようにセルラーサーマルシフトアッセイ(CETSA)のために回収した。抗FLAG抗体を使用してENLタンパク質を検出し、γ−アクチンブロッティングをネガティブコントロールとした。サーマルシフトアッセイにより、生きている細胞における、化合物XL−13l、XL−13m、およびXL−13nによるENLタンパク質の標的を明らかにした。
36個のAF9 YEATSドメイン阻害剤を設計および合成した。競合阻害物質の阻害活性を定量的に測定するために、光架橋と「クリックケミストリー」を組み合わせた確実な戦略を採用した。AF9 YEATSドメインへの結合親和性が弱い競合阻害物質を排除するために、すべての阻害剤の予備的スクリーニングを行った。同等の活性を有する阻害剤の50%最大阻害濃度(IC50)を最終的に決定した。それでも、阻害剤は改善された阻害活性を示さなかった。競合阻害物質Cbz−4は、N末端に拡張された芳香族系を有し、他の設計された競合阻害物質の中で最大の活性を示した。競合阻害物質Cbz−4のIC50は、0.226μMと測定され、これは、対照の競合阻害物質(0.189μM)よりわずかに大きい。
Claims (17)
- ベースオリゴマーおよび側鎖を含んでなる化合物又はその薬学的に許容される塩であって、該化合物が式(I):
AはCR2又はNであり;
B1及びB2はそれぞれ独立して選択された二価の連結単位であり得、該連結単位は、アミド、エステル、チオエステル、チオアミド、イミダート、イミド、スルホネート、又はスルホンアミド結合で頭−尾方向に連結し;
D1は、H又は置換されていない又は置換されたヒドロカルビル、カルボシクリル又はヘテロシクリルであり;
D2はH、NH2、NHR15、NR16R17、OH、OR18、又は置換されていない又は置換されたヒドロカルビル、カルボシクリル又はヘテロシクリルであり;
Xは置換されていない又は置換されたC1−10アルキル、C1−10アルケニル、C1−10アルキニル、C1−10カルボシクリル、C1−10ヘテロアルキル、C1−10ヘテロアルケニル、C1−10ヘテロアルキニル、又はC1−10ヘテロシクリルであり;
YはNR3、O、又はSであり;
Zは−CO−、−CS−、−CNR4−、−SO−、又は−SO2−であり;
R2、R3、R4は、独立して、H又はC1−10ヒドロカルビル、C1−10カルボシクリル、又はC1−10ヘテロシクリルであり;
R1は、置換された又は置換されていない、ヘテロ環又は炭素環、芳香環(単環、二環、三環、四環の)又は置換されていない又は置換されたアルケニル又はアルキニル基のような、共役/非局在化基であり;
R15、R16、R17およびR18は、H又はアルキル、アルケニル、アルキニル、置換されたアルキル、置換されたアルケニル、置換されたアルキニル、アルコキシ、アルキルアミノ、ジアルキルアミノ、ヒドロキシ、アリール、置換されたアリール、ヘテロアリール、置換されたヘテロアリール、置換されたアルコキシ、カルボキシル、置換されたカルボキシル、アミノ、置換されたアミノ、アミド、置換されたアミド、C3−C20環、置換されたC3−C20環、ヘテロ環、又は置換されたヘテロ環であり;
mおよびnはそれぞれ独立して0〜10の整数であって、m又はnの少なくとも一方は0ではない]
で定義される、化合物又はその薬学的に許容される塩。 - 化合物が、式(III):
J1およびJ2は、それぞれ独立に任意のα−アミノ酸であり;
Xは置換されていない又は置換されたC1−10アルキル、C1−10アルケニル、C1−10アルキニル、C1−10カルボシクリル、C1−10ヘテロアルキル、C1−10ヘテロアルケニル、C1−10ヘテロアルキニル、又はC1−10ヘテロシクリルであり;
YはNR3、O、又はSであり;
Zは−CO−、−CS−、−CNR4−、−SO−、及び−SO2−であり;
R3及びR4は独立してH又はC1−10ヒドロカルビル、C1−10カルボシクリル又はC1−10ヘテロシクリルであり;
R1は、置換された又は置換されていない、ヘテロ環又は炭素環、芳香環(単環、二環、三環、四環の)、または置換されていない又は置換されたアルケニル又はアルキニルのような、共役/非局在化基であり;
mおよびnはそれぞれ独立して0〜10の整数であって、m又はnの少なくとも一方は0ではない]
で定義される、請求項1記載の化合物。 - 化合物が、式(IV):
E1及びE2はそれぞれ、独立して置換されていない又は置換されたC1−10アルキル、C1−10アルケニル、C1−10アルキニル、C1−10カルボシクリル、C1−10ヘテロアルキル、C1−10ヘテロアルケニル、C1−10ヘテロアルキニル、又はC1−10ヘテロシクリル、又はO、S、又はNR5であり;
Xは置換されていない又は置換されたC1−10アルキル、C1−10アルケニル、C1−10アルキニル、C1−10カルボシクリル、C1−10ヘテロアルキル、C1−10ヘテロアルケニル、C1−10ヘテロアルキニル、又はC1−10ヘテロシクリルであり;
YはNR3、O、又はSであり;
Zは−CO−、−CS−、−CNR4−、−SO−、又は−SO2−であり;
R3、R4、R5は独立してH、C1−10ヒドロカルビル、C1−10カルボシクリル又はC1−10ヘテロシクリルであり;
R1は、置換された又は置換されていない、ヘテロ環又は炭素環、芳香環(単環、二環、三環、四環の)又は置換されていない又は置換されたアルケニル又はアルキニルのような、共役/非局在化基であり;
mおよびnはそれぞれ独立して0〜10の整数であって、m又はnの少なくとも一方は0ではない]
で示される、請求項1記載の化合物。 - B1連結単位の少なくとも2つは側鎖を含み、B1連結単位の側鎖の2つが互いに共有結合して環状オリゴマーを形成している、請求項1〜4のいずれかに記載の化合物。
- 化合物が、式(V):
R1は置換された又は置換されていない、芳香環(単環、二環、三環、四環の)又は置換されていない又は置換されたアルケニル又はアルキニルのような、共役/非局在化基であり;
R6、R7、R8、R9、およびR10は独立してH又はC1−10ヒドロカルビル、C1−10カルボシクリル又はC1−10ヘテロシクリルであり;
G1、G2、及びG3はそれぞれ置換されていない又は置換されたC1−10アルキル、C1−10アルケニル、C1−10アルキニル、C1−10カルボシクリル、C1−10ヘテロアルキル、C1−10ヘテロアルケニル、C1−10ヘテロアルキニル、C1−10ヘテロシクリル、又は5〜9員のヘテロアリールであり;
i1、i2、j1、j2、k1、k2はそれぞれ独立して0〜10の整数である]
で定義される、請求項5記載の化合物。 - B2連結単位の少なくとも2つは側鎖を含み、B2連結単位の側鎖の2つが互いに共有結合して環状オリゴマーを形成している、請求項1〜4のいずれかに記載の化合物。
- 化合物がπ−π−πスタッキング相互作用を阻害する、請求項1〜7のいずれかに記載の化合物。
- 化合物がYEATSタンパク質ドメインを選択的に標的とする、請求項1〜8のいずれかに記載の化合物。
- 請求項1〜9のいずれかに記載の化合物の有効量を含む医薬組成物。
- 1以上の薬学的に許容される担体または添加物をさらに含む、請求項10に記載の組成物。
- 化合物がπ−π−πスタッキング相互作用を選択的に阻害する、請求項10または11に記載の組成物。
- 化合物がYEATSタンパク質ドメインを選択的に標的とする、請求項10〜12のいずれかに記載の組成物。
- 化合物が癌の治療に有効である、請求項10〜13のいずれかに記載の組成物。
- 癌が急性白血病である、請求項10〜14のいずれかに記載の組成物。
- 請求項10〜15のいずれかに記載の組成物を、それを必要とする対象に投与することを含む、癌を治療する方法。
- 対象が急性白血病を有する、請求項16に記載の方法。
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- 2018-11-26 EP EP18880889.3A patent/EP3717504A4/en active Pending
- 2018-11-26 WO PCT/CN2018/117418 patent/WO2019101195A1/en unknown
- 2018-11-26 JP JP2020528873A patent/JP7239202B2/ja active Active
- 2018-11-26 CN CN201880076657.2A patent/CN111615517B/zh active Active
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Also Published As
Publication number | Publication date |
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EP3717504A1 (en) | 2020-10-07 |
EP3717504A4 (en) | 2021-10-20 |
CN111615517B (zh) | 2024-01-09 |
US20210277061A1 (en) | 2021-09-09 |
CN111615517A (zh) | 2020-09-01 |
JP7239202B2 (ja) | 2023-03-14 |
US11512111B2 (en) | 2022-11-29 |
WO2019101195A1 (en) | 2019-05-31 |
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