JP6810146B2 - 受容体媒介化学療法による癌の治療のためのペプチド化合物およびペプチドコンジュゲート - Google Patents
受容体媒介化学療法による癌の治療のためのペプチド化合物およびペプチドコンジュゲート Download PDFInfo
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Classifications
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- C—CHEMISTRY; METALLURGY
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- C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
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-
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
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- C07D—HETEROCYCLIC COMPOUNDS
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- C07K1/06—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length using protecting groups or activating agents
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- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/001—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof by chemical synthesis
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- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
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Description
本出願は、2015年11月24日に出願された米国特許出願第62/259178号の優先権の利益を主張するものであり、当該出願は参照によりその全体が本明細書に組み込まれる。
最近の世界保健機関(WHO)の報告書(2014年2月)によると、2012年には820万人の患者が癌で死亡した。したがって、癌は、発展途上国と先進国の両方において増えつつある健康問題である。また、年間癌症例数は2012年の1400万人から今後20年間で2200万人に増加すると推定されている(WHO、2014年)。現在、癌の古典的治療法は、化学療法、放射線療法および外科手術である。
多剤耐性
腫瘍不均一性
腫瘍内および腫瘍間の不均一性
腫瘍の進行および不均一性のモデルとしてのクローン進化
腫瘍不均一性の臨床的意義
X1X2X3X4X5GVX6AKAGVX7NX8FKSESY(I)(配列番号1)
(X9)nGVX10AKAGVX11NX12FKSESY(配列番号2)
YKX13LRRX14APRWDX15PLRDPALRX16X17L(III)(配列番号3)
YKX18LRR(X19)nPLRDPALRX20X21L(IV)(配列番号4)
IKLSGGVQAKAGVINMDKSESM(V)(配列番号5)
IKLSGGVQAKAGVINMFKSESY(VI)(配列番号6)
IKLSGGVQAKAGVINMFKSESYK(VII)(配列番号7)
GVQAKAGVINMFKSESY(VIII)(配列番号8)
GVRAKAGVRNMFKSESY(IX)(配列番号9)
GVRAKAGVRN(Nle)FKSESY(X)(配列番号10)
YKSLRRKAPRWDAPLRDPALRQLL(XI)(配列番号11)
YKSLRRKAPRWDAYLRDPALRQLL(XII)(配列番号12)
YKSLRRKAPRWDAYLRDPALRPLL(XIII)(配列番号13)
(式中、
X1、X2、X3、X4、X5、X6、X7、X8、X9、X10、X11、X12、X13、X14、X15、X18およびX19は独立して、任意のアミノ酸から選択され、
X16、X17、X20およびX21は独立して、Q、P、Y、IおよびLから選択され、
nは0、1、2、3、4または5であり、
X9が複数存在する場合、X9の各々は独立して、任意のアミノ酸から選択され、
X19が複数存在する場合、X9の各々は独立して、任意のアミノ酸から選択され、
少なくとも1つの保護基および/または少なくとも1つの標識剤が、場合によりN末端および/またはC末端においてペプチドに連結されている)
の化合物から選択される化合物と少なくとも80%の配列同一性を有するペプチド化合物である。
X1X2X3X4X5GVX6AKAGVX7NX8FKSESY(I)(配列番号1)
(X9)nGVX10AKAGVX11NX12FKSESY(配列番号2)
YKX13LRRX14APRWDX15PLRDPALRX16X17L(III)(配列番号3)
YKX18LRR(X19)nPLRDPALRX20X21L(IV)(配列番号4)
IKLSGGVQAKAGVINMDKSESM(V)(配列番号5)
IKLSGGVQAKAGVINMFKSESY(VI)(配列番号6)
IKLSGGVQAKAGVINMFKSESYK(VII)(配列番号7)
GVQAKAGVINMFKSESY(VIII)(配列番号8)
GVRAKAGVRNMFKSESY(IX)(配列番号9)
GVRAKAGVRN(Nle)FKSESY(X)(配列番号10)
YKSLRRKAPRWDAPLRDPALRQLL(XI)(配列番号11)
YKSLRRKAPRWDAYLRDPALRQLL(XII)(配列番号12)
YKSLRRKAPRWDAYLRDPALRPLL(XIII)(配列番号13)
(式中、
X1、X2、X3、X4、X5、X6、X7、X8、X9、X10、X11、X12、X13、X14、X15、X18およびX19は独立して、任意のアミノ酸から選択され、
X16、X17、X20およびX21は独立して、Q、P、Y、IおよびLから選択され、
nは0、1、2、3、4または5であり、
X9が複数存在する場合、X9の各々は独立して、任意のアミノ酸から選択され、
X19が複数存在する場合、X9の各々は独立して、任意のアミノ酸から選択され、
少なくとも1つの保護基および/または少なくとも1つの標識剤が、場合によりN末端および/またはC末端においてペプチドに連結されている)
の化合物から選択される化合物と少なくとも80%の配列同一性を有するペプチド化合物である。
A−(B)n
(式中、
nは1、2、3または4であり、
Aは、場合により保護基によって保護されている本開示に定義されるペプチド化合物であり、および
Bは、BがAに連結されている少なくとも1つの治療剤である)
の式を有するコンジュゲート化合物が本明細書において開示される。
A−(B)n
(式中、
nは1、2、3または4であり、
Aは、場合により保護基によって保護されている本開示に定義されるペプチド化合物であり、および
Bは、ペプチド化合物の遊離アミンにおいて、ペプチド化合物のN末端位において、ペプチド化合物の遊離−SHにおいて、またはペプチド化合物の遊離カルボキシルにおいて、BがAに連結されている少なくとも1つの治療剤である)
の式を有するコンジュゲート化合物が本明細書において開示される。
A−(B)n
(式中、
nは1、2、3または4であり、
Aは、場合により保護基によって保護されている本開示に定義されるペプチド化合物であり、および
Bは、ペプチド化合物のリジン残基の遊離アミンにおいて場合によりリンカーを介して、またはペプチド化合物のN末端位において、場合によりリンカーを介してBがAに連結されている少なくとも1つの治療剤である)
の式を有するコンジュゲート化合物である。
中間体を得るためにリンカーと治療剤とを反応させる工程;
場合により中間体を精製する工程;
治療剤がリンカーを介してペプチド化合物に連結されているコンジュゲート化合物を得るように、中間体とペプチド化合物とを反応させる工程;および
場合によりコンジュゲート化合物を精製する工程;
を含み、
治療剤が、リジン残基の遊離アミンにおいて、またはN末端においてペプチド化合物に連結されており、ペプチド化合物が1、2、3または4つの連結治療剤分子を含む方法が提供される。
を有する抗癌剤、またはこれらの医薬として許容され得る塩、溶媒和物もしくはプロドラッグ、ならびにこれらの混合物を意味する。例えば、ドセタキセルは、その側鎖の2位の炭素原子に結合した酸素原子を介して、本開示のペプチド化合物にコンジュゲートすることができる。ドセタキセルは、直接またはリンカーを介してペプチド化合物に連結させることができる。
を有する抗癌剤、またはこれらの医薬として許容され得る塩、溶媒和物もしくはプロドラッグ、ならびにこれらの混合物を意味する。例えば、ドキソルビシンは、14位の炭素原子に結合した酸素原子を介して、本開示のペプチド化合物にコンジュゲートすることができる。ドキソルビシンは、直接またはリンカーを介してペプチド化合物に連結させることができる。
を有する抗癌剤、またはこれらの医薬として許容され得る塩、溶媒和物もしくはプロドラッグ、ならびにこれらの混合物を意味する。例えば、カバジタキセルは、その側鎖の2位の炭素原子に結合した酸素原子を介して、本開示のペプチド化合物にコンジュゲートすることができる。カバジタキセルは、直接またはリンカーを介してペプチド化合物に連結させることができる。
を有する植物化学物質、またはこれらの医薬として許容され得る塩、溶媒和物もしくはプロドラッグ、ならびにこれらの混合物を意味する。例えば、クルクミンは、そのフェノール基の酸素原子を介して、本開示のペプチド化合物にコンジュゲートすることができる。クルクミンは、直接またはリンカーを介してペプチド化合物に連結させることができる。
(式中、R1はH、C1−6アルキル、C2−6アルケニル、C6−12アリールもしくはアラルキルまたはこれらの二価の有機−O−、−S−と結合したもの、または
(式中、R’は、C1−6アルキル、連結部分である)であり、R2は、H、C1−12アルキル、C6−12アリール、またはC6−12アラルキルであり、R3は、
または隣接する窒素の孤立電子対を非局在化することができる別の化学構造であり、R4は、R3をペプチドベクターまたは薬剤に結合することができるペンダント反応性基である)を有する(例えば、米国特許第5,306,809号を参照されたい)。
X1X2X3X4X5GVX6AKAGVX7NX8FKSESY(I)(配列番号1)
(X9)nGVX10AKAGVX11NX12FKSESY(配列番号2)
YKX13LRRX14APRWDX15PLRDPALRX16X17L(III)(配列番号3)
YKX18LRR(X19)nPLRDPALRX20X21L(IV)(配列番号4)
IKLSGGVQAKAGVINMDKSESM(V)(配列番号5)
IKLSGGVQAKAGVINMFKSESY(VI)(配列番号6)
IKLSGGVQAKAGVINMFKSESYK(VII)(配列番号7)
GVQAKAGVINMFKSESY(VIII)(配列番号8)
GVRAKAGVRNMFKSESY(IX)(配列番号9)
GVRAKAGVRN(Nle)FKSESY(X)(配列番号10)
YKSLRRKAPRWDAPLRDPALRQLL(XI)(配列番号11)
YKSLRRKAPRWDAYLRDPALRQLL(XII)(配列番号12)
YKSLRRKAPRWDAYLRDPALRPLL(XIII)(配列番号13)
(式中、
X1、X2、X3、X4、X5、X6、X7、X8、X9、X10、X11、X12、X13、X14、X15、X18およびX19は独立して、任意のアミノ酸から選択され、
X16、X17、X20およびX21は独立して、Q、P、Y、IおよびLから選択され、
nは0、1、2、3、4または5であり、
X9が複数存在する場合、X9の各々は独立して、任意のアミノ酸から選択され、
X19が複数存在する場合、X9の各々は独立して、任意のアミノ酸から選択され、
少なくとも1つの保護基および/または少なくとも1つの標識剤が、場合によりN末端および/またはC末端においてペプチドに連結されている)
の化合物から選択される化合物と少なくとも80%の配列同一性を有するペプチド化合物である。
X1X2X3X4X5GVX6AKAGVX7NX8FKSESY(I)(配列番号1)
(X9)nGVX10AKAGVX11NX12FKSESY(配列番号2)
YKX13LRRX14APRWDX15PLRDPALRX16X17L(III)(配列番号3)
YKX18LRR(X19)nPLRDPALRX20X21L(IV)(配列番号4)
IKLSGGVQAKAGVINMDKSESM(V)(配列番号5)
IKLSGGVQAKAGVINMFKSESY(VI)(配列番号6)
IKLSGGVQAKAGVINMFKSESYK(VII)(配列番号7)
GVQAKAGVINMFKSESY(VIII)(配列番号8)
GVRAKAGVRNMFKSESY(IX)(配列番号9)
GVRAKAGVRN(Nle)FKSESY(X)(配列番号10)
YKSLRRKAPRWDAPLRDPALRQLL(XI)(配列番号11)
YKSLRRKAPRWDAYLRDPALRQLL(XII)(配列番号12)または
YKSLRRKAPRWDAYLRDPALRPLL(XIII)(配列番号13)。
X1X2X3X4X5GVX6AKAGVX7NX8FKSESY(I)(配列番号1)
(X9)nGVX10AKAGVX11NX12FKSESY(配列番号2)
YKX13LRRX14APRWDX15PLRDPALRX16X17L(III)(配列番号3)
YKX18LRR(X19)nPLRDPALRX20X21L(IV)(配列番号4)
IKLSGGVQAKAGVINMDKSESM(V)(配列番号5)
IKLSGGVQAKAGVINMFKSESY(VI)(配列番号6)
IKLSGGVQAKAGVINMFKSESYK(VII)(配列番号7)
GVQAKAGVINMFKSESY(VIII)(配列番号8)
GVRAKAGVRNMFKSESY(IX)(配列番号9)
GVRAKAGVRN(Nle)FKSESY(X)(配列番号10)
YKSLRRKAPRWDAPLRDPALRQLL(XI)(配列番号11)
YKSLRRKAPRWDAYLRDPALRQLL(XII)(配列番号12)または
YKSLRRKAPRWDAYLRDPALRPLL(XIII)(配列番号13)。
X1X2X3X4X5GVX6AKAGVX7NX8FKSESY(I)(配列番号1)
(X9)nGVX10AKAGVX11NX12FKSESY(配列番号2)
YKX13LRRX14APRWDX15PLRDPALRX16X17L(III)(配列番号3)
YKX18LRR(X19)nPLRDPALRX20X21L(IV)(配列番号4)
IKLSGGVQAKAGVINMDKSESM(V)(配列番号5)
IKLSGGVQAKAGVINMFKSESY(VI)(配列番号6)
IKLSGGVQAKAGVINMFKSESYK(VII)(配列番号7)
GVQAKAGVINMFKSESY(VIII)(配列番号8)
GVRAKAGVRNMFKSESY(IX)(配列番号9)
GVRAKAGVRN(Nle)FKSESY(X)(配列番号10)
YKSLRRKAPRWDAPLRDPALRQLL(XI)(配列番号11)
YKSLRRKAPRWDAYLRDPALRQLL(XII)(配列番号12)または
YKSLRRKAPRWDAYLRDPALRPLL(XIII)(配列番号13)。
X1X2X3X4X5GVX6AKAGVX7NX8FKSESY(I)(配列番号1)
(X9)nGVX10AKAGVX11NX12FKSESY(配列番号2)
YKX13LRRX14APRWDX15PLRDPALRX16X17L(III)(配列番号3)
YKX18LRR(X19)nPLRDPALRX20X21L(IV)(配列番号4)
IKLSGGVQAKAGVINMDKSESM(V)(配列番号5)
IKLSGGVQAKAGVINMFKSESY(VI)(配列番号6)
IKLSGGVQAKAGVINMFKSESYK(VII)(配列番号7)
GVQAKAGVINMFKSESY(VIII)(配列番号8)
GVRAKAGVRNMFKSESY(IX)(配列番号9)
GVRAKAGVRN(Nle)FKSESY(X)(配列番号10)
YKSLRRKAPRWDAPLRDPALRQLL(XI)(配列番号11)
YKSLRRKAPRWDAYLRDPALRQLL(XII)(配列番号12)
YKSLRRKAPRWDAYLRDPALRPLL(XIII)(配列番号13)
(式中、
X1、X2、X3、X4、X5、X6、X7、X8、X9、X10、X11、X12、X13、X14、X15、X18およびX19は独立して、任意のアミノ酸から選択され、
X16、X17、X20およびX21は独立して、Q、P、Y、IおよびLから選択され、
nは0、1、2、3、4または5であり、
X9が複数存在する場合、X9の各々は独立して、任意のアミノ酸から選択され、
X19が複数存在する場合、X9の各々は独立して、任意のアミノ酸から選択され、
少なくとも1つの保護基および/または少なくとも1つの標識剤が、場合によりN末端および/またはC末端においてペプチドに連結されている)
の化合物から選択される化合物と少なくとも80%の配列同一性を有するペプチド化合物である。
X1X2X3X4X5GVX6AKAGVX7NX8FKSESY(配列番号1);
(X9)nGVX10AKAGVX11NX12FKSESY(配列番号2);
YKX13LRRX14APRWDX15PLRDPALRX16X17L(配列番号3);
YKX18LRR(X19)nPLRDPALRX20X21L(配列番号4);
IKLSGGVQAKAGVINMDKSESM(配列番号5);
スクシニル−IKLSGGVQAKAGVINMFKSESY(スクシニル基がN末端に結合した配列番号6を含む);
IKLSGGVQAKAGVINMFKSESYK(ビオチン)(ビオチン分子がC末端に結合した配列番号7を含む);
GVQAKAGVINMFKSESY(配列番号8);
アセチル−GVRAKAGVRNMFKSESY(配列番号14);
アセチル−GVRAKAGVRN(Nle)FKSESY(配列番号15);
アセチル−YKSLRRKAPRWDAPLRDPALRQLL(配列番号16);
アセチル−YKSLRRKAPRWDAYLRDPALRQLL(配列番号17);および
アセチル−YKSLRRKAPRWDAYLRDPALRPLL(配列番号18)。
A−(B)n
(式中、
nは1、2、3または4であり、
Aは、場合により保護基によって保護されている、請求項1から14のいずれか1項に記載のペプチド化合物であり、および
Bは、BがAに連結されている少なくとも1つの治療剤である)
の式を有するコンジュゲート化合物である。
A−(B)n
(式中、
nは1、2、3または4であり、
Aは、本明細書に記載のペプチド化合物であり、および
Bは、ペプチド化合物のリジン残基の遊離アミンにおいて場合によりリンカーを介して、またはペプチド化合物のN末端位において、場合によりリンカーを介してBがAに連結されている少なくとも1つの治療剤である)
の式を有するコンジュゲート化合物である。
IK(ドセタキセル)LSGGVQAK(ドセタキセル)AGVINMFK(ドセタキセル)SESY(XIV)
(各リジン残基にドセタキセル分子が連結されている、配列番号6を有するペプチド化合物を含む);
GVQAK(ドセタキセル)AGVINMFK(ドセタキセル)SESY(XV)
(各リジン残基にドセタキセル分子が連結されている、配列番号8を有するペプチド化合物を含む);
GVRAK(ドセタキセル)AGVRNMFK(ドセタキセル)SESY(XVI)
(各リジン残基にドセタキセル分子が連結されている、配列番号9を有するペプチド化合物を含む);
GVRAK(ドセタキセル)AGVRN(Nle)FK(ドセタキセル)SESY(XVII)
(各リジン残基にドセタキセル分子が連結されている、配列番号10を有するペプチド化合物を含む);ならびに
YK(ドセタキセル)SLRRK(ドセタキセル)APRWDAPLRDPALRQL(XVIII)
(各リジン残基にドセタキセル分子が連結されている、配列番号11を有するペプチド化合物を含む)。
スクシニル−IK(ドセタキセル)LSGGVQAK(ドセタキセル)AGVINMFK(ドセタキセル)SESY(XIX)
(各リジン残基にドセタキセル分子が連結され、スクシニル基がN末端に結合した、配列番号6を有するペプチド化合物を含む);
アセチル−GVRAK(ドセタキセル)AGVRNMFK(ドセタキセル)SESY(XX)
(各リジン残基にドセタキセル分子が連結されている、配列番号14を有するペプチド化合物を含む);
アセチル−GVRAK(ドセタキセル)AGVRN(Nle)FK(ドセタキセル)SESY(XXI)
(各リジン残基にドセタキセル分子が連結されている、配列番号15を有するペプチド化合物を含む);ならびに
アセチル−YK(ドセタキセル)SLRRK(ドセタキセル)APRWDAPLRDPALRQLL(XXII)
(各リジン残基にドセタキセル分子が連結されている、配列番号16を有するペプチド化合物を含む)。
GVQAK(ドキソルビシン)AGVINMFK(ドキソルビシン)SESY(XXIII)
(各リジン残基にドキソルビシン分子が連結されている、配列番号8を有するペプチド化合物を含む);
GVRAK(ドキソルビシン)AGVRN(Nle)FK(ドキソルビシン)SESY(XXIV)
(各リジン残基にドキソルビシン分子が連結されている、配列番号10を有するペプチド化合物を含む);ならびに
YK(ドキソルビシン)SLRRK(ドキソルビシン)APRWDAPLRDPALRQLL(XXV)
(各リジン残基にドキソルビシン分子が連結されている、配列番号11を有するペプチド化合物を含む)。
アセチル−GVRAK(ドキソルビシン)AGVRN(Nle)FK(ドキソルビシン)SESY(XXVI)
(各リジン残基にドキソルビシン分子が連結されている、配列番号15を有するペプチド化合物を含む);ならびに
アセチル−YK(ドキソルビシン)SLRRK(ドキソルビシン)APRWDAPLRDPALRQLL(XXVII)
(各リジン残基にドキソルビシン分子が連結されている、配列番号16を有するペプチド化合物を含む);
から選択することができる。
GVRAK(カバジタキセル)AGVRNMFK(カバジタキセル)SESY(XXVIII)
(各リジン残基にカバジタキセル分子が連結されている配列番号9を有するペプチド化合物を含む);
GVRAK(カバジタキセル)AGVRN(Nle)FK(カバジタキセル)SESY(XXIX)
(各リジン残基にカバジタキセル分子が連結されている配列番号10を有するペプチド化合物を含む);
およびYK(カバジタキセル)SLRRK(カバジタキセル)APRWDAPLRDPALRQL(XXX)
アセチル−GVRAK(カバジタキセル)AGVRNMFK(カバジタキセル)SESY(XXXI)
(各リジン残基にカバジタキセル分子が連結されている配列番号14を有するペプチド化合物を含む);
アセチル−GVRAK(カバジタキセル)AGVRN(Nle)FK(カバジタキセル)SESY(XXXII)
(各リジン残基にカバジタキセル分子が連結されている配列番号15を有するペプチド化合物を含む);および
アセチル−YK(カバジタキセル)SLRRK(カバジタキセル)APRWDAPLRDPALRQLL(XXXIII)
(各リジン残基にカバジタキセル分子が連結されている配列番号16を有するペプチド化合物を含む)。
GVRAK(クルクミン)AGVRN(Nle)FK(クルクミン)SESY(XXXIV)
(各リジン残基にクルクミン分子が連結されている配列番号10を有するペプチド化合物を含む)。
アセチル−GVRAK(クルクミン)AGVRN(Nle)FK(クルクミン)SESY(XXXV)
(各リジン残基にクルクミン分子が連結されている、配列番号15を有するペプチド化合物を含む)。
中間体を得るためにリンカーと治療薬とを反応させる工程;
場合により中間体を精製する工程;
コンジュゲート化合物を得るように、中間体とペプチド化合物とを反応させる工程;および
場合によりコンジュゲート化合物を精製する工程;
を含み、
治療剤が、リジン残基の遊離アミンにおいて、またはN末端においてペプチド化合物に連結されており、ペプチド化合物が1、2、3または4つの連結治療剤分子を含む方法が提供される。
治療剤を含む本明細書に開示のコンジュゲート化合物を得る工程、および
コンジュゲート化合物の治療有効量をそれを必要とする対象に投与する工程、
を含む方法が本明細書において提供される。
治療剤と本明細書に開示のペプチド化合物とをコンジュゲートして、コンジュゲート化合物を得る工程、および
コンジュゲート化合物の治療有効量をそれを必要とする対象に投与する工程、
を含む方法が本明細書において提供される。
治療剤を含む本明細書に開示のコンジュゲート化合物を得る工程、および
コンジュゲート化合物の治療有効量をそれを必要とする対象に投与する工程、
を含む方法が本明細書において提供される。
治療剤と本明細書に開示のペプチド化合物とをコンジュゲートして、コンジュゲート化合物を得る工程、および
コンジュゲート化合物の治療有効量をそれを必要とする対象に投与する工程、
を含む方法が本明細書において提供される。
治療剤を含む本明細書に開示のコンジュゲート化合物を得る工程、および
コンジュゲート化合物の治療有効量をそれを必要とする対象に投与する工程、
を含む方法が本明細書において提供される。
治療剤と本明細書に開示のペプチド化合物とをコンジュゲートして、コンジュゲート化合物を得る工程、および
コンジュゲート化合物の治療有効量をそれを必要とする対象に投与する工程、
を含む方法が本明細書において提供される。
治療剤と本明細書に開示のペプチド化合物とをコンジュゲートして、コンジュゲート化合物を得る工程、および
少なくとも1つの細胞と、コンジュゲート化合物とを接触させる工程、
を含む方法が本明細書において提供される。
[例1]
ペプチド化合物の生成
[例2]
Katana−ペプチド−薬物コンジュゲートの生成
[例3]
コンジュゲート化合物のインビトロ効果
[例4]
コンジュゲート化合物のインビボ効果
a)ドセタキセル
b)ドキソルビシン
c)クルクミン
[例5]
細胞増殖アッセイ
[例6]
xCELLigenceバイオセンサーシステムによる細胞遊走アッセイ
[例7]
コンジュゲートのヨウ素化
[例8]
MDCK−MDR1における薬物蓄積
[例9]
異種移植腫瘍モデル
[例10]
薬物動態および組織分布
[例11]
ドセタキセル−Katanaペプチド(KBA−106)コンジュゲートの合成
DoceSuOH
KBP106−(SuDoce)2
[例12]
ドキソルビシン−Katanaペプチド(KBA−106)コンジュゲートの合成
ドキソルビシンFmoc−DmgOH
KBB106−(Dmg−FmocDoxo)2コンジュゲート
KBP106−Dmg−FmocDoxoからのFmoc脱保護
[例13]
クルクミン−Katanaペプチド(KBA−106)コンジュゲートの合成
DmgOHへのNHSリンカーの付加
KBP106−(DmgCur)2
[例14]
カバジタキセル−Katanaペプチド(KBA−106)コンジュゲートの合成
カバジタキセル−SuOH
KBP106−(Suカバジタキセル)2
[例15]
ドセタキセル−Katanaペプチド(KBA−105)コンジュゲートの合成
1.ドセタキセルへのリンカーの付加
−コハク酸の付加(一晩)
−Biotageにおける精製(1時間)
−溶媒の蒸発(30分)
2.コンジュゲーション
−TBTUによるドセタキセルの活性化(5〜10分)
−ペプチドの付加
−DMF中での反応(pHに従う必要はない)
−反応時間30分
−30RPCで精製した後、−80℃において凍結乾燥
全収率約75%
純度>95%。
[例16]
ドキソルビシン−Katanaペプチド(KBB−106)コンジュゲートの合成
1.ドキソルビシン遊離アミンに対するFmocの付加
2.ドキソルビシン−Fmoc中間体へのリンカーの組み込み
−ジメチルグルタル酸(DMG)リンカー
−Aktaでのドキソルビシン(Fmoc)−DMGの精製、その後の凍結乾燥
3.コンジュゲーション
−TBTUによるドキソルビシン−DMGの活性化(5〜10分)
−ペプチドの付加
−DMSO中での反応(pHに従う必要はない)
−反応時間30分
−AKTA(30RPC樹脂)で精製した後、凍結乾燥
4.ピペリジンによるFmoc基の脱保護(5〜10分)、その後の精製
全収率約42%
純度>95%。
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<223>合成構築体
<223>Xaaは任意のアミノ酸であってよい
<223>Xaaは任意のアミノ酸であってよい
<223>Xaaは任意のアミノ酸であってよい
<223>Xaaは任意のアミノ酸であってよい
配列表2
<223>合成構築体
<223>Xaaは任意のアミノ酸であってよく、存在または非存在のいずれであってもよい
<223>Xaaは任意のアミノ酸であってよい
<223>Xaaは任意のアミノ酸であってよい
<223>Xaaは任意のアミノ酸であってよい
配列表3
<223>合成構築体
<223>Xaaは任意のアミノ酸であってよい
<223>Xaaは任意のアミノ酸であってよい
<223>Xaaは任意のアミノ酸であってよい
<223>XaaはGln、Pro、Tyr、IleまたはLeuのいずれかであってよい
配列表4
<223>合成構築体
<223>Xaaは任意のアミノ酸であってよい
<223>Xaaは任意のアミノ酸であってよく、存在または非存在のいずれであってもよい
<223>XaaはGln、Pro、Tyr、IleまたはLeuのいずれかであってよい
配列表5〜9 <223>合成構築体
配列表10
<223>合成構築体
<223>XaaはNleである
配列表11〜13 <223>合成構築体
配列表14
<223>合成構築体
<223>アセチル化
配列表15
<223>合成構築体
<223>アセチル化
<223>XaaはNleである
配列表16
<223>合成構築体
<223>アセチル化
配列表17
<223>合成構築体
<223>アセチル化
配列表18
<223>合成構築体
<223>アセチル化
配列表22 <223>Xaaは任意のアミノ酸であってよい
Claims (33)
- 式(X)
GVRAKAGVRN(Nle)FKSESY(X)(配列番号10)
のアミノ酸配列からなる化合物であって、
少なくとも1つの保護基および/または少なくとも1つの標識剤が、N末端および/またはC末端において前記ペプチド化合物に連結されていて、
Vacuolar Protein Sorting 10(Vps10)ファミリー受容体に結合する、
ペプチド化合物。 - 式(X)
GVRAKAGVRN(Nle)FKSESY(X)(配列番号10)
のアミノ酸配列からなる化合物であって、
Vacuolar Protein Sorting 10タンパク質(Vps10)ファミリー受容体に結合する、
ペプチド化合物。 - N末端において連結されている少なくとも1つの保護基を含む、請求項1に記載のペプチド化合物。
- 少なくとも1つの保護基としてアセチル又はスクシニルを含む、請求項1又は3に記載のペプチド化合物。
- 式(X)
GVRAKAGVRN(Nle)FKSESY(X)(配列番号10)
からなる、ペプチド化合物。 - 式(XXXIX)により表される、請求項1に記載のペプチド化合物:
アセチル−GVRAKAGVRN(Nle)FKSESY (XXXIX)(配列番号15)。 - 式(XXXIX):
アセチル−GVRAKAGVRN(Nle)FKSESY (XXXIX)(配列番号15)
からなる、ペプチド化合物。 - 式A−(B)nのコンジュゲート化合物:
(式中、
nは1、2、3または4であり、
Aは、保護基によって保護されている請求項1から7のいずれかに記載のペプチド化合物であり、および
Bは、少なくとも1つの治療剤であって、Aに連結されていて、前記ペプチド化合物の遊離アミンにおいて、前記ペプチド化合物のN末端位において、前記ペプチド化合物の遊離−SHにおいて、または前記ペプチド化合物の遊離カルボキシルにおいて、連結されている)。 - 式A−(B)nのコンジュゲート化合物:
(式中、
nは1、2、3または4であり、
Aは、保護基によって保護されている請求項1から7のいずれかに記載のペプチド化合物であり、および
Bは、少なくとも1つの治療剤であって、Aに連結されていて、前記ペプチド化合物のリジン残基の遊離アミンにおいてリンカーを介して、または前記ペプチド化合物のN末端位において、リンカーを介して、連結されている)。 - 式A−(B)nのコンジュゲート化合物:
(式中、
nは1、2、3または4であり、
Aは、請求項1から7のいずれか1項に記載のペプチド化合物であり、および
Bは、少なくとも1つの治療剤であって、Aに連結されている)。 - 式A−(B)nのコンジュゲート化合物:
(式中、
nは1、2、3または4であり、
Aは、請求項1から7のいずれか1項に記載のペプチド化合物であり、および
Bは、少なくとも1つの治療剤であって、Aに連結されていて、前記ペプチド化合物のリジン残基の遊離アミンにおいて、または前記ペプチド化合物のN末端位において、連結されている)。 - Bが、リンカーを介してAに連結されている、請求項8、9又は10に記載のコンジュゲート化合物。
- 少なくとも1つの治療剤が抗癌剤である、請求項8から12のいずれかに記載のコンジュゲート化合物。
- 抗癌剤が、ドセタキセル、カバジタキセル、パクリタキセル、ドキソルビシンまたはダウノマイシンである、請求項13に記載のコンジュゲート化合物。
- 前記抗癌剤がドセタキセルである、請求項14に記載のコンジュゲート化合物。
- 式(XVII)の化合物である、請求項8から11のいずれかに記載のコンジュゲート化合物:
GVRAK(ドセタキセル)AGVRN(Nle)FK(ドセタキセル)SESY(XVII)
(配列番号10の配列を有し、各リジン残基にドセタキセル分子が連結されているペプチド化合物を含む)。 - 式(XXI)の化合物である、請求項8から11のいずれかに記載のコンジュゲート化合物:
アセチル−GVRAK(ドセタキセル)AGVRN(Nle)FK(ドセタキセル)SESY(XXI)
(配列番号15の配列を有し、各リジン残基にドセタキセル分子が連結されているペプチド化合物を含む)。 - 前記抗癌剤がドキソルビシンである、請求項13に記載のコンジュゲート化合物。
- 式(XXIV)の化合物である、請求項8から11のいずれかに記載のコンジュゲート化合物:
GVRAK(ドキソルビシン)AGVRN(Nle)FK(ドキソルビシン)SESY(XXIV)
(配列番号10を有し、各リジン残基にドキソルビシン分子が連結されているペプチド化合物を含む)。 - 式(XXVI)の化合物である、請求項8から11のいずれかに記載のコンジュゲート化合物:
アセチル−GVRAK(ドキソルビシン)AGVRN(Nle)FK(ドキソルビシン)SESY(XXVI)
(配列番号15を有し、各リジン残基にドキソルビシン分子が連結されているペプチド化合物を含む)。 - 式(XXXIV)の化合物である、請求項8から11のいずれかに記載のコンジュゲート化合物:
GVRAK(クルクミン)AGVRN(Nle)FK(クルクミン)SESY(XXXIV)
(配列番号10を有し、各リジン残基にクルクミン分子が連結されているペプチド化合物を含む)。 - 式(XXXV)の化合物である、請求項8から11のいずれかに記載のコンジュゲート化合物:
アセチル−GVRAK(クルクミン)AGVRN(Nle)FK(クルクミン)SESY(XXXV)
(配列番号15を有し、各リジン残基にクルクミン分子が連結されているペプチド化合物を含む)。 - Bが、前記ペプチド化合物の前記リジン残基の前記遊離アミンにおいて、リンカーを介してAに連結されている、請求項8から22のいずれかに記載のコンジュゲート化合物。
- Bが、前記ペプチド化合物の前記N末端位において、リンカーを介してAに連結されている、請求項8から15及び18のいずれかに記載のコンジュゲート化合物。
- リンカーが、コハク酸およびジメチルグルタル酸からなる群から選択される、請求項23または24に記載のコンジュゲート化合物。
- ソルチリン発現を伴う疾患を治療するための、請求項1から25のいずれかに記載の少なくとも1つの化合物を含む医薬組成物。
- Vacuolar Protein Sorting 10(Vps10)ファミリー受容体から選択される少なくとも1つの受容体の発現を伴う疾患を治療するための、請求項1から25のいずれかに記載の少なくとも1つの化合物を含む医薬組成物。
- 少なくとも1つの受容体がソルチリン、SorL1、SorCS1、SorCS2、およびSorCS3から選択される、請求項27に記載の医薬組成物。
- Vacuolar Protein Sorting 10(Vps10)ファミリー受容体から選択される少なくとも1つの受容体の発現を伴う癌を治療するための、請求項1から25のいずれかに記載の化合物を含む医薬組成物。
- 癌が、卵巣癌、脳癌、乳癌、メラノーマ、結腸直腸癌、膠芽細胞腫、肝臓癌、肺癌、前立腺癌、子宮頸癌、頭部癌、胃癌、腎臓癌、子宮内膜癌、精巣癌、尿路上皮癌、急性リンパ芽球性白血病、急性骨髄性白血病、ホジキンリンパ腫、神経芽細胞腫、非ホジキンリンパ腫、軟部組織癌、骨肉腫、甲状腺癌、移行細胞膀胱癌、ウィルムス腫瘍、神経膠腫、膵臓癌または脾臓癌である、請求項29に記載の医薬組成物。
- 癌が乳癌である、請求項30に記載の医薬組成物。
- 請求項1から25のいずれかに記載の少なくとも1つの化合物を含む、リポソーム、グラフェンまたはナノ粒子。
- 治療剤およびsiRNAの少なくとも1つが担持されたリポソーム、グラフェンまたはナノ粒子であって、請求項1から7のいずれかに記載の少なくとも1つの化合物でコーティングされているリポソーム、グラフェンまたはナノ粒子。
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