JP2021521170A - 骨髄増殖性新生物およびがんに関連する線維症の処置のためのpimキナーゼ阻害剤 - Google Patents
骨髄増殖性新生物およびがんに関連する線維症の処置のためのpimキナーゼ阻害剤 Download PDFInfo
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- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
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- A—HUMAN NECESSITIES
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P35/02—Antineoplastic agents specific for leukemia
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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Abstract
Description
または薬学的に許容されるその塩;および有効量のルキソリチニブまたは薬学的に許容されるその塩を投与するステップを含む。
したがって、一実施形態では、それを必要とする哺乳動物において、骨髄増殖性新生物を処置する方法であって、哺乳動物に、有効量のPIMキナーゼ阻害剤を投与するステップを含む方法が提供される。別の実施形態は、哺乳動物における造血細胞の増殖を低減させる方法であって、該細胞にPIMキナーゼ阻害剤(例えば、有効量のPIMキナーゼ阻害剤)を接触させるステップを含む方法を提供する。
または薬学的に許容されるその塩を含む組成物を投与するステップを含む方法を提供する。
またはその立体異性体、もしくは薬学的に許容されるその塩[式中、
Xは、直接結合、N(Ra)、S、O、SOまたはSO2であり、Raは、Hまたはアルキルであり、
Rは、H、アミノ、シアノ、ヒドロキシル、ハロ、アルキル、アルキルアミニル、ハロアルキル、アルコキシまたはハロアルコキシであり、
R1は、1つ、2つまたは3つのR1’により必要に応じて置換されているフェニルであり、R1’は、出現毎に独立して、アミノ、シアノ、アルキル、アルキルアミニル、アルコキシ、ハロ、ハロアルキル、ハロアルコキシ、ヒドロキシル、ニトロ、アルキルカルボニルまたはアルキルスルホンアミジルであり、
R2は、以下の構造:
(式中、
Aは、必要に応じて置換されている3〜8員の炭素環式環または複素環式環であり、
nは、0、1、2、3または4であり、
R3およびR4は、出現毎に独立して、Hまたはアルキルである)を有する]
である、方法を提供する。
を有する。
(i)欧州分類によれば、骨髄が、年齢調整後の正常な細胞充実性(normocellularity)、<5%芽球、および骨髄線維症≦グレード1を示すこと、および
(ii)末梢血中のヘモグロビンが≧100g/Lかつ<UNLであり、好中球数が≧1×109/Lかつ<UNLであること、および
(iii)血小板数が≧100×109/Lかつ<UNLであり、未成熟骨髄性細胞が<2%(脾臓摘出患者では、未成熟骨髄性細胞<5%が許容されることを除外する)であること、ならびに
(iv)疾患症状の消散、触知不能な脾臓および肝臓、ならびにEMHの証拠がないこと
を満たすことを意味する。
他の実施形態は、医薬組成物を対象とする。PIMキナーゼ阻害剤(例えば、化合物1)および/またはJAK阻害剤(例えば、ルキソリチニブ)または他の治療剤は、当分野において公知の方法により、一緒に製剤化されてもよく、または別個に製剤化されてもよい。ある特定の実施形態は、薬学的に許容される担体または賦形剤、PIMキナーゼ阻害剤および/またはJAK阻害剤を含む。一部の実施形態では、本医薬組成物は、上記の実施形態のいずれかによる、PIMキナーゼ阻害剤および/またはJAK阻害剤を含む。
HLB=20×(Mh/M)
(式中、Mhは、その分子の親水性部分の分子質量であり、Mは、分子全体の分子質量である)。したがって、HLBの値は0〜20の範囲であり、0の値は、親油性(すなわち、疎水性)分子に対応し、20の値は、親水性(すなわち、疎油性)分子に対応する。
実施形態1. それを必要とする哺乳動物において、骨髄増殖性新生物を処置する方法であって、哺乳動物に、有効量の以下の構造式によって表される化合物:
または薬学的に許容されるその塩を投与するステップを含む、方法。
以下の構造式によって表される化合物:
または薬学的に許容されるその塩、および
ルキソリチニブまたは薬学的に許容されるその塩
を投与するステップを含む、方法。
以下の構造式によって表される化合物:
または薬学的に許容されるその塩、および
ルキソリチニブまたは薬学的に許容されるその塩
を投与するステップを含む、方法。
または薬学的に許容されるその塩
を投与するステップを含む、方法。
または薬学的に許容されるその塩、および
構造式1の化合物または薬学的に許容されるその塩を投与するための書面による指示
を含む、キット。
または薬学的に許容されるその塩、
ルキソリチニブまたは薬学的に許容されるその塩、および
構造式1の化合物または薬学的に許容されるその塩を、ルキソリチニブまたは薬学的に許容されるその塩と組み合わせて投与するための書面による指示
を含む、キット。
または薬学的に許容されるその塩
を投与するステップを含む、方法。
実施形態100. 哺乳動物に有効量のPIMキナーゼ阻害剤を投与するステップを含む、それを必要とする哺乳動物における骨髄増殖性新生物を処置する方法であって、PIMキナーゼ阻害剤が、以下の構造(I)、(II)または(III)の1つを有する化合物:
またはその立体異性体、もしくは薬学的に許容されるその塩[式中、
Xは、直接結合、N(Ra)、S、O、SOまたはSO2であり、Raは、Hまたはアルキルであり、
Rは、H、アミノ、シアノ、ヒドロキシル、ハロ、アルキル、アルキルアミニル、ハロアルキル、アルコキシまたはハロアルコキシであり、
R1は、1つ、2つまたは3つのR1’により必要に応じて置換されているフェニルであり、R1’は、出現毎に独立して、アミノ、シアノ、アルキル、アルキルアミニル、アルコキシ、ハロ、ハロアルキル、ハロアルコキシ、ヒドロキシル、ニトロ、アルキルカルボニルまたはアルキルスルホンアミジルであり、
R2は、以下の構造:
(式中、
Aは、必要に応じて置換されている3〜8員の炭素環式環または複素環式環であり、
nは、0、1、2、3または4であり、
R3およびR4は、出現毎に独立して、Hまたはアルキルである)
を有する]
である、方法。
または薬学的に許容されるその塩
を含む組成物を投与するステップを含む、方法。
または薬学的に許容されるその塩
を含む組成物を投与するステップを含む、方法。
または薬学的に許容されるその塩
を接触させるステップを含む、方法。
または薬学的に許容されるその塩
を含む組成物を投与するステップを含む、方法。
実施形態201. ポリグリコール化グリセリド;および化合物1または薬学的に許容されるその塩を含む、組成物。
化合物1は、複数の細胞タイプおよび細胞系に対して活性を示す
MPNの病因におけるJAK2 V617Fの役割を決定するため、誘発可能なJAK2 V617Fノックインマウスを生成した。ヘテロ接合性JAK2 V617Fノックインマウスは、赤血球、ヘモグロビンおよびヘマトクリットの向上、白血球増加、血小板増加および脾腫を含めた、ヒトPV疾患のすべての特徴を示す(Akada et al., Blood 2010を参照されたい)。100%の浸透を有する高悪性度MF(誘発後10〜12週間以内にグレード3;図8)を速やかに発症する、ホモ接合性JAK2 V617Fノックインマウスも生成した。これらの新規な動物モデルにより、MPN/MFに対する、化合物1、または化合物1/ルキソリチニブ薬物組み合わせのin vivo有効性の試験が可能となった。
PIM1 MRNA発現のマイクロアレイ解析
PIM1 mRNA発現は、MPN患者の造血前駆細胞において上方調節される。MPN患者(データベースシリーズ:GSE54646)に関する公開されている遺伝子発現データの解析により、PIM1発現は、健常な対照の顆粒球と比べると、MPN(すなわち、PV、ETおよびMF)顆粒球が顕著に増大することが明らかになった。遺伝子発現オムニバスデータベースシリーズナンバー:GSE54646から解析したマイクロアレイデータ。PIM1の発現は、健常な対照の顆粒球と比べて、MPN(PV、ETおよびMF)顆粒球において顕著に増大することに留意されたい(図1A中、**は、p<0.005を示す)。
PIM1タンパク質発現の免疫アッセイ分析
ヒトおよびマウスMPN造血細胞におけるPIM1タンパク質発現をイムノブロッティングによって評価した。MF患者(patent)の骨髄および末梢血単核細胞(PBMC)、ならびにヘテロ接合性(MxCre;VF/+)およびホモ接合性(MxCre;VF/VF)JAK2 V617Fノックインマウスの骨髄において、対照と比べて、PIM1タンパク質のレベルの顕著な増加が観察された(図2A〜C)。
JAK2 V617Fを発現する造血細胞に対するPIM1ノックダウン
野生型JAK2またはJAK2 V617Fを表現するマウスBA/F3−EpoR細胞(BA/F3−EpoR−JAK2 V617F)およびヒトJAK2 V617F陽性白血病細胞(HEL)に、レンチウイルスPIM1 shRNAまたは対照shRNAを形質導入した。感染細胞は、ピューロマイシンで選別した。PIM1のノックダウンにより、BA/F3−EpoR−JAK2 V617FおよびJAK2 V617Fを発現するHEL細胞の増殖が顕著に阻害されたが、野性型JAK2を発現するBA/F3−EpoR細胞は阻害されなかった(図3A〜C)。これらのデータにより、JAK2 V617Fを発現するMPN細胞の生存/増殖において、PIM1が重要な役割を果たすことが示される。
JAK2 V617Fの選択的阻害
野生型JAK2を発現するマウスBA/F3細胞、またはJAK2 V617Fを発現するBA/F3−EpoR−JAK2 V617F細胞、ならびにヒトJAK2 V617F陽性白血病細胞HELおよびUKE−1の増殖に及ぼす化合物1の効果を評価した。
CD34+造血前駆細胞の化合物1による処置
化合物1の効果は、MPN患者CD34+造血前駆細胞で評価した。化合物1を使用する処置により、MPN患者のCD34+細胞では、造血前駆細胞のコロニーが顕著に阻害されたが、健常な対照のCD34+細胞に対しては、最小限の効果を示すことが観察された(図5A〜B中、*は、p<0.05を示し、***は、p<0.0005を示す。「ns」は、統計学的に有意ではない差異を示す)。
化合物1とルキソリチニブとの相乗作用
野生型JAK2を発現するBA/F3細胞、ならびにHEL細胞、BA/F3−EpoR−JAK2 V617F細胞、UKE−1細胞およびJAK2 V617Fを発現するSET−2細胞を化合物1により単独で、またはルキソリチニブと組み合わせて、図6A〜Cおよび6E〜Fに示されている様々な濃度で処置した。アポトーシスは、アネキシンV染色とその後のフローサイトメトリーを使用する処置の48時間後に決定した。試験した各細胞系において、表示濃度の化合物1を単独でまたはルキソリチニブと組み合わせると、有意なアポトーシスが示されたが、野生型JAK2発現BA/F3細胞ではそうではなかった(図6A〜Cおよび6E〜F)。BA/F3−EpoR−JAK2 V617F細胞において、0.3未満の組み合わせ指数(combination index)値で、アポトーシスを相乗的に誘発した化合物1とルキソリチニブとの組み合わせ(図6D)は、強力な相乗作用を示している。
化合物1は、JAK2阻害に対する抵抗性を克服する
化合物1を使用する処置により、JAK2 V617Fを発現する細胞において、JAK2阻害に対する抵抗性が克服されるかどうかを評価した。JAK2阻害剤抵抗性細胞を生成するため、濃度を増加させたルキソリチニブ(最大で2μM)の存在下で、BA/F3−EpoR−JAK2 V617F細胞を3か月間を超えて培養した。予想外なことに、ルキソリチニブ抵抗性BA/F3−EpoRJAK2 V617F細胞において、ルキソリチニブに感受性のBA/F3−EpoR−JAK2 V617F細胞と比べると、PIM1の発現に顕著な増加が観察された。ルキソリチニブ抵抗性BA/F3−EpoR−JAK2 V617F細胞において、ルキソリチニブ処置(0.5〜2μM)によって、STAT5のリン酸化は阻害されなかった(図7A)。同様に、ルキソリチニブ抵抗性BA/F3−EpoRJAK2 V617F細胞において、ルキソリチニブ処置(0.5〜2μM)によって、細胞増殖は顕著に阻害されなかった(図7B)。対照的に、化合物1を使用する処置により、ルキソリチニブ抵抗性BA/F3−EpoR−JAK2 V617F細胞の増殖が顕著に阻害され(図7C)、化合物1による処置は、重大な臨床的意味を有する重要な知見である、MPN細胞におけるJAK2阻害に対する抵抗性を克服することができることを示唆している。
化合物1を使用する処置に起因する血液細胞数の改善
ルキソリチニブと組み合わせた化合物1の有効性を、MFの本発明者らのホモ接合性JAK2 V617Fノックインマウスモデルを使用して試験した(実施例1を参照されたい)。ホモ接合性JAK2 V617Fノックインマウス由来の骨髄細胞を、致死的に照射したC57BL/6レシピエントに移植し、類似の年齢のMFマウスのコホートを得た。移植して8週間後に、末梢血球数を測定し、次に、マウスを無作為化し、1日1回、経口胃管栄養によって、ビヒクル、化合物1(150mg/kg)、ルキソリチニブ(60mg/kg)、または化合物1(150mg/kg)とルキソリチニブ(60mg/kg)による処置を受けさせた。マウスはすべて、6週間、処置した。末梢血白血球(WBC)および好中球数は、化合物1とルキソリチニブの併用処置時に、ほとんど正常なレベルにまで低下した(図9A〜B)。化合物1単独での処置により、血液中のWBCおよび好中球数の低下がもたらされた。
化合物1を使用する線維症の低減
MFを示すホモ接合性JAK2 V617Fマウスを、6週間、ビヒクル、化合物1単独(150mg/kg)、ルキソリチニブ単独(60mg/kg)、またはルキソリチニブ(60mg/kg)と組み合わせた化合物1(150mg/kg)により処置した。マウスを化合物1単独で処置した場合、レチクリン染色により、線維症の顕著な低減が示される。化合物1とルキソリチニブとの併用処置は、ホモ接合性JAK2 V617Fマウスの骨髄(BM)および脾臓(SPL)における線維症が有効になくなった(図10)。
投薬算出 − 毒性研究
化合物1に関する1日あたりの投薬範囲を、骨髄線維症の処置のために、ヒトにおいて、10〜10,000mgの等価範囲で算出した。用量算出は、ラットにおけるGLP毒物学研究、およびイヌにおける非GLP毒物学研究から求めた。ラットでは、500mg/kgにおいて、動物の10パーセントにおいて重度な毒性用量が観察され、これは、以下の通り算出すると、1人あたり平均で5286mgに等しい。
TNFαおよびWNTシグナル伝達経路の下方調節
RNA配列決定を使用して、ビヒクル単独、化合物1単独、ルキソリチニブ単独、または化合物1とルキソリチニブとの組み合わせにより処置したホモ接合性JAK2 V617Fマウスに由来する精製されたLSK(Lin−Sca−1+c−kit+)細胞を解析した。RNA配列の解析により、造血幹細胞(HSC)維持、TNFαおよびWNTシグナル伝達経路に関連する遺伝子は、ビヒクルと比較した場合、化合物1単独、またはルキソリチニブと組み合わせた化合物1により処置した試料の場合、有意に下方調節されることが示された(図11A〜E)。
MPL W515L細胞の化合物1による処置
野性型MPLを発現するマウスBA/F3細胞、またはMPL W515Lを発現するBA/F3の増殖に及ぼす化合物1の効果を評価した。
(実施例14)
化合物1 − 生化学プロファイル
Claims (22)
- 前記哺乳動物に、1日あたり約300mg〜約1.5gの前記構造式1の化合物または薬学的に許容されるその塩を投与するステップを含む、請求項1に記載の方法。
- 前記哺乳動物に、1日あたり約450mg〜約1.5gの前記構造式1の化合物または薬学的に許容されるその塩を投与するステップを含む、請求項1に記載の方法。
- 前記骨髄増殖性新生物が骨髄線維症である、請求項1〜3のいずれか一項に記載の方法。
- 前記骨髄線維症が、中リスクの骨髄線維症または高リスクの骨髄線維症である、請求項4に記載の方法。
- 前記骨髄線維症が、原発性骨髄線維症である、請求項1〜5のいずれか一項に記載の方法。
- 前記骨髄線維症が、続発性骨髄線維症である、請求項1〜5のいずれか一項に記載の方法。
- 前記骨髄増殖性新生物の処置により、前記哺乳動物が測定可能残存病変(MRD)陰性となる、請求項1〜7のいずれか一項に記載の方法。
- 前記骨髄増殖性新生物の処置により、前記哺乳動物において完全寛解がもたらされる、請求項1〜8のいずれか一項に記載の方法。
- 前記構造式1の化合物または薬学的に許容されるその塩が経口投与される、請求項1〜9のいずれか一項に記載の方法。
- 前記構造式1の化合物または薬学的に許容されるその塩が、1日1回投与される、請求項1〜10のいずれか一項に記載の方法。
- 前記構造式1の化合物または薬学的に許容されるその塩が、1日2回投与される、請求項1〜10のいずれか一項に記載の方法。
- 前記構造式1の化合物または薬学的に許容されるその塩が、約7日間〜約1年間、投与される、請求項1〜12のいずれか一項に記載の方法。
- 前記構造式1の化合物または薬学的に許容されるその塩が、28日間、投与される、請求項13に記載の方法。
- 前記構造式1の化合物または薬学的に許容されるその塩が、1年間、投与される、請求項13に記載の方法。
- ルキソリチニブまたは薬学的に許容されるその塩の前記有効量が、約5mg/日〜約100mg/日である、請求項1〜15のいずれか一項に記載の方法。
- ルキソリチニブまたは薬学的に許容されるその塩の前記有効量が、約10mg/日〜約50mg/日である、請求項16に記載の方法。
- 前記ルキソリチニブまたは薬学的に許容されるその塩が、経口投与される、請求項1〜17のいずれか一項に記載の方法。
- 前記ルキソリチニブまたは薬学的に許容されるその塩が、1日2回、投与される、請求項1〜18のいずれか一項に記載の方法。
- 前記ルキソリチニブまたは薬学的に許容されるその塩が、約7日間〜約1年間、投与される、請求項1〜19のいずれか一項に記載の方法。
- 前記骨髄増殖性新生物が、前記構造式1の化合物または薬学的に許容されるその塩の非存在下で、ルキソリチニブにより以前に処置されている、請求項1〜20のいずれか一項に記載の方法。
- 前記骨髄増殖性新生物が、ルキソリチニブ抵抗性骨髄増殖性新生物である、請求項1〜21のいずれか一項に記載の方法。
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KR20200143454A (ko) | 2020-12-23 |
WO2019200254A1 (en) | 2019-10-17 |
CN112236139A (zh) | 2021-01-15 |
AU2019252793A1 (en) | 2020-10-15 |
CA3095580A1 (en) | 2019-10-17 |
JP2024038485A (ja) | 2024-03-19 |
MX2023001425A (es) | 2023-03-03 |
MX2020010556A (es) | 2021-03-02 |
CN117838695A (zh) | 2024-04-09 |
US20210113562A1 (en) | 2021-04-22 |
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