JP7475062B2 - MEK/PI3K及びmTOR/MEK/PI3K生物学的経路の多官能性阻害剤、並びに同多官能性阻害剤を用いた治療方法 - Google Patents
MEK/PI3K及びmTOR/MEK/PI3K生物学的経路の多官能性阻害剤、並びに同多官能性阻害剤を用いた治療方法 Download PDFInfo
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- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229960005353 testolactone Drugs 0.000 description 1
- BPEWUONYVDABNZ-DZBHQSCQSA-N testolactone Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(OC(=O)CC4)[C@@H]4[C@@H]3CCC2=C1 BPEWUONYVDABNZ-DZBHQSCQSA-N 0.000 description 1
- 229960003604 testosterone Drugs 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000005329 tetralinyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- GVIJJXMXTUZIOD-UHFFFAOYSA-N thianthrene Chemical compound C1=CC=C2SC3=CC=CC=C3SC2=C1 GVIJJXMXTUZIOD-UHFFFAOYSA-N 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 238000002877 time resolved fluorescence resonance energy transfer Methods 0.000 description 1
- QVMPZNRFXAKISM-UHFFFAOYSA-N tirapazamine Chemical compound C1=CC=C2[N+]([O-])=NC(=N)N(O)C2=C1 QVMPZNRFXAKISM-UHFFFAOYSA-N 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 229960005026 toremifene Drugs 0.000 description 1
- XFCLJVABOIYOMF-QPLCGJKRSA-N toremifene Chemical compound C1=CC(OCCN(C)C)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 XFCLJVABOIYOMF-QPLCGJKRSA-N 0.000 description 1
- MFAQYJIYDMLAIM-UHFFFAOYSA-N torkinib Chemical compound C12=C(N)N=CN=C2N(C(C)C)N=C1C1=CC2=CC(O)=CC=C2N1 MFAQYJIYDMLAIM-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- 102000027257 transmembrane receptors Human genes 0.000 description 1
- 108091008578 transmembrane receptors Proteins 0.000 description 1
- GFNANZIMVAIWHM-OBYCQNJPSA-N triamcinolone Chemical compound O=C1C=C[C@]2(C)[C@@]3(F)[C@@H](O)C[C@](C)([C@@]([C@H](O)C4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 GFNANZIMVAIWHM-OBYCQNJPSA-N 0.000 description 1
- 229960005294 triamcinolone Drugs 0.000 description 1
- 229940066528 trichloroacetate Drugs 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- 125000000165 tricyclic carbocycle group Chemical group 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 230000004565 tumor cell growth Effects 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 1
- 239000002525 vasculotropin inhibitor Substances 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- KDQAABAKXDWYSZ-JKDPCDLQSA-N vincaleukoblastine sulfate Chemical compound OS(O)(=O)=O.C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 KDQAABAKXDWYSZ-JKDPCDLQSA-N 0.000 description 1
- 229960002110 vincristine sulfate Drugs 0.000 description 1
- 229950001576 voxtalisib Drugs 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 229940033942 zoladex Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5355—Non-condensed oxazines and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicinal Preparation (AREA)
- Steroid Compounds (AREA)
Description
本発明は、米国国立衛生研究所によって授与された助成CA085878及びCA197701の下に政府援助を受けて為されたものである。本発明における一定の権利は、政府が有するものとする。
関連出願の相互参照
あるいはm及びnの任意の組み合わせを含む。
R3はH、アルキル、アリール、-(CH2)p-OH、又は-(CH2)p-NR4であり、式中、p=1~6、及びR4=H、アルキル、アリールであり、及びXは以下からなる群から選択される:
DはI、-C≡CH、又は-C≡C-Rである:Rはアルキル又はアリールであり、及びXは以下からなる群から選択される:
DはI又は-C≡-CRであり、式中、R=H、アルキル又はアリールであり、
R5、R6は独立にH、アルキル又はアリールであるか、又は一緒になって5員環又は6員環を形成し、
X、W及びZは独立にカルボニル又は(CR1R2)nであり、式中、R5、R6は独立にH、アルキル又はアリールであり、及びn=0、1、2、3,4又は5である。
xは以下の通りである:
及び
D=I、-C≡CH、-D≡C-Rであり、式中、R=アルキル又はアリールであり、式中、Xは以下からなる群から選択される:
R3はH、アルキル、アリール、-(CH2)p-OH、又は-(CH2)p-NR4であり、式中、p=1~6であり、及びR4=H、アルキル又はアリールであり、及びXは以下からなる群から選択される:
DはI、-C≡CH、又は-C≡C-Rであり、Rはアルキル又はアリールであり、及びXは以下からなる群から選択される:
DはI又は-C≡CRであり、式中、R=H、アルキル又はアリールであり、
R5、R6は独立にH、アルキル、アリールであるか、又は一緒になって5員環又は6員環を形成し、
X、W及びZは独立にカルボニル又は(CR1R2)nであり、式中、R5、R6は独立にH、アルキル又はアリールであり、及びn=0、1、2、3、4又は5である。
xは以下の通りである:
および
D=I、-C≡CH、-C≡C-Rであり、式中、R=アルキル又はアリールであり、式中、Xは以下からなる群から選択される:
m及びnは独立に1、2、3、4又は5であり、及びoは2、3、4又は5である。)
m及びnは独立に1、2、3、4又は5であり、及びoは2、3、4又は5である。)
m及びnは独立に1、2、3、4又は5であり、及びoは2、3、4又は5である。)
本化合物は、MEK阻害剤をmTOR/PI3K阻害剤又はPI3K阻害剤と共役又は連結し、本発明の多官能性阻害剤に到達した結果として得られたものである。ベンズヒドロキサメート型MEK阻害剤は、例えば、本明細書において参照により援用されている国際公開第2002/006213号パンフレットに開示されているようにして合成される。SMK-17型MEK阻害剤は、例えば、本明細書において参照により援用されている国際公開第2004/083167号パンフレットに開示されているようにして合成される。トリアジン系PI3K阻害剤は、米国特許出願公開第2011/0053907号明細書、同第2011/0009405号明細書、及び同第2010/0249099号明細書に開示されているようにして合成される。これらの各文献はその全体が本明細書において参照により援用されている。mTOR阻害剤は、AM Venketasan et al., J. Med.Chem.53:2636, 2010;N. Nishimur et al., J. Med.Chem.54:4735-51, 2011;及び国際公開第2008/032162号パンフレットに開示されているようにして合成される。これらの各文献は本明細書において参照により援用されている。
空気又は湿気に敏感な試薬と溶媒とを含む化学合成を、オーブン乾燥ガラス製品中、窒素の陽圧下で行った。他の全ての化学試薬及び無水溶媒を、ウィスコンシン州ミルウォーキーのAldrich Chemical Co.から入手し、更に精製せずに使用した。前報と同様に、重要な化合物中間体1,3,5-トリアジン類似体(2a、2b)(7)、及び3,4-ジフルオロ-2-(2-フルオロ-4-ヨードフェニルアミノ)安息香酸ペンタフルオロフェニルエステル(21)(化合物3)を合成した。16,16-ジメチル-15-オキソ-3,6,9,12,14-ペンタオキサ-13-アザヘプタデシル4-メチルベンゼンスルホネート(t-Boc-アミノオキシPEG4トシレート)、及び4-クロロブタン-1-スルホニルクロリドをそれぞれ、カリフォルニア州サンディエゴのBroadpharm、及びニュージャージー州モンマスジャクソンのEnamine Ltd.から購入した。他の全ての化学試薬及び無水溶媒を、ウィスコンシン州ミルウォーキーのAldrich Chemical Co.から入手し、更に精製せずに使用した。
使用されている略語
Akt........プロテインキナーゼB
MEK........分子変容マイトジェン活性化タンパク質キナーゼ
PI3K........ホスファチジルイノシトール3-キナーゼ
mTor........ラパマイシンの哺乳動物標的
br s........ブロードシグナル
cLogP........対数Pの計算値
CH3CN........アセトニトリル
DCM........ジクロロメタン
DMF........N,N-ジメチルホルムアミド
DIEA........N,N-ジイソプロピルエチルアミン
DMSO........ジメチルスルホキシド
Et3N........トリメチルアミン
HPBCD........(2-ヒドロキシプロピル)-β-シクロデキストリン
MEK........メチルエチルケトン
rt........室温
TFA........トリフルオロ酢酸
THF........テトラヒドロフラン
PdCl2dppf........1,1’-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリド
HAc........酢酸
EDCI........1-(3-ジメチルアミノプロピル)-3-エチルカルボジイミド
HOBT........1-ヒドロキシベンゾトリアゾール
P(Ph)3........トリフェニルホスフィン
DEAD........アゾジカルボン酸ジエチル
LHMDS........リチウムヘキサメチルジシラジド
TBAF........フッ化テトラ-n-ブチルアンモニウム
PyBOP........(ベンゾトリアゾール-1-イル-オキシトリピロリジノホスホニウムヘキサフルオロホスフェート)
(c)Cl(CH2)4SO2Cl、Et3N、CH2Cl2、0℃ないし室温、18時間、92%;CH3CN、還流、18時間、30%(d)5、Nal、K2CO3、CH3CN、還流、18時間、30%
化学式3:14(ST-162)の合成
MV4-168(ST-168)に対する計算値
注記:化合物中間体2の合成は、国際公開第2002/006213(A2)号パンフレットに報告されている。
化合物中間体1,3,5-トリアジン類似体(2a)(2)及び3,4-ジフルオロ-2-(2-フルオロ-4-ヨードフェニルアミノ)-安息香酸(2)(3)を、前報と同様にして合成した。2,2-ジメチル-4-オキソ-3,6,9,12,15-ペンタオキサ-5-アザオクタデカン-18-オイック酸(t-Boc-アミノキシ-PEG3-酸)は、カリフォルニア州サンディエゴのBroadpharmから購入したものである。逆相勾配HPLC分析で、生物学的に試験されたいずれの化合物も、化学純度が98%超であることが実証された。
3(0.184g、0.25mmol)をDCM(4mL)中に溶かした撹拌溶液を氷浴で0℃に冷却し、TFA(2mL)をDCM(2mL)中に溶かした溶液で処理した。反応物を0~5℃で更に2時間撹拌し、次いで氷冷水(25mL)で処理してから、水層のpHを飽和NaHCO3水溶液でpH8になるように調整した。混合物をEtOAc(25mL)で2回抽出し、有機抽出物をブライン及びH2Oで連続して洗浄してから、Na2SO4上で乾燥させた。減圧下で濃縮し、生成物4を淡黄色油状物(130mg;82%)として得た。この生成物は、次の工程で直接使用した。1H NMR(CDCl3):δ8.33(d,1H,J=7.8Hz),7.90(d,1H,J=8.4Hz),7.56(t,1H,J=53.6Hz),7.47-7.39(m,2H),3.52(br s,1H),3.93-3.65(m,30H),2.70(t,2H,J=6.4Hz),1.68(br s,2H)。HRMS(ESI+):m/z;C28H40N9F2O6[M+H+]に対する計算値:636.3064。実測値:636.3068(100%);[M+Na+]に対する計算値:658.2884。実測値:658.2885。HPLC(方法I):tR=7.7分。
4(127mg、0.20mmol)、3,4-ジフルオロ-2-(2-フルオロ-4-ヨードフェニルアミノ)-安息香酸2(79mg、0.20mmol)、及びDIEA(57mg、77L、0.44mmol)をTHF:DCM(1:1)の混合物4mL中に溶かした溶液を、PyBop(105mg、0.20mmol)で処理し、室温で18時間撹拌した。HPLC分析(方法1)及びTLC分析(Analtechシリカ;DCM:CH3OH:NH4OH;95:5:1;生成物ST-168のRf=0.20)は反応の完了を示した。混合物を減圧下で濃縮し、残渣をEtOAc(50mL)中に溶解させ、0.1規定のHCl水溶液、飽和NaHCO3水溶液、ブラインで洗浄してから、Na2SO4上で乾燥させた。シリカゲルフラッシュクロマトグラフィで、粗生成物を、1~6%CH3OHを1%NH4OH含有のCHに溶かした溶液の勾配を用いて精製し、表題化合物を白色無定形固体110mg(54%)として得た。1H NMR(CDCl3):δ8.90(br s,1H),8.32(d,1H,J=7.8Hz),7.88(d,1H,J=7.6Hz),7.55(t,1H,J=53.5Hz),7.44-7.28(m,5H),6.83-6.77(m,1H),6.58-6.52(m,1H),4.13(m,2H),3.88-3.50(m,28H),2.62(m,2H),1.89(br s,2H)。HRMS(ESI+):m/z;C41H45N10F5IO7[M+H+]に対する計算値:1011.2432。実測値:1011.2431;[M+Na+]に対する計算値:1033.2251。実測値:1033.2247(100%)。HPLC(方法II):tR=17.7分。
WatersXSELECTCSHC-18カラム(4.6x250mm)上で、周囲温度にて、5μ粒子、0.1%TFAのH2O(A)溶液及び0.1%TFAを、1mL/分の流速でCH3CN(B)中に溶かした溶媒混合物を用いて、HPLC分析を実施した。254nm及び280nmでUV吸光度をモニターしながら、25分の実行時間にわたって30%B(初期)から90%Bまでの溶媒勾配で、分析を実施した。
25分の運転時間にわたって50%B(初期)から90%Bへの溶媒勾配を用い、HPLC分析を上記のようにして実施した。
一連の単一実体である、二官能性MEK1/PI3K阻害剤の合成が、ATP競合PI3K阻害剤ZSTK474とATP非競合MEK阻害剤PD0325901の構造類似体の共有結合によって達成されることが、記載されている。酵素阻害アッセイにおいて、生体機能阻害剤は、MEK1の強力なインビトロ阻害(0.05<IC50(nM)<500)及びPI3K(54<IC50(nM)<341)を示した。2つの腫瘍細胞株(A549、D54)において化合物14を添加すると、MEK1及びPI3Kが同時的に阻害されることが、実証された。阻害剤は、等量のZSTK474及びPD0325901を併用投与した場合と同様に、用量依存的に細胞生存率を低下させた。D54神経膠腫及びA549肺腫瘍担持マウスにおいて、経口投与後の化合物14のインビボ効力が実証された。ウエスタンブロット分析で、化合物14を投与してから2時間後に、腫瘍ERK1/2並びにAktリン酸化のそれぞれ95%及び67%の阻害を示し、MEK1/PI3Kの併用阻害に対する生体利用能及び本二官能性阻害剤戦略の有効性が確認された。
MEK1及びPI3K結合ポケットでの化合物14の仮想ドッキング
ST-162は、MEK1アロステリック結合領域内に強力なMEK1阻害剤PD318088によって示される、多くの結合相互作用を保持すると予測され、ヒドロキサメート酸素とLys97;A環上の4-フッ素原子とVal211の主鎖NH;並びにSer212と疎水性ポケット内のヨウ素含有B環の重要な相互作用(図4A)を含む。同様に、ST-162は、モルホリン基酸素とバリン骨格アミドNH基との水素結合相互作用(Val828)、及びイミダゾール窒素とLys779側鎖アミン基との相互作用を保持することから、PI3K阻害剤としても機能するものと予測される(図4B)。
下記化学式中の化合物4及び9は、文献において公知であり、Nishimura, N. et al. J. Med Chem.54, 4735 - 4751, 2011に報告されているようにして合成される。
(d)酸塩化物、Et3N、DMF
(b)(CH3)3Sil、CH3CN、25℃;(c)3,4-ジフルオロ-2-(2-フルオロ-4-ヨードフェニルアミノ)安息香酸、DIEA、PyBop、THF:DCM;(d)4、PdCl2dppf、K2CO3、ジオキサン、H2O、90~100℃。
図1は、MEK1アロステリックポケット及びPI3Kαにおける化合物14の、ドッキング構造を示す。図1Aは、MEK1(PDBコード3WIG)アロステリック触媒部位内の化合物14の、結合様式を示す。化合物14のPI3K部分は、溶媒へ溶出している(左図)。図1Bは、化合物14からPI3K(PDBコード2WXK)触媒部位内への、結合様式を示す。MEK1結合部分は溶媒へ溶出している(左図)。π軌道スタッキング相互作用はハッシュ線として図示されており、同様に水素結合もハッシュ線として図示されている。
阻害剤類似体に対するインビトロMEK1及びPI3Kの阻害データを、表1に示す。系列中の全ての類似体のMEK1阻害率が有意に高く、低ナノモルから下位ナノモルの範囲(0.015nM<IC50<56.7nM)内にあることが、実証された。類似体9及び類似体14によって例示されるように、高度なMEK阻害が観察された。このことは、阻害剤構造のリンカー部分における強力なMEK1阻害剤PD0316684及び5の重要なヒドロキサメート側鎖構造要素が保持されていることに起因する可能性がある。これら一連の阻害剤に対応しているPI3K阻害活性は、それほど顕著ではなく(54nM<IC50<341nM)、化合物7は系列中で最も高いPI3K阻害を呈した(IC50=54nM)。7のPI3K阻害が9と比較して改善されたことは、そのリンカー鎖長の延長に起因する可能性があるが、同様に、リンカー中のアミド結合による追加的な電子的相互作用も役目を果たした可能性がある。類似体9、11及び14によって示される同様なPI3K効力(191nM<IC50<341nM)もまた、ピペラジン窒素におけるリンカー結合の性質がPI3K阻害に影響を与える上で、最小限の役目を果たすことを示唆する。二官能性阻害剤の計算された親油性(cLogP)は4.84-5.71(表1)の範囲内に含まれ、経口生体利用能の許容閾値(cLogP<5)に近接していた。
これらの一連の化合物のインビトロMEK1及びPI3Kの阻害活性もまた、培養腫瘍細胞において評価された(D54、A549)。阻害剤化合物によるMEK1及びPI3K阻害の細胞効率は、それぞれpErk1/2及びpAktのリン酸化の変化によって測定した。図2は、培養物A549肺腫瘍図2A及びD54神経膠腫細胞図2Bから得られたタンパク質溶解物のウエスタンブロット分析による、化合物7、9、11及び14のインビトロ活性、すなわち、インビトロでMAPK/ERK経路及びPI3K/AKT経路を標的化する化合物の活性を示す。指示された化合物の存在下で細胞を1時間インキュベートし、溶解物をpAKT及びpERK1/2に対する特異的抗体でプローブして、ビヒクル対照(DMSO)と比較した。A549(図2A)及びD54(図2B)細胞を指示濃度の阻害剤で1時間処理してから、ウエスタンブロット分析に供した。図2Aに示すように、培養されたA549細胞において、この系列内の全ての化合物はpERK1/2のリン酸化の低減を示し、これらの化合物がMEK1キナーゼの酵素活性を阻害する効力が強力であることが実証された。同様に、化合物7、9及び14もまた、処置された細胞試料中のpAKTレベルが低いことから解明されたように、PI3K活性を阻害する効力が高いことが明らかにされた。注目すべきことに、全ての阻害剤類似体も同様に、両方の細胞株においてMEK活性の阻害が有意であり、これはインビトロ阻害データと充分に相関することを実証している(表1)。化合物9及び14で処置された細胞株において、BMEK及びPI3Kの阻害は両方とも、化合物7及び11と比較して、最も顕著であった。
インビトロ阻害データと細胞の有効性/生存率試験との併用に基づいて、更なるインビボ評価に化合物14を使用した。無胸腺ヌードFoxn1nuマウス4匹を使用して、発癌性標的の調節活性をインビボで評価した。側腹部D54(n=2)及びA549(n=2)腫瘍を有するマウスを、屠殺2時間前に経口胃管栄養法によりビヒクル又は375mg/kgの化合物14のいずれかで処置した。図4A及び図4Bは、腫瘍担持マウスにおけるMEK1及びPI3Kのインビボ阻害活性を示す。D54及びA549皮下腫瘍を有するマウスを、屠殺2時間前に経口胃管栄養法によりビヒクル又は375mg/kgの化合物14のいずれかで処置した。図4Aにおいて、切除された腫瘍組織のウエスタンブロット分析によって明らかにされたように、化合物14は、ビヒクル対照と比較してD54腫瘍におけるMEK1及びPI3K活性の両方の調節に成功した。図4Bにおいて、切除されたA549腫瘍組織のウエスタンブロット分析によって明らかにされたように、化合物14は、ビヒクル対照と比較してA549腫瘍におけるMEK1及びPI3K活性の両方の調節に成功した。これらのデータは、固形腫瘍においてインビボMEK1/PI3Kキナーゼ活性の抑制に対する化合物14のインビボ生体利用能及び有効性を実証し、単一の化学実体二官能性阻害剤(化合物14)を使用することによってRas/MEK/ERK経路及びPI3K/Akt/mTor経路に対しインビボ同時的阻害を遂行しうることを確証するものである。切除された腫瘍組織のウエスタンブロット分析で解明されたように、両方の腫瘍型においてERK1/2及びAktのリン酸化が、化合物14によって阻害された(図4A及び図4B)。更にそのうえ、化合物9を用いた別の予備実験において、ERK1/2及びpAktレベルの調節は、マウス腫瘍におけるA549及びD54腫瘍の両方に対しても達成された(データ不図示)。総合的に要約すると、これらのデータが明らかに実証しているように、二機能性阻害剤化合物9及び14によって、インビトロ及びインビボの両方でMEK1/PI3K活性の同時抑制を達成することが可能である。
Promega(米国ウィスコンシン州)製のKinase-Glo Luminescent Kinaseアッセイキットを、メーカーの指示に従って使用して、阻害剤類似体のインビトロMEK1阻害活性を、定量化した。精製MEK1及び非活性過Erk2はそれぞれ、Sigma-Aldrich(米国ミズーリ州セントルイス)及びカルナバイオサイエンス(Carna Bioscience、日本国神戸)から購入されたものである。概略説明すると、一連の化合物希釈物を96ウェルプレートに加え、続いてMEK1、Erk2及びATP溶液を加えた。キナーゼ反応を30℃で30分間行った。次いで、等容量のKinase-Glo溶液を加え、反応物を室温で更に30分間インキュベートした。PerkinElmer製のEnvisionマルチラベルリーダーを使用して、生物発光シグナルを取得した。各阻害剤濃度で2回ずつのアッセイを、3連で実行した。IC50データを、グラフパッド社(GraphPad)のプリズム(Prism)ソフトウェア(バージョン5.0、カリフォルニア州La Jolla)を使用して計算した。
Life Technologies(ウィスコンシン州マディソン)で、蛍光ベースのAdapta TR-FRETアッセイプロトコルを使用し、精製酵素を用いて、PI3K脂質キナーゼ活性の定量を行った。各阻害剤濃度(0.1nM~10μM)で2回ずつのアッセイを、3連で実行した。
二官能性阻害剤類似体のドッキングモデルを、Schrodinger製のソフトウェアを使用して得た。MEK1のX線結晶構造(PDBコード3WIG)及びPI3K(PDBコード2WXK)のX線結晶構造は、MaestroのProtein Preparationウィザード(Protein Preparation Wizard, Schrodinger, LLC、ニューヨーク州ニューヨーク)を使用して調製した。次いで、タンパク質構造を使用して、結合部位が天然リガンドによって画定されているOPLS2005を使用して、ドッキング用の受容体グリッドを生成した。LigPrep 3.4(LigPrep、Schrodinger, LLC、ニューヨーク州ニューヨーク)を使用して、二官能性阻害剤リガンドをMaestroでドッキング用に構築して調製した。標準の精度モードでGlide 6.7を使用して、デフォルトのパラメータを用い、制約なしでドッキング手順を実行した(23)。
ヒト肺腺癌上皮細胞株A549及び神経膠腫細胞株D54を、10%熱不活性化ウシ胎児血清(FBS)及び1%ペニシリン/ストレプトマイシン/グルタミンを添加したRPMI中で生育した(Gibco、カリフォルニア州カールスバッド)。細胞を、5%CO2を供給しながら、37℃の加湿インキュベーター中で成長させた。細胞生存率アッセイを用いて、阻害剤化合物の治療効果の初期試験を達成した。阻害剤化合物(10mM)、ZSTK474(代表的なPI3K阻害剤)、PD0325901(代表的なMEK阻害剤)のストック溶液をDMSO中で調製し、このストック溶液を使用して、RPMI培地中で連続希釈して最終的な溶液を調製した。対照ウェルに、1%DMSO担体溶媒を含有する培地を投薬した。48時間後に、AlamarBlueアッセイ(Life Technologies、カリフォルニア州カールスバッド)を製造元の指示に従って用いて細胞生存率を決定した。PerkinElmer EnVision Xciteマルチラベルリーダー(PerkinElmer、マサチューセッツ州ウォルサム)を使用して、蛍光シグナルを定量化した。
細胞を処置の24時間前に6ウェルディッシュ内に播種し、それぞれの阻害剤化合物溶液と共に1時間インキュベートした。細胞をリン酸緩衝生理食塩水(PBS)で洗浄し、プロテアーゼ阻害剤(完全プロテアーゼ阻害剤カクテル(Complete protease inhibitor cocktail)、Roche、スイス国バーゼル)、及びホスファターゼ阻害剤(PhosSTOP、Roche、スイス国バーゼル)を補充したNP-40溶解緩衝液(1%NP40、150mMのNaCl、並びに25mMのTris、pH8.0)で溶解した。Lowryアッセイ(Bio-Rad、カリフォルニア州ハーキュリーズ)を使用してタンパク質の濃度を算定し、等量の全細胞タンパク質溶解物を各レーンに充填して、4~12%勾配Bis-Trisゲル(Invitrogen、カリフォルニア州)を用いて分離した。タンパク質を0.2μmのニトロセルロース膜(Invitrogen、カリフォルニア州)に移送した。ブロッキング後、膜を一次抗体と共に4℃で一晩インキュベートし、続いて適切な西洋ワサビペルオキシダーゼ(HRP)共役二次抗体と共に室温で1時間インキュベートした。製造元のプロトコル(Amersham Pharmacia、スウェーデン国ウプサラ)に従って、ECL-Plusを使用してペルオキシダーゼの活性を検出した。phospho-p44/42 MAPK(Erk1/2)(Thr202/Tyr204)、pAKT(S473)及びphospho-p70 S6K*に対する抗体、並びにTotal ERK及びAKT抗体を、Cell Signaling Technology(米国マサチューセッツ州ビバリー)から購入し、西洋ワサビペルオキシダーゼ(HRP)に共役された抗βアクチンをAbcam(米国マサチューセッツ州ケンブリッジ)から購入した。二次HRP抗体は、Jackson ImmunoResearch(米国ミズーリ州セントルイス)から購入したものであった。
阻害剤効力のインビボ評価
全ての動物実験は、ミシガン大学における、動物の使用と管理に関する大学委員会(UCUCA)によって承認された。5週齢の無胸腺ヌードFoxn1nuマウス2匹の脇腹に対し完全に懸濁されたD54細胞1×106個を皮下接種してから、同様に、更にマウス2匹の脇腹に対しA549細胞を接種した。各注射液は、50%BDマトリゲル(BD Matrigel)基底膜マトリックスと50%RPMI培地(ベクトン・ディッキンソン・アンド・カンパニー(Becton, Dickinson and Company)ニュージャージー州イースト・ラザフォード)との混合物中に溶かされた、総容量200μLの細胞懸濁液を含有していた。キャリパー測定による腫瘍体積が約150mm3に達した後、マウスに給餌しない状態で2~4時間置き、続いて、屠殺2時間前にビヒクル(DMSO:HPBCD(3:2)200μL)、又は阻害剤類似体ST-162(14)(375mg/kgのDMSO/HPBCD(3:2)溶液200μL)のいずれかを経口投与した。ビヒクル処置群及び薬物処置群の両方から腫瘍組織を収集して、上述のようにウエスタンブロット分析に供した。
5週齢の無胸腺ヌードFoxn1nuマウス2匹の脇腹に対し完全に懸濁されたD54細胞1×106個を皮下接種してから、同様に、更にマウス2匹の脇腹に対しA549細胞を接種した。各注射液は、50%BDマトリゲル(BD Matrigel)基底膜マトリックスと50%RPMI培地(ベクトン・ディッキンソン・アンド・カンパニー(Becton, Dickinson and Company)、ニュージャージー州イースト・ラザフォード)との混合物中に溶かされた、総容量200μLの細胞懸濁液を含有していた。キャリパー測定による腫瘍体積が約150mm3に達した後、マウスに給餌しない状態で2~4時間置き、続いて、屠殺2時間前にビヒクル(DMSO:HPBCD(3:2)200μL)、又は阻害剤類似体(14)(375mg/kgのDMSO/HPBCD(3:2)溶液200μL)のいずれかを経口投与した。ビヒクル処置群及び薬物処置群の両方から腫瘍組織を収集して、上述のようにウエスタンブロット分析に供した。
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Claims (9)
- 下記構造
DはI、-C≡CH、又はC≡C-R(式中、R=アルキル又はアリールである)であり、かつ、
Xは以下からなる群から選択される:
あるいは、
Wは
DはI、-C≡CH、又は-C≡C-R(式中、Rはアルキル又はアリールである)であり、かつ、
Xは以下からなる群から選択される:
を有する化合物。 - 請求項1又は2に記載の化合物と、医薬的に許容される担体又はビヒクルとを含む医薬組成物。
- mTOR、MEK及びPI3Kのうちの少なくとも1つを阻害することによって奏効が得られる、疾患又は病態を治療するための、請求項3に記載の医薬組成物。
- 前記疾患又は病態が、癌、炎症性疾患、アレルギー性疾患、炎症性腸疾患、血管炎、ベーチェット症候群、乾癬、炎症性皮膚病、喘息、呼吸器アレルギー疾患、自己免疫疾患、移植片拒絶、発熱、心血管障害、脳血管障害、線維症、結合組織病、サルコイドーシス、性器障害、生殖障害、胃腸障害、神経障害、睡眠障害、疼痛、腎障害、HIVを包含する感染症、神経因性疼痛(神経自体への損傷又は神経機能不全に起因する疼痛)及び侵害受容性(nociceptive)の疼痛(侵害受容体(nociceptor)は損傷中に活性化される神経系内の受容体である)を包含する慢性疼痛、並びに臨床診断に関連する慢性疼痛から選択される疾患及び病態である、請求項4に記載の医薬組成物。
- 前記疾患又は病態が癌である、請求項5に記載の医薬組成物。
- 前記癌が、膀胱(加速性及び転移性膀胱癌を包含)、乳房、大腸(結腸直腸癌を包含)、腎臓、肝臓、肺(小細胞肺癌、非小細胞肺癌及び肺腺癌を包含)、卵巣、前立腺、精巣、尿生殖路、リンパ系、直腸、喉頭、膵臓(外分泌膵臓癌を包含)、食道、胃、胆嚢、子宮頸部、甲状腺、腎臓及び皮膚(扁平上皮癌を包含)を包含する癌腫;白血病、急性リンパ性白血病、急性リンパ芽球性白血病、B細胞リンパ腫、T細胞リンパ腫、ホジキンリンパ腫、非ホジキンリンパ腫、有毛細胞リンパ腫、組織球性リンパ腫及びバーキットリンパ腫を包含するリンパ系統の造血器腫瘍;急性及び慢性骨髄性白血病、骨髄異形成症候群、骨髄性白血病、及び前骨髄球性白血病を包含する骨髄系統の造血器腫瘍;星状細胞腫、神経芽細胞腫、神経膠腫及びシュワン細胞腫を包含する中枢及び末梢神経系の腫瘍;線維肉腫、横紋筋肉腫及び骨肉腫を包含する間葉起源の腫瘍;並びに他の腫瘍類、メラノーマ、色素性乾皮症、角化腺腫、セミノーマ、甲状腺濾胞癌、奇形癌、腎細胞癌(RCC)、膵臓癌、骨髄腫、骨髄腫及びリンパ芽球性白血病、神経芽細胞腫、並びに神経膠芽腫、成人及び小児腫瘍、固形腫瘍/悪性腫瘍の成長、粘液様及び円形細胞癌、局所進行腫瘍、転移性癌、ユーイング肉腫を包含するヒト軟部肉腫、リンパ節転移、特に頭頸部の扁平上皮癌、食道扁平上皮癌、口腔癌を包含する癌の転移、多発性骨髄腫を包含する血球悪性腫瘍、急性リンパ性白血病、急性非リンパ性白血病、慢性リンパ性白血病、慢性骨髄性白血病及び有毛細胞白血病を包含する白血病;滲出性リンパ腫(体腔リンパ腫)、胸腺リンパ腫肺癌(小細胞癌、皮膚T細胞リンパ腫、ホジキンリンパ腫、非ホジキンリンパ腫、副腎皮質癌、ACTH産生腫瘍、非小細胞癌を包含、小細胞癌及び乳管癌を包含する乳癌)、消化器癌(結腸直腸腫瘍に付随する胃癌、結腸癌、結腸直腸癌及びポリープを包含);膵臓癌、肝臓癌、泌尿器科癌(原発性表在性膀胱腫瘍などの膀胱癌、膀胱の浸潤性移行上皮癌及び筋肉浸潤性膀胱癌を包含)、前立腺癌、女性器の悪性腫瘍(卵巣癌、原発性腹膜上皮腫瘍、子宮頸癌、子宮内膜癌、膣癌、外陰癌、子宮癌及び卵巣濾胞中の固形腫瘍を包含)、男性生殖管の悪性腫瘍(精巣癌及び陰茎癌を包含)、腎臓癌(腎細胞癌を包含、脳腫瘍(内因性脳腫瘍、神経芽細胞腫、星状細胞脳腫瘍、神経膠腫、及び中枢神経系への転移性腫瘍細胞の浸潤を包含)、骨癌(骨腫及び骨肉腫を包含)、皮膚癌(悪性メラノーマ、ヒト皮膚ケラチノサイトの腫瘍進行及び扁平上皮癌を包含)、甲状腺癌、網膜芽細胞腫、神経芽細胞腫、腹水、悪性胸水、中皮腫、ウィルムス腫瘍、胆嚢癌、栄養膜性腫瘍、血管周皮腫、骨髄線維症、急性骨髄性白血病(AML)、骨髄異形成症候群(MDS)及び慢性骨髄性白血病(CML)を包含する骨髄性悪性腫瘍、カポジ肉腫、膵臓癌及び結腸直腸癌、並びに腫瘍転移性疾患から選択される、請求項6に記載の医薬組成物。
- 前記疾患又は病態が、臨床診断に関連する慢性疼痛から選択される疾患及び病態である、請求項4に記載の医薬組成物。
- 前記臨床診断に関連する慢性疼痛から選択される疾患及び病態が、線維筋痛症、炎症、又は筋骨格系機能不全である、請求項8に記載の医薬組成物。
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J. Med. Chem.,2011年,54,4735-4751 |
MARCIAN E VAN DORT,DISCOVERY OF BIFUNCTIONAL ONCOGENIC TARGET INHIBITORS AGAINST ALLOSTERIC MITOGEN-以下備考,JOURNAL OF MEDICINAL CHEMISTRY,2016年03月24日,VOL:59, NR:6,PAGE(S):2512 - 2522,http://dx.doi.org/10.1021/acs.jmedchem.5b01655,ACTIVATED PROTEIN KINASE (MEK1) AND PHOSPHATIDYLINOSITOL 3-KINASE (PI3K) |
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US20190224207A1 (en) | 2019-07-25 |
AU2017291838A1 (en) | 2019-01-17 |
EP3481822A1 (en) | 2019-05-15 |
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CA3029875A1 (en) | 2018-01-11 |
AU2017291838B2 (en) | 2021-01-28 |
JP2022019812A (ja) | 2022-01-27 |
ES2922898T3 (es) | 2022-09-21 |
WO2018009638A1 (en) | 2018-01-11 |
EP4086250A2 (en) | 2022-11-09 |
CN109563088B (zh) | 2022-10-11 |
EP3481822B1 (en) | 2022-06-22 |
AU2021202619A1 (en) | 2021-05-27 |
EP4086250A3 (en) | 2023-03-22 |
US10919877B2 (en) | 2021-02-16 |
CN109563088A (zh) | 2019-04-02 |
CA3029875C (en) | 2023-12-19 |
AU2021202619B2 (en) | 2022-03-10 |
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