JP2021530507A - 神経細胞に抗がん剤を送達するためのコンジュゲート、その使用方法及び製造方法 - Google Patents
神経細胞に抗がん剤を送達するためのコンジュゲート、その使用方法及び製造方法 Download PDFInfo
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- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
Description
米国特許法第119条(e)に準じて、本出願は、2018年7月18日出願の米国仮特許出願第62/700,131号の出願日に基づく優先権を主張し、その出願の開示は参照により本明細書に組み込まれる。
中枢神経系(CNS)の腫瘍は、遺伝性疾患の神経線維腫症を有する小児の最大20%まで発生する。CNS腫瘍では、大部分(約90%)の視路神経膠腫は、低悪性度神経膠腫であり、良好な予後を有する無痛性の緩徐増殖型である。対照的に高悪性度神経膠腫は急速に出現し、迅速に進行し、ほぼ常に致死性である。小児は、50%の症例で視力喪失を示し、これらの視路神経膠腫の約85%は、切除不能であり、視神経および/または視交叉に位置している。神経膠腫を治療するために、薬物療法は、典型的にはカルボプラチンまたはビンブラスチンの投与などの全身化学療法を含む。しかし、推定40%の小児が用量毒性によってカルボプラチン治療を停止している。
B−L−X (I)
式中、Bは、ニューロトロフィン受容体に選択的に結合するタンパク質、ペプチドまたはペプチド模倣体であり、Lはリンカーであり、Xは抗がん剤である。一実施形態において、抗がん剤は、ニューロトロフィン受容体に選択的に結合するように構成される。一部の実施形態において、抗がん剤(一部の場合では、コンジュゲート全体)は、がん細胞に内部移行するように構成される。一部の実施形態において、がんは、成人および小児神経膠腫、視路神経膠腫、脊椎腫瘍、神経線維腫症、シュワン細胞腫、悪性末梢神経鞘腫瘍、悪性シュワン細胞腫、神経線維肉腫、神経肉腫からなる群から選択されるがんなどの中枢神経系のがんである。ある特定の場合では、がんは視路神経膠腫である。他の場合では、がんは神経周囲浸潤を含む。さらに他の場合では、がんは皮膚がんである。
以下の用語は、特に指示されない限り、以下の意味を有する。任意の未定義用語は、当該技術に認識されている意味を有する。
本発明が更に記載される前に、本発明は記載されている特定の実施形態に限定されないこと、したがって、当然のことながら変わりうることが理解されるべきである。また、本明細書に使用される用語は、特定の実施形態を記載する目的のみであり、本発明の範囲は添付の特許請求の範囲によってのみ制限されるので、限定的であることを意図しないことが理解されるべきである。
本開示の化合物の合成に有用な一般的に知られている化学合成スキームおよび条件を提供する多くの一般的な参考文献が、利用可能である(例えば、Smith and March,March’s Advanced Organic Chemistry:Reactions,Mechanisms,and Structure,Fifth Edition,Wiley−Interscience,2001、またはVogel,A Textbook of Practical Organic Chemistry, Including Qualitative Organic Analysis,Fourth Edition,New York:Longman,1978を参照すること)。
ここで様々な実施形態が詳細に参照される。本発明は、これらの実施形態に限定されないことが理解される。対照的に、本発明は、容認される特許請求の範囲の精神および範囲内に含まれうる代替物、変更、および等価物を網羅することが意図される。
上記に要約されたように、本開示の態様は、抗がん剤を神経細胞に送達するためのコンジュゲート化合物を含む。ある特定の実施形態によるコンジュゲート化合物は、ニューロトロフィン受容体に選択的に結合するタンパク質、ペプチドまたはペプチド模倣体、抗がん剤、および抗がん剤を、ニューロトロフィン受容体に選択的に結合するタンパク質、ペプチドまたはペプチド模倣体に共有結合させるリンカーを有する化合物を含む。ある特定の実施形態において、目的の化合物は、式I:
B−L−X (I)
[式中、
Bは、ニューロトロフィン受容体に選択的に結合するタンパク質、ペプチドまたはペプチド模倣体であり、
Lはリンカーであり、
Xは抗がん剤である]
のコンジュゲートを含む。
上記に要約されたように、本開示の態様は、抗がん剤を神経細胞に送達するための方法を含む。ある特定の実施形態による主題方法の実践において、方法は、神経細胞を、神経細胞のニューロトロフィン受容体に選択的に結合するタンパク質、ペプチドまたはペプチド模倣体、抗がん剤、および抗がん剤をタンパク質、ペプチドまたはペプチド模倣体に共有結合させるリンカーを有する化合物と接触させることを含む。一部の実施形態において、方法は、1つまたは複数の主題コンジュゲート化合物を対象に投与することを含む。本開示の方法を記載する際に、用語「対象」は、コンジュゲート化合物が投与される人間または生物体を意味する。このように、本開示の対象は、哺乳動物、例えば、ヒト、ならびに他の霊長類、例えば、チンパンジー、および他の類人猿およびサルの種、イヌ、ウサギ、ネコ、および他の飼い慣らされたペット(domesticated pets)などを含むが、これらに限定されず、ある特定の実施形態において、対象はヒトである。対象という用語は、任意の年齢、体重または他の身体的特徴の人間または生物体を含むことも意図され、対象は、成人、小児、乳幼児、または新生児でありうる。ある特定の実施形態において、対象は小児であり、方法は、視路神経膠腫などの神経膠腫の治療のために、1つまたは複数のコンジュゲート化合物を投与することを含む。
容易に理解されるように、本明細書に記載されている対象に化合物コンジュゲート(すなわち、式Iの抗がんコンジュゲート)の治療有効量を投与することによる治療方法は、一部の場合では、1つまたは複数の慣用の治療と組み合わせることができる。例えば、腫瘍学の場合、本明細書に記載されている方法は、一部の場合では、例えば、慣用の化学療法、慣用の放射線療法、慣用の免疫療法、外科手術などを含むが、これらに限定されない慣用のがん療法と組み合わせることができる。
上記に要約されたように、本開示の態様は、主題のコンジュゲート化合物を調製する方法を含む。ある特定の実施形態による方法の実践において、方法は、抗がん剤をリンカー前駆体と接触させて、活性化された抗がん剤を生成すること、および活性化された抗がん剤を、ニューロトロフィン受容体に選択的に結合するタンパク質、ペプチドまたはペプチド模倣体と接触させることを含む。実施形態において、リンカー前駆体は、ゼロ長クロスリンカー前駆体、ホモ二官能性リンカー前駆体、ヘテロ二官能性リンカー前駆体、または三官能性クロスリンカー前駆体でありうる。ある特定の実施形態において、抗がん剤を二官能性リンカー前駆体に接触させて、ホモ二官能性またはヘテロ二官能性リンカー前駆体などの活性化された抗がん剤を生成する。一部の実施形態において、二官能性リンカー前駆体はスクシンイミドを含み、例えば、二官能性リンカー前駆体は、N,N’−ジスクシンイミジルカーボネートである。
本明細書に記載されている化合物の代表的な合成が以下のスキームに示されている。用語「RG」は反応性基(例えば、ヒドロキシル、アミン、スルフヒドリル)を指し、「LG」は脱離基(例えば、スクシンイミド基)を指す。用語「X」はリンカー部分(例えば、カーボネート、カルバメートなど)を指す。
本開示の態様はキットを更に含み、キットは、1つまたは複数の主題化合物、または上記に記載されたコンジュゲート化合物および薬学的に許容される担体を有する組成物、ならびに、化合物/組成物を対象に投与するための1つまたは複数の構成成分を含む。ある特定の実施形態において、キットは、例えば組成物を投与するために、針を有する、または有さないシリンジを含む。ある特定の場合では、キットは、化合物/組成物の大槽内または髄腔内注射のために針およびシリンジを含む。一部の場合では、キットは、1つまたは複数の追加の構成成分(例えば、緩衝液、水、注射部位清浄構成成分など)を含むことができる。一部の場合では、キットは、試料採集デバイス、例えば採血デバイス、例えば、望ましい場合には真空採血管、針、シリンジ、ピペット、止血帯などを更に含む。
1.式I:
B−L−X(I)
[式中、
Bは、ニューロトロフィン受容体に選択的に結合するタンパク質、ペプチドまたはペプチド模倣体であり、
Lはリンカーであり、
Xは抗がん剤である]
の化合物。
2.抗がん剤が、がん細胞に内部移行するように構成される、1に記載の化合物。
3.がんが神経膠腫である、2に記載の化合物。
4.がんが視路神経膠腫である、3に記載の化合物。
5.抗がん剤が、哺乳類標的のラパマイシン(mTOR)阻害剤またはマイトジェン活性化プロテインキナーゼ(MEK)阻害剤である、1から4のいずれか一項に記載の化合物。
6.mTOR阻害剤が、シロリムス、テムシロリムス、エベロリムスおよびリダフォロリムスからなる群から選択される化合物である、5に記載の化合物。
7.抗がん剤がエベロリムスである、6に記載の化合物。
8.式IA1の化合物である、6に記載の化合物。
11.抗がん剤がセルメチニブある、10に記載の化合物。
12.式IB1の化合物である、11に記載の化合物。
15.抗がん剤が、熱ショックタンパク質90(hsp90)阻害剤である、14に記載の化合物。
16.hsp90阻害剤が、
a)アルベスピノマイシン:
r)ゲルダナマイシン:
17.hsp90阻害剤がアルベスピノマイシンである、16に記載の化合物。
21.チェックポイント阻害剤が、PD−1、PD−L1、CTLA4、TIM3、LAG3、VISTA、BTLA、TIGIT、LAIR1、CD160、2B4およびTGFRβのうちの1つまたは複数を標的にする阻害性化合物である、20に記載の化合物。
22.チェックポイント阻害剤が、PD−1を標的にする阻害性化合物である、21に記載の化合物。
23.チェックポイント阻害剤が、
a)S7911:
c)S8158:
24.チェックポイント阻害剤がS7911である、23に記載の化合物。
28.CX4/CXCL12阻害剤が、
a)ブリキサホル:
d)AMD3465:
29.CX4/CXCL12阻害剤がLY2510924である、28に記載の化合物。
25.イミキモドである、24に記載の化合物。
27.抗がん剤がイミダゾキノロンアミンである、26に記載の化合物。
25.イミキモドである、27に記載の化合物。
27.リンカーが、酸開裂性リンカー、塩基開裂性リンカー、光開裂性リンカー、または酵素開裂性リンカーである、26に記載の化合物。
28.リンカーが非開裂性である、1から27のいずれか一項に記載の化合物。
29.リンカーがカルバメートを含む、1から28のいずれか一項に記載の化合物。
30.Bが、脳由来神経栄養因子(BDNF)またはそのフラグメントである、1から29のいずれか一項に記載の化合物。
31.Bが、神経増殖因子(NGF)またはそのフラグメントである、1から29のいずれか一項に記載の化合物。
32.Bが、トロポミオシン受容体キナーゼB(trkB)に結合するBDNFもしくはそのフラグメント、またはトロポミオシン受容体キナーゼA(trkA)に結合するNGFまたはそのフラグメントである、30から32のいずれか一項に記載の化合物。
33.trkBへのBDNFもしくはそのフラグメントの結合、またはtrkAへのNGFもしくはそのフラグメントの結合が、がん細胞への化合物の内部移行を誘発する、30から32のいずれか一項に記載の化合物。
34.がんが神経膠腫である、32から34のいずれか一項に記載の化合物。
35.がんが視路神経膠腫である、34に記載の化合物。
36.がんが神経周囲浸潤を含む、32または33に記載の化合物。
37.がんが皮膚がんである、32または33に記載の化合物。
38.Bが、p75ニューロトロフィン受容体に結合する、BDNFもしくはそのフラグメントまたはNGFもしくはそのフラグメントである、1に記載の化合物。
39.p75への、BDNFもしくはそのフラグメントまたはNGFもしくはそのフラグメントの結合が、がん細胞への化合物の内部移行を誘発する、38に記載の化合物。
40.がんが神経膠腫である、38または39に記載の化合物。
41.がんが視路神経膠腫である、40に記載の化合物。
42.がんが神経周囲浸潤を含む、38から40のいずれか一項に記載の化合物。
43.がんが皮膚がんである、38から40のいずれか一項に記載の化合物。
44.Bが、毛様体神経栄養因子(CTNF)またはそのフラグメントである、1から31のいずれか一項に記載の化合物。
45.Bが、神経栄養因子3(NT−3)またはそのフラグメントである、1から31のいずれか一項に記載の化合物。
46.Bが、グリア細胞由来神経栄養因子(GDNF)である、1から31のいずれか一項に記載の化合物。
1.薬学的に許容される担体と、
式I:
B−L−X(I)
[式中、
Bは、ニューロトロフィン受容体に選択的に結合するタンパク質、ペプチドまたはペプチド模倣体であり、
Lはリンカーであり、
Xは抗がん剤である]
の化合物と
を含む組成物。
2.注射薬として処方される、1に記載の組成物。
3.大槽内投与用に処方される、1に記載の組成物。
4.髄腔内投与用に処方される、1に記載の組成物。
5.抗がん剤が、がん細胞に内部移行するように構成される、1に記載の組成物。
6.がんが神経膠腫である、5に記載の組成物。
7.がんが視路神経膠腫である、6に記載の組成物。
8.抗がん剤が、哺乳類標的のラパマイシン(mTOR)阻害剤またはマイトジェン活性化プロテインキナーゼ(MEK)阻害剤である、1から7のいずれか一項に記載の組成物。
9.mTOR阻害剤が、シロリムス、テムシロリムス、エベロリムスおよびリダフォロリムスからなる群から選択される化合物である、8に記載の組成物。
10.抗がん剤がエベロリムスである、9に記載の組成物。
11.化合物が式IA1の化合物である、9に記載の組成物。
14.抗がん剤がセルメチニブである、13に記載の組成物。
15.化合物が式IB1の化合物である、13に記載の組成物。
18.抗がん剤が、熱ショックタンパク質90(hsp90)阻害剤である、17に記載の組成物。
19.hsp90阻害剤が、
a)アルベスピノマイシン:
r)ゲルダナマイシン:
20.hsp90阻害剤がアルベスピノマイシンである、19に記載の組成物。
24.チェックポイント阻害剤が、PD−1、PD−L1、CTLA4、TIM3、LAG3、VISTA、BTLA、TIGIT、LAIR1、CD160、2B4およびTGFRβのうちの1つまたは複数を標的にする阻害性化合物である、23に記載の組成物。
25.チェックポイント阻害剤が、PD−1を標的にする阻害性化合物である、24に記載の化合物。
26.チェックポイント阻害剤が、
a)S7911:
c)S8158:
27.チェックポイント阻害剤がS7911である、26に記載の組成物。
31.CX4/CXCL12阻害剤が、
a)ブリキサホル:
d)AMD3465:
32.CX4/CXCL12阻害剤がLY2510924である、31に記載の組成物。
37.化合物がイミキモドである、24に記載の組成物。
39.抗がん剤がイミダゾキノロンアミンである、38に記載の組成物。
40.化合物がイミキモドである、39に記載の組成物。
42.リンカーが、酸開裂性リンカー、塩基開裂性リンカー、光開裂性リンカー、または酵素開裂性リンカーである、40に記載の組成物。
43.リンカーが非開裂性である、1から42のいずれか一項に記載の組成物。
44.リンカーがカルバメートを含む、1から42のいずれか一項に記載の組成物。
45.Bが、脳由来神経栄養因子(BDNF)またはそのフラグメントである、1から44のいずれか一項に記載の組成物。
46.Bが、神経増殖因子(NGF)またはそのフラグメントである、1から44のいずれか一項に記載の組成物。
47.Bが、トロポミオシン受容体キナーゼB(trkB)に結合するBDNFもしくはそのフラグメント、またはトロポミオシン受容体キナーゼA(trkA)に結合するNGFまたはそのフラグメントである、43から46のいずれか一項に記載の組成物。
48.trkBへのBDNFもしくはそのフラグメントの結合、またはtrkAへのNGFもしくはそのフラグメントの結合が、がん細胞への化合物の内部移行を誘発する、43から46のいずれか一項に記載の組成物。
49.がんが神経膠腫である、47または48に記載の組成物。
50.がんが視路神経膠腫である、48に記載の組成物。
51.がんが神経周囲浸潤を含む、43から48のいずれか一項に記載の組成物。
52.がんが皮膚がんである、43から48のいずれか一項に記載の組成物。
53.Bが、p75ニューロトロフィン受容体に結合する、BDNFもしくはそのフラグメントまたはNGFもしくはそのフラグメントである、1から48のいずれか一項に記載の組成物。
54.p75への、BDNFもしくはそのフラグメントまたはNGFもしくはそのフラグメントの結合が、がん細胞への化合物の内部移行を誘発する、53に記載の組成物。
55.がんが神経膠腫である、53または54に記載の組成物。
56.がんが視路神経膠腫である、55に記載の組成物。
57.がんが神経周囲浸潤を含む、53または54に記載の組成物。
58.がんが皮膚がんである、53または54に記載の組成物。
61.Bが、毛様体神経栄養因子(CNTF)またはそのフラグメントである、1から46のいずれか一項に記載の組成物。
62.Bが、神経栄養因子3(NT−3)またはそのフラグメントである、1から46のいずれか一項に記載の組成物。
63.Bが、グリア細胞由来神経栄養因子(GDNF)である、1から46のいずれか一項に記載の組成物。
1.抗がん剤を神経細胞に選択的に送達する方法であって、
式I:
B−L−X(I)
[式中、
Bは、ニューロトロフィン受容体に選択的に結合するタンパク質、ペプチドまたはペプチド模倣体であり、
Lはリンカーであり、
Xは抗がん剤である]
の化合物を投与すること
を含む方法。
2.抗がん剤が、神経細胞受容体へのBの結合に応答してがん細胞に内部移行する、1に記載の方法。
3.神経細胞受容体がニューロトロフィン受容体である、2に記載の方法。
4.抗がん剤が、トロポミオシン受容体キナーゼA(trkA)またはトロポミオシン受容体キナーゼB(trkB)へのBの結合に応答してがん細胞に内部移行する、2に記載の方法。
5.抗がん剤が、p75ニューロトロフィン受容体へのBの結合に応答してがん細胞に内部移行する、2に記載の方法。
6.化合物が対象に大槽内投与される、1から5のいずれか一項に記載の方法。
7.化合物が対象に鞘内投与される、1から5のいずれか一項に記載の方法。
8.対象を、がんを有していると診断することを更に含む、1から7のいずれか一項に記載の方法。
9.がんが神経膠腫である、8に記載の方法。
10.がんが視路神経膠腫である、9に記載の方法。
11.抗がん剤が、哺乳類標的のラパマイシン(mTOR)阻害剤またはマイトジェン活性化プロテインキナーゼ(MEK)阻害剤である、1から10のいずれか一項に記載の方法。
12.mTOR阻害剤が、シロリムス、テムシロリムス、エベロリムスおよびリダフォロリムスからなる群から選択される化合物である、11に記載の方法。
13.抗がん剤がエベロリムスである、12に記載の方法。
14.化合物が式IA1の化合物である、12に記載の方法。
17.抗がん剤がセルメチニブである、16に記載の方法。
18.化合物が式IB1の化合物である、17に記載の方法。
21.抗がん剤が、熱ショックタンパク質90(hsp90)阻害剤である、20に記載の方法。
22.hsp90阻害剤が、
a)アルベスピノマイシン:
r)ゲルダナマイシン:
23.hsp90阻害剤がアルベスピノマイシンである、22に記載の方法。
27.チェックポイント阻害剤が、PD−1、PD−L1、CTLA4、TIM3、LAG3、VISTA、BTLA、TIGIT、LAIR1、CD160、2B4およびTGFRβのうちの1つまたは複数を標的にする阻害性化合物である、26に記載の方法。
28.チェックポイント阻害剤が、PD−1を標的にする阻害性化合物である、27に記載の方法。
29.チェックポイント阻害剤が、
a)S7911;
c)S8158:
30.チェックポイント阻害剤がS7911である、27に記載の方法。
34.CX4/CXCL12阻害剤が、
a)ブリキサホル:
d)AMD3465:
35.CX4/CXCL12阻害剤がLY2510924である、34に記載の方法。
40.化合物がイミキモドである、39に記載の方法。
42.抗がん剤がイミダゾキノロンアミンである、41に記載の方法。
43.化合物がイミキモドである、42に記載の方法。
45.リンカーが、酸開裂性リンカー、塩基開裂性リンカー、光開裂性リンカー、または酵素開裂性リンカーである、44に記載の方法。
46.リンカーが非開裂性である、1から13のいずれか一項に記載の方法。
47.リンカーがカルバメートを含む、1から16のいずれか一項に記載の方法。
48.Bが、脳由来神経栄養因子(BDNF)またはそのフラグメントである、1から47のいずれか一項に記載の方法。
49.Bが、神経増殖因子(NGF)またはそのフラグメントである、1から47のいずれか一項に記載の方法。
50.Bが、毛様体神経栄養因子(CNTF)またはそのフラグメントである、1から47のいずれか一項に記載の方法。
51.Bが、神経栄養因子3(NT−3)またはそのフラグメントである、1から47のいずれか一項に記載の方法。
52.Bが、グリア細胞由来神経栄養因子(GDNF)である、1から47のいずれか一項に記載の方法。
1.抗がん剤を二官能性リンカー前駆体と接触させて、活性化された抗がん剤を生成することと、
活性化された抗がん剤を、ニューロトロフィン受容体に選択的に結合するタンパク質、ペプチドまたはペプチド模倣体と接触させて、下記式:
B−L−X(I)
[式中、
Bは、ニューロトロフィン受容体に選択的に結合するタンパク質、ペプチドまたはペプチド模倣体であり、
Lはリンカーであり、
Xは抗がん剤である]
を有する化合物を生成することと
を含む方法。
2.二官能性リンカー前駆体がホモ二官能性リンカーである、1に記載の方法。
3.二官能性リンカー前駆体がスクシンイミドを含む、2に記載の方法。
4.二官能性リンカー前駆体がN,N’−ジスクシンイミジルカーボネートである、2に記載の方法。
5.抗がん剤がヒドロキシル基を含み、二官能性リンカー前駆体を接触させることが、二官能性リンカー前駆体を、抗がん剤のヒドロキシル基と反応させることを含む、1から4のいずれか一項に記載の方法。
6.ヒドロキシル基が第一級ヒドロキシル基である、5に記載の方法。
7.抗がん剤をヒドロキシル基で官能化することを更に含む、5または6に記載の方法。
8.活性化された抗がん剤が、タンパク質、ペプチドまたはペプチド模倣体のアミン基またはスルフヒドリル基と反応する、1から7のいずれか一項に記載の方法。
9.活性化された抗がん剤が、タンパク質、ペプチドまたはペプチド模倣体のアミン基と反応する、8に記載の方法。
10.活性化された抗がん剤が、タンパク質、ペプチドまたはペプチド模倣体のリシン側鎖と反応する、8に記載の方法。
11.活性化された抗がん剤が、タンパク質、ペプチドまたはペプチド模倣体のスルフヒドリル基と反応する、8に記載の方法。
12.抗がん剤が、タンパク質、ペプチドまたはペプチド模倣体のシステイン側鎖と反応する、11に記載の方法。
13.タンパク質、ペプチドまたはペプチド模倣体が、トロポミオシン受容体キナーゼA(trkA)またはトロポミオシン受容体キナーゼB(trkB)に結合する、1から12のいずれか一項に記載の方法。
14.抗がん剤が、神経細胞受容体へのBの結合に応答してがん細胞に内部移行する、1から13のいずれか一項に記載の方法。
15.神経細胞受容体がニューロトロフィン受容体である、14に記載の方法。
16.抗がん剤が、トロポミオシン受容体キナーゼA(trkA)またはトロポミオシン受容体キナーゼB(trkB)へのBの結合に応答してがん細胞に内部移行する、14に記載の方法。
神経栄養因子BDNFは、高親和性受容体トロポミオシンキナーゼB(trkB)への選択性がある。BDNFは、神経増殖因子(NGF)、NT−3およびNT−4を含むニューロトロフィンファミリーのメンバーである。Trk受容体は、Trk遺伝子のTrkA、TrkBおよびTrkC、ならびに低親和性p75受容体によりコードされる。外因的に投与されたBDNFはTrkBに選択的に結合し、そのことが、BDNF/TrkB複合体の、シグナル伝達エンドソームへの内部移行を誘発し、これは軸索微小管に沿ってダイニンモーターにより神経細胞体へ逆行輸送され、順行輸送も発生する。BDNFおよびTrkBは、哺乳類およびヒトにおいて相同性が高い。外因性ニューロトロフィンのラットにおける研究は、臨床吸収のパターンが再現されている。TrkB受容体は、CNSの全体にわたって分布されており、視神経の遠心端にある大槽を含む。
Dyomics Near InfraRed(NIR)色素800をrhBDNFに、上記に記載されたようにコンジュゲートした(800−rhBDNF)。色素800の分子量(MW)は1050.15g/mol、であり、800−rhBDNFを小分子コンジュゲート化合物と同等にしている。HPLCを使用して、800−rhBDNFを特徴決定し、続いてRGC培養においてバイオアッセイして、TrkB受容体結合が合成後に無傷のままであることを確認した。未処置ラットでの予備研究において、大槽内に与えられた800−rhBDNFは、800色素を注射部位から離して、視交叉を介して視神経頭へ移送する。800−rhBDNFの3回の単一用量を未処置ラットの正中線で大槽内に注射した(n=4匹、n=3匹が800−rhBDNF、n=1匹が対照、未変性色素800カルボン酸形態)。3つの試験用量の800−rhBDNFを選択した:最低(5μLをシリンジで0.20の濃度=1μgの研究物品)、中間、および最高(30μL、上限量は50μL)。両眼(左の目、左眼(oculus sinister)、OS;右の眼、右眼(oculus dexter)、OD)に2つの画像診断法を使用して、治療の直前、15分および6時間の3つの時点で画像を収集した。画像化および組織病理学の方法を使用して、視交叉または視神経頭において800−rhBDNFを検出した。
生体動物におけるNear InfraRed 800を、Spectralis(登録商標)のIRAFおよびIR設定の両方において、ベースライン、15分および6時間で検出し、網膜に局在化した炎症は観察されなかった。正中線注射は両側に分布された。NIR顕微鏡法の形態をHE染色と比較すると、対照では800−BDNFコンジュゲートより分散されており、800−BDNFコンジュゲートは、800色素を局在化しており、800色素を注射部位から離して、視交叉を介して視神経頭へ移送している。
Claims (15)
- 下記式I:
B−L−X (I)
[式中、Bは、ニューロトロフィン受容体に選択的に結合するタンパク質、ペプチドまたはペプチド模倣体であり、
Lはリンカーであり、
Xは抗がん剤である]で表される化合物。 - Xが、シロリムス、テムシロリムス、エベロリムスおよびリダフォロリムスからなる群から選択される化合物である、請求項1に記載の化合物。
- Xが、トラメチニブ、ダブラフェニブ、コビメチニブ、ベムラフェニブ、ビニメチニブ、セルメチニブからなる群から選択される化合物である、請求項1に記載の化合物。
- Xが、
a)アルベスピノマイシン:
r)ゲルダナマイシン:
- Bが、脳由来神経栄養因子(BDNF)またはそのフラグメント、神経増殖因子(NGF)またはそのフラグメント、毛様体神経栄養因子(CTNF)またはそのフラグメント、神経栄養因子3(NT−3)またはそのフラグメント、およびグリア細胞由来神経栄養因子(GDNF)またはそのフラグメントからなる群から選択される、請求項1から11のいずれか一項に記載の化合物。
- 前記抗がん剤が、神経膠腫、皮膚がん、または神経周囲浸潤の治療のための化合物である、請求項1から12のいずれか一項に記載の化合物。
- 請求項1から13のいずれか一項に記載の化合物と、
薬学的に許容される担体とを含む組成物。 - 抗がん剤を神経細胞に選択的に送達する方法であって、請求項1から13のいずれか一項に記載の化合物を対象に投与することを含む方法。
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