JP2022520079A - Tno155及びkrasg12c阻害剤を含む医薬組合せ - Google Patents
Tno155及びkrasg12c阻害剤を含む医薬組合せ Download PDFInfo
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- 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
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Abstract
Description
(a)構造:
を有する(3S,4S)-8-(6-アミノ-5-((2-アミノ-3-クロロピリジン-4-イル)チオ)ピラジン-2-イル)-3-メチル-2-オキサ-8-アザスピロ[4.5]デカン-4-アミン(TNO155)、又はその薬学的に許容される塩;及び
構造:
を有する6-(4-アミノ-4-メチルピペリジン-1-イル)-3-(2,3-ジクロロフェニル)ピラジン-2-アミン(SHP099)、又はその薬学的に許容される塩
から選択されるSHP2阻害剤;並びに
(b)KRASG12C阻害剤。
以前、そして以降で用いられる一般的な用語は、好ましくは、特に明記しない限り、本開示の文脈内で、以下の意味を有し、用いられる場合はいつでも、より一般的な用語が、互いに独立して、より具体的な定義によって置き換えられて、又はそのままであることで、本発明のより詳細な実施形態を定義してもよい。
TNO155は、SHP2活性の経口投与可能な小分子阻害剤である治験薬である。SHP2は、活性化RTKの下流のシグナル伝達を行う。前臨床モデルにおいて、RTKへの腫瘍依存性は、SHP2への依存性を予測する。
非小細胞肺癌-2012年には、世界で約180万人が、肺癌と診断され、160万人が、肺癌で死亡したと推定された。非小細胞肺癌は、肺癌の約85%を占め、腺癌及び扁平上皮癌が、最も一般的な亜型である。EGFR、ALK、又はROSなどのドラッガブルなドライバー癌遺伝子における遺伝子変異を有さない進行期の非小細胞肺癌(NSCLC)のための標準治療は、同時に又は連続して投与される、化学療法及び免疫療法を含む。これらの処置は、臨床的利点を提供するが、患者の大部分は、1年以内に疾患の進行を示し、進行NSCLCに罹患した患者の予後は、不良な状態のままである。免疫チェックポイント阻害剤を用いたNSCLCのための免疫療法は、有望さを実証したが、一部のNSCLC患者は、何年間も持続的な疾患管理を受ける。しかしながら、このような長期非進行者は、稀であり、チェックポイント阻害剤を用いた免疫療法に反応し、寛解を維持する患者の割合を増加させ得る組合せ治療法が、緊急に必要とされている。KRAS癌遺伝子の活性化突然変異は、肺腺癌の約30%で発生し、いくつかの研究において不良転帰と関連付けられている。突然変異型KRASを直接標的にする承認薬がないため、進行期のKRAS突然変異型NSCLCのための標準治療も、上述される化学療法及び免疫療法である。
別の態様において、本発明は、1つ以上の薬学的に許容されるキャリア(添加物)及び/又は希釈剤と一緒に製剤化された、治療的に有効な量のTNO155及びKRASG12C阻害剤を含む、薬学的に許容される組成物を提供する。以下に詳細に記載されるように、本発明の医薬組成物は、固体又は液体の形態での投与用に特別に製剤化されていてもよく、経口投与に適合するもの、例えば、水薬(水性又は非水性の溶液又は懸濁液)、タブレット、例えば、口腔内、舌下、及び体内吸収を対象とするもの、ボーラス、粉末、顆粒、舌への塗布用のペーストが挙げられる。
細胞を、RPMI Glutamax+10%のFCS+それぞれ1%:ピルビン酸ナトリウム、Hepes緩衝液中で成長させた。1日目に、細胞を、示される細胞数で6ウェルプレート中に播種した。2日目に、化合物処理を、示される化合物濃度から開始した。細胞に、3~4日置きに、新鮮な化合物/培地を再供給した。クリスタルバイオレット染色を、指示される日に行った。200μLのホルムアルデヒド(ストック濃度37.8%)を、各ウェル(2mlの細胞培地の上)に加え、室温で10分間インキュベートした。ウェルを空にし、5mLの水で少なくとも1回すすぎ、再度、空にした。1mLのパープルバイオレット0.1%の水を、各ウェルに加え、室温で15分間インキュベートした。ウェルを空にし、2mLの水で少なくとも2回すすいだ。プレートを乾燥させ、画像を、CanoScan4400Fでスキャンし、PDFとして保存した。
胸腺欠損ヌードマウスの右脇腹に、50%のマトリゲル(matrigel)/HBSS中で懸濁された300万個のMiaPaCa-2細胞を、25G針を用いて皮下注射した。腫瘍増殖を、測径器による測定によって追跡し、立方ミリメートルとして表した。腫瘍を、200~300立方mmのサイズまで増殖させ、その後、動物を、以下のような個々の群に無作為に分けた:ビヒクル対照(4匹の動物;MC:Tween80:水(0.5:0.1:99.4));TNO155-10mg/kg経口で1日1回(qd po)(4匹の動物);化合物2-50mg/kg経口で1日1回(qd po)(4匹の動物);化合物2-200mg/kg経口で1日1回(qd po)(4匹の動物);TNO155 10mg/kgと組み合わせた化合物2-50mg/kg(5匹の動物);TNO155 10mg/kgによる前処置、続いて、化合物2-50mg/kgによる処置(6匹の動物)。Combo:化合物を、同時に投与する。ComboP:TNO155を、化合物2の3時間前に投与する。処置の2週間後に、動物を安楽死させ、腫瘍サンプルを、最後の処置の6時間後に更なる分析のために採取した。
Claims (18)
- 癌を処置する方法であって、それを必要とする対象に、(3S,4S)-8-(6-アミノ-5-((2-アミノ-3-クロロピリジン-4-イル)チオ)ピラジン-2-イル)-3-メチル-2-オキサ-8-アザスピロ[4.5]デカン-4-アミン、又はその薬学的に許容される塩を含む医薬組成物を、第2の治療剤と組み合わせて投与することを含む方法。
- 前記癌は、食道若しくは頭頸部扁平上皮細胞癌;大腸癌、卵巣癌、膵臓癌又は非小細胞肺癌;及び腎細胞癌から選択される、請求項1に記載の方法。
- (3S,4S)-8-(6-アミノ-5-((2-アミノ-3-クロロピリジン-4-イル)チオ)ピラジン-2-イル)-3-メチル-2-オキサ-8-アザスピロ[4.5]デカン-4-アミン、又はその薬学的に許容される塩、及び前記第2の治療剤は、同時に、別々に、又はある期間にわたって投与される、請求項1又は2に記載の方法。
- それを必要とする前記対象に投与される、(3S,4S)-8-(6-アミノ-5-((2-アミノ-3-クロロピリジン-4-イル)チオ)ピラジン-2-イル)-3-メチル-2-オキサ-8-アザスピロ[4.5]デカン-4-アミン、又はその薬学的に許容される塩の量は、前記癌を処置するのに有効である、請求項1~3のいずれか一項に記載の方法。
- それを必要とする前記対象に投与される、(3S,4S)-8-(6-アミノ-5-((2-アミノ-3-クロロピリジン-4-イル)チオ)ピラジン-2-イル)-3-メチル-2-オキサ-8-アザスピロ[4.5]デカン-4-アミン、又はその薬学的に許容される塩、及び前記第2の治療剤の量は、前記癌を処置するのに有効である、請求項1~4のいずれか一項に記載の方法。
- 前記第2の治療剤は、KRASG12C阻害剤である、請求項1~5のいずれか一項に記載の方法。
- 前記KRASG12C阻害剤は、1-(4-(6-クロロ-8-フルオロ-7-(3-ヒドロキシ-5-ビニルフェニル)キナゾリン-4-イル)ピペラジン-1-イル)プロパ-2-エン-1-オン--メタン(1/2)(化合物1)、(S)-1-(4-(6-クロロ-8-フルオロ-7-(2-フルオロ-6-ヒドロキシフェニル)キナゾリン-4-イル)ピペラジン-1-イル)プロパ-2-エン-1-オン(化合物2)、及び2-((S)-1-アクリロイル-4-(2-(((S)-1-メチルピロリジン-2-イル)メトキシ)-7-(ナフタレン-1-イル)-5,6,7,8-テトラヒドロピリド[3,4-d]ピリミジン-4-イル)ピペラジン-2-イル)アセトニトリル(化合物3)、又はその薬学的に許容される塩から選択される、請求項6に記載の方法。
- (3S,4S)-8-(6-アミノ-5-((2-アミノ-3-クロロピリジン-4-イル)チオ)ピラジン-2-イル)-3-メチル-2-オキサ-8-アザスピロ[4.5]デカン-4-アミンは、約1.5mg/日、又は3mg/日、又は6mg/日、又は10mg/日、又は20mg/日、又は30mg/日、又は40mg/日、又は50mg/日、又は60mg/日の用量で経口投与される、請求項1~7のいずれか一項に記載の方法。
- 前記一日用量は、2週間の投薬とその後の1週間の休薬の21日サイクルで投与される、請求項8に記載の方法。
- 前記一日用量は、20mg QDである、請求項9に記載の方法。
- 癌を処置する方法であって、それを必要とする患者に、約1.5mg/日、又は3mg/日、又は6mg/日、又は10mg/日、又は20mg/日、又は30mg/日、又は40mg/日、又は50mg/日、又は60mg/日の用量で経口投与される、(3S,4S)-8-(6-アミノ-5-((2-アミノ-3-クロロピリジン-4-イル)チオ)ピラジン-2-イル)-3-メチル-2-オキサ-8-アザスピロ[4.5]デカン-4-アミンを投与することを含む方法。
- 前記一日用量は、2週間の投薬とその後の1週間の休薬の21日サイクルで投与される、請求項11に記載の方法。
- 前記一日用量は、20mg QDである、請求項12に記載の方法。
- 前記癌は、食道若しくは頭頸部扁平上皮細胞癌;大腸癌、卵巣癌、膵臓癌又は非小細胞肺癌;及び腎細胞癌から選択される、請求項11に記載の方法。
- 第2の治療剤を更に含む、請求項11に記載の方法。
- (3S,4S)-8-(6-アミノ-5-((2-アミノ-3-クロロピリジン-4-イル)チオ)ピラジン-2-イル)-3-メチル-2-オキサ-8-アザスピロ[4.5]デカン-4-アミン、又はその薬学的に許容される塩、及び前記第2の治療剤は、同時に、別々に、又はある期間にわたって投与される、請求項11に記載の方法。
- 前記第2の治療剤は、KRASG12C阻害剤である、請求項11~16のいずれか一項に記載の方法。
- 前記KRASG12C阻害剤は、1-(4-(6-クロロ-8-フルオロ-7-(3-ヒドロキシ-5-ビニルフェニル)キナゾリン-4-イル)ピペラジン-1-イル)プロパ-2-エン-1-オン--メタン(1/2)(化合物1)、(S)-1-(4-(6-クロロ-8-フルオロ-7-(2-フルオロ-6-ヒドロキシフェニル)キナゾリン-4-イル)ピペラジン-1-イル)プロパ-2-エン-1-オン(化合物2)、及び2-((S)-1-アクリロイル-4-(2-(((S)-1-メチルピロリジン-2-イル)メトキシ)-7-(ナフタレン-1-イル)-5,6,7,8-テトラヒドロピリド[3,4-d]ピリミジン-4-イル)ピペラジン-2-イル)アセトニトリル(化合物3)、又はその薬学的に許容される塩から選択される、請求項17に記載の方法。
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MX2023002248A (es) | 2020-09-03 | 2023-05-16 | Revolution Medicines Inc | Uso de inhibidores de sos1 para tratar neoplasias malignas con mutaciones de shp2. |
CR20230165A (es) | 2020-09-15 | 2023-06-02 | Revolution Medicines Inc | Derivados indólicos como inhibidores de ras en el tratamiento del cáncer |
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CN116710094A (zh) * | 2020-12-22 | 2023-09-05 | 诺华股份有限公司 | 包含kras g12c抑制剂的药物组合以及kras g12c抑制剂用于治疗癌症的用途 |
WO2022133731A1 (en) * | 2020-12-22 | 2022-06-30 | Novartis Ag | Pharmaceutical combinations comprising a kras g12c inhibitor and uses of a kras g12c inhibitor and for the treatment of cancers |
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