JP2022141846A - 急性骨髄性白血病を処置するためのHCK阻害剤及びBcl-2阻害剤 - Google Patents
急性骨髄性白血病を処置するためのHCK阻害剤及びBcl-2阻害剤 Download PDFInfo
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- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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Abstract
Description
1.細胞においてHCK及びBCL-2を共に阻害する方法であって、細胞を、HCK阻害剤及びBCL-2阻害剤、又はその薬学的に許容される組成物と接触させる工程を含む、方法。
2.FLT3-ITD変異を有する細胞を致死させる方法であって、細胞を、HCK阻害剤及びBCL-2阻害剤、又はその薬学的に許容される組成物と接触させる工程を含む、方法。
3.細胞を、FLT3-ITD阻害剤と接触させる工程を更に含む、項目1又は2の方法。
4.HCK阻害剤が、HCK/FLT3-ITD二重阻害剤である、項目1又は2の方法。
5.急性骨髄性白血病を処置する方法であって、対象に、HCK阻害剤及びBCL-2阻害剤、又はその薬学的に許容される組成物を共同的に投与する工程を含む、方法。
6.対象が、FLT3-ITD+急性骨髄性白血病を有する、項目5の方法。
7.対象が、DNMT3A、IDH2、IDH1、NPM1、TET2、CEBPA、ASXL1、EZH2、SETBP1、SMC3、KIT、NRAS及びWT1から選択される遺伝子に1つ以上の変異を有する細胞により特徴付けられる悪性造血及び/又は非悪性多系統造血を有する、項目5又は6の方法。
8.FLT3-ITD阻害剤を共同的に投与する工程を更に含む、項目5から7のいずれか一項の方法。
9.HCK阻害剤が、HCK/FLT3-ITD二重阻害剤である、項目5から8のいずれか一項の方法。
10.HCK阻害剤、FLT3-ITD阻害剤及びBCL-2阻害剤が、別々の単位剤形で同時に又は逐次的に投与される、項目8又は9の方法。
11.HCK阻害剤、BCL-2阻害剤、及び薬学的に許容される担体、アジュバント又は媒体を含む単一の単位剤形を投与する工程を含む、項目5から10のいずれか一項の方法。
12.単一の単位剤形が、FLT3-ITD阻害剤を更に含み、又はHCK阻害剤が、HCK/FLT3-ITD二重阻害剤である、項目11の方法。
13.HCK阻害剤が、RK-20449、RK-20693、RK-24466、RK-20444、RK-20445及びRK-20466から選択される、前の項目のいずれか1つの方法。
14.FLT3-ITD阻害剤が、AC220、ソラフェニブ、PKC412、CEP-701、UNC2025、MLN518、KW-2449、AMG-925、スニチニブ、SU5614、AC2206、クレノラニブ及びPLX3397から選択される、項目3、4、又は7から12のいずれか1つの方法。
15.BCL-2阻害剤が、AT-101、TW-37、TM-1206、ゴシポール酸(gossypolic acid)、ゴシポロン酸(gossypolonic acid)、アポゴシポール、アポゴシポロン、A385358、ABT-737、ABT-263、ABT-199、WEHI-539、BXI-61、BXI-72、オバトクラックス、JY-1-106及びSAHBペプチドから選択される、前の項目のいずれか1つの方法。
16.BCL-2阻害剤が、ゴシポール、オバトクラックス、ABT-737、ABT-199及びABT-263から選択される、項目15の方法。
17.BCL-2阻害剤が、ABT-199である、項目16の方法。
18.HCK阻害剤が、RK-20449であり、BCL-2阻害剤が、ABT-199である、項目17の方法。
19.HCK阻害剤が、RK-20693であり、BCL-2阻害剤が、ABT-199である、項目17の方法。
20.FLT3-ITD阻害剤が、AC220であり、BCL-2阻害剤が、ABT-199である、項目17の方法。
21.FLT3-ITD阻害剤が、SU5614であり、BCL-2阻害剤が、ABT-737である、項目16の方法。
22.HCK阻害剤、及び/又はFLT3-ITD阻害剤、及び/又はBCL-2阻害剤が、薬学的に許容される塩として各々存在する、前の項目のいずれ1つの方法。
23.HCK阻害剤、及び/又はFLT3-ITD阻害剤、及び/又はBCL-2阻害剤が、薬学的に許容される組成物中に各々存在する、前の項目のいずれか1つの方法。
別段の規定がない限り、本明細書において使用される技術及び科学的用語の全ては、本開示の当業者により一般に理解される意味を有する。以下の参照文献は、本開示において使用される用語の多くの一般的定義を当業者に提供する:Singletonら、Dictionary of Microbiology and Molecular Biology(第2版1994年); The Cambridge Dictionary of Science and Technology(Walker編、1988年); The Glossary of Genetics、第5版、R, Riegerら(編)、Springer Verlag (1991年);及びHale & Marham、The Harper Collins Dictionary of Biology (1991年)。本明細書では、次に述べる用語は、特に明記しない限り、以下に帰する意味を有する。
体細胞変異の様々な組合せによって定義される大量のクローン多様性にもかかわらず、SFK及びFLT3-ITDの複数キナーゼ阻害は、in vivoでAMLを効果的に減少させ、BCL2阻害の追加は、抵抗性AMLを相乗的に排除した。ある特定の実施形態において、患者間の大量の異質性及び個々の患者内のクローン多様性にもかかわらず、FLT3-ITD及びHCKの複数キナーゼ阻害剤であるRK-20449、並びにBCL-2の小分子阻害剤であるABT-199の同時投与による抗アポトーシス及びキナーゼシグナル伝達経路の複合阻害により、in vivoでヒトFLT3-ITD+AMLの排除に成功した。
本発明は、HCK阻害剤及びBCL-2阻害剤を含み、任意選択でFLT3-ITD阻害剤を伴う共同療法に一般に関する。本発明のある特定の実施形態において、FLT3-ITD及び/又はHCK阻害剤の治療有効量は、BCL-2阻害剤が投与されない場合になると予想される治療有効量未満である。同様に、BCL-2阻害剤の治療有効量は、FLT3-ITD阻害剤及び/又はHCK阻害剤が投与されない場合になると予想される治療有効量未満であり得、HCK阻害剤の治療有効量は、FLT3-ITD阻害剤及び/又はBCL-2阻害剤が投与されない場合になると予想される治療有効量未満であり得る。このように、いずれかの薬剤の高用量に関連する好ましくない副作用が、最小化され得る。他の潜在的利点(服用計画の改善及び/又は薬物費用の減少を含むがこれに限定されない)は、当業者に明らかになろう。FLT3-ITD阻害剤、HCK阻害剤及び/又はBCL-2阻害剤は、互いに別々に、例えば、複数回投与計画の部分として、投与され得る。別法として、2つ以上の阻害剤は、単一剤形の部分であり、例えば、単一組成物に一緒に混合され得る。
一部の実施形態において、開示された化合物は、薬学的に許容される組成物の形態であり得る。本明細書に記述されるFLT3-ITD阻害剤、及び/又はHCK阻害剤、及び/又はBCL-2阻害剤並びに薬学的に許容される担体を含む医薬組成物が、本明細書に開示される。
本発明の組成物は、経口的、非経口的(皮下、筋肉内、静脈及び皮内を含める)、吸入スプレーにより、局所的、直腸的、経鼻的、口腔的、経膣的又は埋め込み型容器を介して投与され得る。一部の実施形態において、得られた化合物又は組成物は、静脈内及び/又は腹腔内投与可能である。特定の好ましい実施形態において、開示された方法は、FLT3-ITD阻害剤、HCK阻害剤及びBCL-2阻害剤のうち任意の2つ又は3つ全部を経口的若しくは非経口的に投与する工程を含む。
各個別の刊行物、特許又は特許出願を参照により組み込むことを特別に及び個別に示す場合と同程度に、本明細書に記載の刊行物、特許及び特許出願の全てを、参照により本明細書に組み込む。一致しない場合、本明細書におけるあらゆる定義を含めて、本出願が支配することになる。
当業者は、日常の実験だけを使用して、本明細書に記述される特定の手順、実施形態、請求項及び例の多数の等価物を認識する、又は確認することが可能になる。そのような等価物は、本発明の範囲内にあると見なされ、本明細書に添付された特許請求の範囲により網羅された。例えば、当業者に認識される代替物を用いる及び日常の実験だけを使用する反応条件の修飾は、本出願の範囲内であると理解されるべきである。
以下の化合物は、例えば、WO2014/017659に開示される方法に従って合成することができる。
RK-20449(別名A 419259):
7-((1R,4R)-4-(4-メチルピペラジン-1-イル)シクロヘキシル)-5-(4-フェノキシフェニル)-7H-ピロロ[2,3-d]ピリミジン-4-アミン
N-(4-(4-アミノ-7-(trans-4-(4-メチルピペラジン-1-イル)シクロヘキシル)-7H-ピロロ[2,3-d]ピリミジン-5-イル)フェニル)-3-フェニルプロパンアミド
N-(4-(4-アミノ-7-((1R,4R)-4-(3-メチル-5,6-ジヒドロ-[1,2,4]トリアゾロ[4,3-a]ピラジン-7(8H)-イル)シクロヘキシル)-7H-ピロロ[2,3-d]ピリミジン-5-イル)-2-メトキシフェニル)-1-メチル-1H-インドール-2-カルボキサミド
7-((1R,4R)-4-(8-メチル-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)シクロヘキシル)-5-(4-フェノキシフェニル)-7H-ピロロ[2,3-d]ピリミジン-4-アミン
1-((1S,4S)-4-((8-メチル-8-アザビシクロ[3.2.1]オクタン-3-イル)アミノ)シクロヘキシル)-3-(4-フェノキシフェニル)-1H-ピラゾロ[3,4-d]ピリミジン-4-アミン
7-((1R,4R)-4-(3-メチル-5,6-ジヒドロ-[1,2,4]トリアゾロ[4,3-a]ピラジン-7(8H)-イル)シクロヘキシル)-5-(4-フェノキシフェニル)-7H-ピロロ[2,3-d]ピリミジン-4-アミン
N-(4-(4-アミノ-1-((1R,4R)-4-(4-メチルピペラジン-1-イル)シクロヘキシル)-1H-ピラゾロ[3,4-d]ピリミジン-3-イル)-2-メトキシフェニル)-1-メチル-1H-インドール-2-カルボキサミド
1-((1R,4R)-4-(8-メチル-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)シクロヘキシル)-3-(4-フェノキシフェニル)-1H-ピラゾロ[3,4-d]ピリミジン-4-アミン
N-(4-(4-アミノ-7-((1S,4S)-4-(3-メチル-5,6-ジヒドロ-[1,2,4]トリアゾロ[4,3-a]ピラジン-7(8H)-イル)シクロヘキシル)-7H-ピロロ[2,3-d]ピリミジン-5-イル)-2-メトキシフェニル)-1-メチル-1H-インドール-2-カルボキサミド
N-(4-(4-アミノ-7-((1r,4r)-4-(4-メチルピペラジン-1-イル)シクロヘキシル)-7H-ピロロ[2,3-d]ピリミジン-5-イル)フェニル)-1-メチル-1H-インドール-2-カルボキサミド
N-(4-(4-アミノ-1-((1r,4r)-4-(8-メチル-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)シクロヘキシル)-1H-ピラゾロ[3,4-d]ピリミジン-3-イル)フェニル)ピコリンアミド
N-(4-(4-アミノ-1-((1R,4R)-4-(8-メチル-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)シクロヘキシル)-1H-ピラゾロ[3,4-d]ピリミジン-3-イル)フェニル)-1-メチル-1H-インドール-2-カルボキサミド
N-(4-(4-アミノ-1-(1-(8-メチル-8-アザビシクロ[3.2.1]オクタン-3-イル)ピペリジン-4-イル)-1H-ピラゾロ[3,4-d]ピリミジン-3-イル)フェニル)-1-メチル-1H-インドール-2-カルボキサミド
N-(4-(4-アミノ-7-((1S,4S)-4-(4-メチルピペラジン-1-イル)シクロヘキシル)-7H-ピロロ[2,3-d]ピリミジン-5-イル)-2-メトキシフェニル)-1-メチル-1H-インドール-2-カルボキサミド
N-(4-(4-アミノ-7-((1R,4R)-4-(4-メチルピペラジン-1-イル)シクロヘキシル)-7H-ピロロ[2,3-d]ピリミジン-5-イル)-2-メトキシフェニル)-1-メチル-1H-インドール-2-カルボキサミド
N-(4-(4-アミノ-1-((1R,4R)-4-(4-メチルピペラジン-1-イル)シクロヘキシル)-1H-ピラゾロ[3,4-d]ピリミジン-3-イル)フェニル)-1-メチル-1H-インドール-2-カルボキサミド
N-(4-(4-アミノ-1-((1R,4R)-4-(3-メチル-5,6-ジヒドロ-[1,2,4]トリアゾロ[4,3-a]ピラジン-7(8H)-イル)シクロヘキシル)-1H-ピラゾロ[3,4-d]ピリミジン-3-イル)-2-メトキシフェニル)-1-メチル-1H-インドール-2-カルボキサミド
N-(4-(4-アミノ-7-((1R,4R)-4-(3-(トリフルオロメチル)-5,6-ジヒドロ-[1,2,4]トリアゾロ[4,3-a]ピラジン-7(8H)-イル)シクロヘキシル)-7H-ピロロ[2,3-d]ピリミジン-5-イル)-2-メトキシフェニル)-1-メチル-1H-インドール-2-カルボキサミド
N-(4-(4-アミノ-7-((1s,4s)-4-(3-エチル-5,6-ジヒドロ-[1,2,4]トリアゾロ[4,3-a]ピラジン-7(8H)-イル)シクロヘキシル)-7H-ピロロ[2,3-d]ピリミジン-5-イル)-2-メトキシフェニル)-1-メチル-1H-インドール-2-カルボキサミド
N-(4-(4-アミノ-7-((1r,4r)-4-(3-エチル-5,6-ジヒドロ-[1,2,4]トリアゾロ[4,3-a]ピラジン-7(8H)-イル)シクロヘキシル)-7H-ピロロ[2,3-d]ピリミジン-5-イル)-2-メトキシフェニル)-1-メチル-1H-インドール-2-カルボキサミド
N-(4-(4-アミノ-7-((1s,4s)-4-(3-イソプロピル-5,6-ジヒドロ-[1,2,4]トリアゾロ[4,3-a]ピラジン-7(8H)-イル)シクロヘキシル)-7H-ピロロ[2,3-d]ピリミジン-5-イル)-2-メトキシフェニル)-1-メチル-1H-インドール-2-カルボキサミド
N-(4-(4-アミノ-7-((1R,4R)-4-(3-イソプロピル-5,6-ジヒドロ-[1,2,4]トリアゾロ[4,3-a]ピラジン-7(8H)-イル)シクロヘキシル)-7H-ピロロ[2,3-d]ピリミジン-5-イル)-2-メトキシフェニル)-1-メチル-1H-インドール-2-カルボキサミド
N-(4-(4-アミノ-7-((1S,4S)-4-(3-メチル-5,6-ジヒドロイミダゾ[1,5-a]ピラジン-7(8H)-イル)シクロヘキシル)-7H-ピロロ[2,3-d]ピリミジン-5-イル)-2-メトキシフェニル)-1-メチル-1H-インドール-2-カルボキサミド
N-(4-(4-アミノ-7-((1R,4R)-4-(3-メチル-5,6-ジヒドロイミダゾ[1,5-a]ピラジン-7(8H)-イル)シクロヘキシル)-7H-ピロロ[2,3-d]ピリミジン-5-イル)-2-メトキシフェニル)-1-メチル-1H-インドール-2-カルボキサミド
N-(4-(4-アミノ-7-((1S,4S)-4-(2-メチル-6,7-ジヒドロピラゾロ[1,5-a]ピラジン-5(4H)-イル)シクロヘキシル)-7H-ピロロ[2,3-d]ピリミジン-5-イル)-2-メトキシフェニル)-1-メチル-1H-インドール-2-カルボキサミド
N-(4-(4-アミノ-7-((1S,4S)-4-(6,7-ジヒドロピラゾロ[1,5-a]ピラジン-5(4H)-イル)シクロヘキシル)-7H-ピロロ[2,3-d]ピリミジン-5-イル)-2-メトキシフェニル)-1-メチル-1H-インドール-2-カルボキサミド
N-(4-(4-アミノ-7-((1R,4R)-4-(3-メチル-5,6-ジヒドロイミダゾ[1,2-a]ピラジン-7(8H)-イル)シクロヘキシル)-7H-ピロロ[2,3-d]ピリミジン-5-イル)-2-メトキシフェニル)-1-メチル-1H-インドール-2-カルボキサミド
7-((1S,4S)-4-(((1-メチル-1H-ピラゾール-5-イル)メチル)アミノ)シクロヘキシル)-5-(4-フェノキシフェニル)-7H-ピロロ[2,3-d]ピリミジン-4-アミン
7-((1R,4R)-4-(((1-メチル-1H-ピラゾール-5-イル)メチル)アミノ)シクロヘキシル)-5-(4-フェノキシフェニル)-7H-ピロロ[2,3-d]ピリミジン-4-アミン
7-((1S,4S)-4-(((1-メチル-1H-ピラゾール-3-イル)メチル)アミノ)シクロヘキシル)-5-(4-フェノキシフェニル)-7H-ピロロ[2,3-d]ピリミジン-4-アミン
1-((1S,4S)-4-(8-メチル-3,8-ジアザビシクロ[3.2.1]オクタン-3-イル)シクロヘキシル)-3-(4-フェノキシフェニル)-1H-ピラゾロ[3,4-d]ピリミジン-4-アミン
7-((1S,4S)-4-((8-メチル-8-アザビシクロ[3.2.1]オクタン-3-イル)アミノ)シクロヘキシル)-5-(4-フェノキシフェニル)-7H-ピロロ[2,3-d]ピリミジン-4-アミン
5-(4-フェノキシフェニル)-7-((1R,4R)-4-(3-(トリフルオロメチル)-5,6-ジヒドロ-[1,2,4]トリアゾロ[4,3-a]ピラジン-7(8H)-イル)シクロヘキシル)-7H-ピロロ[2,3-d]ピリミジン-4-アミン
AC220(別名キザルチニブ):
N-[5-(1,1-ジメチルエチル)-3-イソオキサゾリル]-N'-[4-[7-[2-(4-モルホリニル)エトキシ]イミダゾ[2,1-b]ベンゾチアゾール-2-イル]フェニル]尿素
4-[4-[2-(4-クロロフェニル)-4,4-ジメチル-1-シクロヘキセン-1-イル]メチル]-1-ピペラジニル]-N-[[3-ニトロ-4-[[(テトラヒドロ-2H-ピラン-4-イル)メチル]アミノ]フェニル]スルホニル]-2-(1H-ピロロ[2,3-b]ピリジン-5-イルオキシ)ベンズアミド
全ての実験は、理化学研究所及び虎の門病院の研究倫理委員会の承認により実行された。全ての患者サンプルは、書面による同意書と共に虎の門病院で採取された。CBサンプルは、Lonzaから購入した。
マウス
NOD.Cg-PrkdcscidIl2rgtmlWjl/Sz(NSG)マウスは、The Jackson Laboratory (Shultz LDら、J Immunol 2005年、Ishikawa Fら、Blood 2005年)で開発された。マウスは、各機関の施設動物委員会により設置されたガイドラインに従って、理化学研究所及びThe Jackson Laboratoryの動物施設で定義済みのフローラ下で育種され、維持された。
以下のモノクローナル抗体(mAb):マウス抗ヒトCD19、CD3、CD33、CD34、CD38、CD4及びCD45;ラット抗マウスTer119及びCD45(BD Biosciences)が、フローサイトメトリーに使用された。分析は、FACSAriaIII及びFACSCantoII(BD)で実行された。異種間移植用の細胞を得るために、BV786-コンジュゲート抗CD3 mAb、BV605-コンジュゲート抗CD19 mAb、BV421-コンジュゲート抗CD33 mAb、PE-Cy7-コンジュゲート抗CD34 mAb、APC-コンジュゲート抗CD38 mAb、FITC-コンジュゲート抗CD90 mAb及びPE-コンジュゲート抗CD45RA mAbが使用された。単一細胞選別のために、100μmノズルが使用された。
NSG新生児は、1.5Gyの全身放射線照射を受けた後に精製したヒト細胞を静脈注射した。ドナー細胞は、ヒトCD34、CD38、CD90、CD45RA、CD3、CD19及びCD33に対するモノクローナル抗体を使用して細胞表面表現型により精製された。NSGレシピエントにおけるヒト細胞の生着レベルは、眼窩後静脈しゃ血及びフローサイトメトリーにより判定された。
DNAは、DNeasy Blood & Tissue Kit(QIAGEN)を使用して患者サンプル又はレシピエント器官から精製されたヒト細胞から抽出された。FLT3-ITDのPCR検出は、TaKaRa PCR FLT3-ITD Mutation Detection Set (Takara)を使用して実行された。大量のDNA配列が、次世代DNA配列決定(NGS)により決定された。Covaris S220(Covaris Inc.、Wobum、MA USA)で断片化した後、断片化したゲノムDNA(10ng)は、供給元により提供されるプロトコールに従ってKAPA Hyper Prep Kit(KAPA Biosystems、Wilmington、MA)でNGS配列決定ライブラリーに変換された。AML関連遺伝子の標的化配列決定は、供給元により提供されるプロトコールに従って、xGen AML Cancer Panel v1.0 (Integrated DNA Technologies, Inc.、Coralville、IA)によるハイブリダイゼーション捕捉方法により実施された。ハイブリダイゼーション捕捉されたDNAライブラリーは、Illumina Miseq(Illumina、Inc. San Diego、CA)によるペアエンドリード様式(600サイクル)でNGSに供された。得られたDNA配列は、BWAを使用してヒトゲノム配列(hg19)にマッピングされ、次いでGeome Analysis Toolkit内のRealigner Target Creatorで再整列された。Picard内のFix Mate Information並びにGenome Analysis Toolkit (v.1.6-13)内のQuality Score Covariate及びTable Recalibrationによる処理後に、バリアントは、VarScanで検出された。
in vivo処置実験は、RK-20449(参考STM 2013)及びABT-199(Souers AJら、Nature Medicine 2013年、Pan Rら、Cancer Discovery 2014年)を使用して、AML生着NSGレシピエントで実行された。レシピエントは、RK-20449を30mg/kg 1日2回腹腔内に、ABT-199を70mg/kg 1日に1回経口的に又はこれらの服用スケジュールでRK-20449及びABT-199両方を投与された。マウスは、それが死にかかった場合又は処置後4~6週間で屠殺され、BM、脾臓及びPBにおけるヒトAMLキメラ現象が、フローサイトメトリーを使用して決定された。二次移植において、各マウスは、屠殺時にAML生着レシピエントに残存していた2.5%の全BMからの7-AAD(-)ヒトCD45+生存細胞を受けて、残留AML生存細胞により生じる再発をシミュレーションした。処置したレシピエントの全て及びそれらの処置前後の生着データが、図8及び9において表にされる。
数値的なデータは、平均+/-SEMとして示される。誤差は、両側t検定(GraphPad Prism、GraphPad)で調べられた。
FLT3-ITD+白血病サブクローンの評価
骨髄(BM)又は末梢血(PB)サンプルを、FLT3-ITD+AMLである23名の患者から得、その診断、臨床経過及び臨床転帰を、図7に詳述する。大多数の患者は、FLT3-ITD変異に加えて悪い予後因子、例えば、複合染色体異常を有し、及び/又は公知の悪性疾患(誘導不全、複数の幹細胞移植後の再発)を有した。
多様な変異を持つヒトFLT3-ITD+AMLサブクローンにおけるキナーゼ阻害の効果
これらの検討は、NSG PDXモデルを使用して、変異したキナーゼ単独の阻害がin vivoでAMLを排除するかどうか調べた。FLT3-ITD変異を持つ患者由来細胞は、in vivoで生着し、AMLを開始するが、個々のFLT3-ITD+細胞は、他の複数の変異を様々な組合せで保有する。これらの変異は、FLT3-ITDと協同して治療応答性に寄与し得、ヒトAML細胞の変異の複雑さを反映するPDXモデルは、共存する複数の変異の寄与を調べるのに必要である。従って、AML関連体細胞変異の頻度を、新生児のNSG異種移植を使用して、開示されたPDXモデルにおいて評価し、同じ組の変異が、患者由来白血病開始集団及びレシピエントにおける生着したAML細胞に存在した(図4を参照のこと)。更に、単一細胞配列決定は、NSG PDXモデルが、様々な組合せの変異を持つ複数の白血病開始サブクローンの生着を可能にすることを実証した(図3A及び図3Bを参照のこと)。FLT3経路単独の標的化がin vivoで、複数の変異を保有するヒトAML細胞の減少をもたらし得る程度を、以下の通りに調べた。RK-20449は、ヒトAML細胞を効果的に標的するSrcファミリーキナーゼHCK及びFLT3のピロロ-ピリミジン-誘導体複数キナーゼ阻害剤である。従って、RK-20449を、19名のFLT3-ITD+AML患者由来AMLが生着した58匹のNSGマウスに投与し、結果を図8に示す。
in vivoでのFLT3-ITD+AML細胞に対するキナーゼ及び抗アポトーシス経路の複合阻害の効果
キナーゼ阻害単独ではBM及び脾臓においてヒトAML細胞を完全に根絶しなかった症例由来のAMLが生着したレシピエントを、ABT-199と組み合わせてRK-20449で処置した。データ及び統計については図9~図11を参照のこと。処置したレシピエントのPB hCD45+AML細胞キメラ現象の時間的経過は、処置の型に関連した周辺応答の率及び程度における差異を例示する(図6Aを参照のこと)。大多数の症例において、BCL-2阻害剤ABT-199単独によるアポトーシス誘導は、僅かな応答をもたらした。それに対し、12症例全てにおいて、組合せ処置は、PB、BM及び脾臓においてヒトAMLキメラ現象を有意に減少させた。更に、12症例のうちの9つにおいて、キナーゼ及び抗アポトーシス経路の複合阻害は、in vivoで他の共存している変異を標的することなくヒトAML細胞を検出限界以下に排除した(図6B及び図8を参照のこと)。
Claims (19)
- RK-20449、RK-20693、RK-24466、RK-20444、RK-20445、RK-20466、RK-20730、RK-20690、RK-20781、RK-20786、RK-20888、RK-20658、RK-20686、RK-20696、RK-20709、RK-20721、RK-20694、RK-20703、RK-20718、RK-20719、RK-20722、RK-20744、RK-20752、RK-20952、RK-20618、RK-20725、RK-20729、RK-20732、RK-20746、RK-20755、RK-20768、RK-20770、RK-20775、RK-20777、RK-20791、RK-20798、RK-20819、RK-20820、RK-20824、RK-20826、RK-20901、RK-20908、RK-20909、RK-20918、RK-20919、RK-20920、RK-20921、RK-20930、RK-20932、RK-20942、RK-20627、RK-20629、RK-20640、RK-20695、RK-20697、RK-20698、RK-20710、RK-20711、RK-20712、RK-20724、RK-20733、RK-20734、RK-20758、RK-20898及びRK-20620から選択されるHCK阻害剤を含む、急性骨髄性白血病を処置するための組成物であって、対象に、BCL-2阻害剤と共同的に投与される組成物、又はその薬学的に許容される組成物。
- 前記対象が、FLT3-ITD+急性骨髄性白血病を有する、請求項1に記載の組成物。
- 前記対象が、DNMT3A、IDH2、IDH1、NPM1、TET2、CEBPA、ASXL1、EZH2、SETBP1、SMC3、KIT、NRAS及びWT1から選択される遺伝子に1つ以上の変異を有する細胞により特徴付けられる悪性造血及び/又は非悪性多系統造血を有する、請求項1又は2に記載の組成物。
- FLT3-ITD阻害剤と共同的に投与される、請求項1から3のいずれか一項に記載の組成物。
- 前記HCK阻害剤が、HCK/FLT3-ITD二重阻害剤である、請求項1から4のいずれか一項に記載の組成物。
- 前記HCK阻害剤、前記FLT3-ITD阻害剤、及び前記BCL-2阻害剤が、別々の単位剤形で同時に又は逐次的に投与される、請求項4又は5に記載の組成物。
- 前記HCK阻害剤が、前記HCK阻害剤、前記BCL-2阻害剤、及び薬学的に許容される担体、アジュバント又は媒体を含む単一の単位剤形で投与される、請求項1から6のいずれか一項に記載の組成物。
- 前記単一の単位剤形が、FLT3-ITD阻害剤を更に含む、請求項7に記載の組成物。
- 前記HCK阻害剤が、RK-20449、RK-20693、RK-24466、RK-20444、RK-20445及びRK-20466から選択される、請求項1から8のいずれか一項に記載の組成物。
- 前記FLT3-ITD阻害剤が、AC220、ソラフェニブ、PKC412、CEP-701、UNC2025、MLN518、KW-2449、AMG-925、スニチニブ、SU5614、AC2206、クレノラニブ及びPLX3397から選択される、請求項4から8のいずれか一項に記載の組成物。
- 前記BCL-2阻害剤が、AT-101、TW-37、TM-1206、ゴシポール酸、ゴシポロン酸(gossypolonic acid)、アポゴシポール、アポゴシポロン、A385358、ABT-737、ABT-263、ABT-199、WEHI-539、BXI-61、BXI-72、オバトクラックス、JY-1-106及びSAHBペプチドから選択される、請求項1から10のいずれか一項に記載の組成物。
- 前記BCL-2阻害剤が、ゴシポール、オバトクラックス、ABT-737、ABT-199及びABT-263から選択される、請求項11に記載の組成物。
- 前記BCL-2阻害剤が、ABT-199である、請求項12に記載の組成物。
- 前記HCK阻害剤が、RK-20449であり、前記BCL-2阻害剤が、ABT-199である、請求項13に記載の組成物。
- 前記HCK阻害剤が、RK-20693であり、前記BCL-2阻害剤が、ABT-199である、請求項13に記載の組成物。
- 前記FLT3-ITD阻害剤が、AC220であり、前記BCL-2阻害剤が、ABT-199である、請求項13に記載の組成物。
- 前記FLT3-ITD阻害剤が、SU5614であり、前記BCL-2阻害剤が、ABT-737である、請求項12に記載の組成物。
- 前記HCK阻害剤、及び/又は前記FLT3-ITD阻害剤、及び/又は前記BCL-2阻害剤が、薬学的に許容される塩として各々存在する、請求項1から17のいずれか一項に記載の組成物。
- 前記HCK阻害剤、及び/又は前記FLT3-ITD阻害剤、及び/又は前記BCL-2阻害剤が、薬学的に許容される組成物中に各々存在する、請求項1から18のいずれか一項に記載の組成物。
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