CN108314703B - 分子定点靶向和激活的激酶抑制剂的制备和用途 - Google Patents
分子定点靶向和激活的激酶抑制剂的制备和用途 Download PDFInfo
- Publication number
- CN108314703B CN108314703B CN201710037230.9A CN201710037230A CN108314703B CN 108314703 B CN108314703 B CN 108314703B CN 201710037230 A CN201710037230 A CN 201710037230A CN 108314703 B CN108314703 B CN 108314703B
- Authority
- CN
- China
- Prior art keywords
- compound
- cancer
- formula
- pabc
- tumor
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 230000008685 targeting Effects 0.000 title abstract description 20
- 238000002360 preparation method Methods 0.000 title abstract description 8
- 230000003213 activating effect Effects 0.000 title abstract description 7
- 229940043355 kinase inhibitor Drugs 0.000 title abstract description 4
- 239000003757 phosphotransferase inhibitor Substances 0.000 title abstract description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 155
- 239000003814 drug Substances 0.000 claims abstract description 69
- 229940079593 drug Drugs 0.000 claims abstract description 59
- UOQHWNPVNXSDDO-UHFFFAOYSA-N 3-bromoimidazo[1,2-a]pyridine-6-carbonitrile Chemical group C1=CC(C#N)=CN2C(Br)=CN=C21 UOQHWNPVNXSDDO-UHFFFAOYSA-N 0.000 claims abstract description 25
- 229940099563 lactobionic acid Drugs 0.000 claims abstract description 19
- 235000004279 alanine Nutrition 0.000 claims abstract description 18
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 claims abstract description 11
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000004473 Threonine Substances 0.000 claims abstract description 11
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000004474 valine Substances 0.000 claims abstract description 10
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 claims abstract description 9
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 claims abstract description 8
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 claims abstract description 7
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 claims abstract description 7
- 229960001230 asparagine Drugs 0.000 claims abstract description 7
- 235000009582 asparagine Nutrition 0.000 claims abstract description 7
- 125000004185 ester group Chemical group 0.000 claims abstract description 5
- 206010028980 Neoplasm Diseases 0.000 claims description 76
- 150000003839 salts Chemical class 0.000 claims description 29
- 201000011510 cancer Diseases 0.000 claims description 26
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 claims description 25
- 238000011282 treatment Methods 0.000 claims description 23
- 210000004881 tumor cell Anatomy 0.000 claims description 22
- 239000008194 pharmaceutical composition Substances 0.000 claims description 18
- 229960002465 dabrafenib Drugs 0.000 claims description 9
- 229960004679 doxorubicin Drugs 0.000 claims description 9
- 208000014018 liver neoplasm Diseases 0.000 claims description 9
- 208000024770 Thyroid neoplasm Diseases 0.000 claims description 7
- 125000003295 alanine group Chemical group N[C@@H](C)C(=O)* 0.000 claims description 7
- 201000002510 thyroid cancer Diseases 0.000 claims description 7
- 206010006187 Breast cancer Diseases 0.000 claims description 6
- 208000026310 Breast neoplasm Diseases 0.000 claims description 6
- BFSMGDJOXZAERB-UHFFFAOYSA-N dabrafenib Chemical compound S1C(C(C)(C)C)=NC(C=2C(=C(NS(=O)(=O)C=3C(=CC=CC=3F)F)C=CC=2)F)=C1C1=CC=NC(N)=N1 BFSMGDJOXZAERB-UHFFFAOYSA-N 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 6
- 201000007270 liver cancer Diseases 0.000 claims description 6
- 206010060862 Prostate cancer Diseases 0.000 claims description 5
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 5
- 150000004936 Sorafenib derivatives Chemical class 0.000 claims description 5
- 206010000830 Acute leukaemia Diseases 0.000 claims description 4
- 206010005003 Bladder cancer Diseases 0.000 claims description 4
- 208000006168 Ewing Sarcoma Diseases 0.000 claims description 4
- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 4
- 206010025323 Lymphomas Diseases 0.000 claims description 4
- 206010029260 Neuroblastoma Diseases 0.000 claims description 4
- 206010033128 Ovarian cancer Diseases 0.000 claims description 4
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 4
- 206010039491 Sarcoma Diseases 0.000 claims description 4
- 208000021712 Soft tissue sarcoma Diseases 0.000 claims description 4
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 4
- 208000024313 Testicular Neoplasms Diseases 0.000 claims description 4
- 206010057644 Testis cancer Diseases 0.000 claims description 4
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 4
- 208000008383 Wilms tumor Diseases 0.000 claims description 4
- 206010017758 gastric cancer Diseases 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 230000001394 metastastic effect Effects 0.000 claims description 4
- 206010061289 metastatic neoplasm Diseases 0.000 claims description 4
- 201000008968 osteosarcoma Diseases 0.000 claims description 4
- 230000000306 recurrent effect Effects 0.000 claims description 4
- 201000009410 rhabdomyosarcoma Diseases 0.000 claims description 4
- 206010041823 squamous cell carcinoma Diseases 0.000 claims description 4
- 201000011549 stomach cancer Diseases 0.000 claims description 4
- 201000003120 testicular cancer Diseases 0.000 claims description 4
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 4
- 206010019695 Hepatic neoplasm Diseases 0.000 claims description 3
- 208000003362 bronchogenic carcinoma Diseases 0.000 claims description 3
- XMBWDFGMSWQBCA-RNFDNDRNSA-M iodine-131(1-) Chemical compound [131I-] XMBWDFGMSWQBCA-RNFDNDRNSA-M 0.000 claims description 3
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 3
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 3
- 208000015799 differentiated thyroid carcinoma Diseases 0.000 claims 1
- 235000001014 amino acid Nutrition 0.000 abstract description 12
- 150000001413 amino acids Chemical class 0.000 abstract description 12
- 229940024606 amino acid Drugs 0.000 abstract description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 75
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 73
- 210000004027 cell Anatomy 0.000 description 40
- 230000015572 biosynthetic process Effects 0.000 description 31
- 238000003786 synthesis reaction Methods 0.000 description 30
- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 description 27
- 239000005511 L01XE05 - Sorafenib Substances 0.000 description 27
- 229960003787 sorafenib Drugs 0.000 description 27
- 239000007787 solid Substances 0.000 description 26
- 230000004913 activation Effects 0.000 description 25
- 238000006243 chemical reaction Methods 0.000 description 19
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 18
- 238000009826 distribution Methods 0.000 description 18
- 230000000694 effects Effects 0.000 description 17
- 238000010898 silica gel chromatography Methods 0.000 description 17
- 230000002829 reductive effect Effects 0.000 description 16
- 238000003756 stirring Methods 0.000 description 16
- 241000699670 Mus sp. Species 0.000 description 15
- 239000012043 crude product Substances 0.000 description 14
- 125000005647 linker group Chemical group 0.000 description 14
- 102000005962 receptors Human genes 0.000 description 14
- 108020003175 receptors Proteins 0.000 description 14
- 210000004981 tumor-associated macrophage Anatomy 0.000 description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 12
- 230000002401 inhibitory effect Effects 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 229940009456 adriamycin Drugs 0.000 description 10
- 238000000034 method Methods 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- 206010027476 Metastases Diseases 0.000 description 9
- 238000002347 injection Methods 0.000 description 9
- 239000007924 injection Substances 0.000 description 9
- 210000001519 tissue Anatomy 0.000 description 9
- 102000030431 Asparaginyl endopeptidase Human genes 0.000 description 8
- 108010055066 asparaginylendopeptidase Proteins 0.000 description 8
- 230000006641 stabilisation Effects 0.000 description 8
- 238000011105 stabilization Methods 0.000 description 8
- 102000009422 Aspartic endopeptidases Human genes 0.000 description 7
- 108030004804 Aspartic endopeptidases Proteins 0.000 description 7
- 102000007365 Sialoglycoproteins Human genes 0.000 description 7
- 108010032838 Sialoglycoproteins Proteins 0.000 description 7
- 230000036039 immunity Effects 0.000 description 7
- 238000009169 immunotherapy Methods 0.000 description 7
- 230000009401 metastasis Effects 0.000 description 7
- 108090000765 processed proteins & peptides Proteins 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- 238000002560 therapeutic procedure Methods 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 6
- 229910002092 carbon dioxide Inorganic materials 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 239000013641 positive control Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 5
- 102000004190 Enzymes Human genes 0.000 description 5
- 108090000790 Enzymes Proteins 0.000 description 5
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 5
- 230000006052 T cell proliferation Effects 0.000 description 5
- 230000004709 cell invasion Effects 0.000 description 5
- 239000006285 cell suspension Substances 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 230000028993 immune response Effects 0.000 description 5
- 230000001965 increasing effect Effects 0.000 description 5
- 230000003902 lesion Effects 0.000 description 5
- 201000005202 lung cancer Diseases 0.000 description 5
- 208000020816 lung neoplasm Diseases 0.000 description 5
- 210000002540 macrophage Anatomy 0.000 description 5
- -1 organic acid salts Chemical class 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- 230000003389 potentiating effect Effects 0.000 description 5
- 230000001737 promoting effect Effects 0.000 description 5
- 230000000638 stimulation Effects 0.000 description 5
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- 241000699666 Mus <mouse, genus> Species 0.000 description 4
- 102100037422 Receptor-type tyrosine-protein phosphatase C Human genes 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 210000001744 T-lymphocyte Anatomy 0.000 description 4
- 238000010171 animal model Methods 0.000 description 4
- 230000000259 anti-tumor effect Effects 0.000 description 4
- 150000001720 carbohydrates Chemical class 0.000 description 4
- 238000003776 cleavage reaction Methods 0.000 description 4
- 239000001963 growth medium Substances 0.000 description 4
- 230000003053 immunization Effects 0.000 description 4
- 230000001976 improved effect Effects 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 231100000682 maximum tolerated dose Toxicity 0.000 description 4
- 230000002441 reversible effect Effects 0.000 description 4
- 230000007017 scission Effects 0.000 description 4
- 238000012216 screening Methods 0.000 description 4
- 230000004936 stimulating effect Effects 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- 231100000419 toxicity Toxicity 0.000 description 4
- 230000001988 toxicity Effects 0.000 description 4
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 4
- FWBHETKCLVMNFS-UHFFFAOYSA-N 4',6-Diamino-2-phenylindol Chemical compound C1=CC(C(=N)N)=CC=C1C1=CC2=CC=C(C(N)=N)C=C2N1 FWBHETKCLVMNFS-UHFFFAOYSA-N 0.000 description 3
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- 125000000539 amino acid group Chemical group 0.000 description 3
- 230000000857 drug effect Effects 0.000 description 3
- 238000000684 flow cytometry Methods 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- 238000002649 immunization Methods 0.000 description 3
- 238000011081 inoculation Methods 0.000 description 3
- 238000010253 intravenous injection Methods 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 230000000527 lymphocytic effect Effects 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 230000010534 mechanism of action Effects 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 229960001592 paclitaxel Drugs 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 238000005556 structure-activity relationship Methods 0.000 description 3
- 239000003981 vehicle Substances 0.000 description 3
- NBJZEUQTGLSUOB-UHFFFAOYSA-N 1-chloro-4-isocyanato-2-(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC(N=C=O)=CC=C1Cl NBJZEUQTGLSUOB-UHFFFAOYSA-N 0.000 description 2
- NHBKXEKEPDILRR-UHFFFAOYSA-N 2,3-bis(butanoylsulfanyl)propyl butanoate Chemical compound CCCC(=O)OCC(SC(=O)CCC)CSC(=O)CCC NHBKXEKEPDILRR-UHFFFAOYSA-N 0.000 description 2
- PLIKAWJENQZMHA-UHFFFAOYSA-N 4-aminophenol Chemical compound NC1=CC=C(O)C=C1 PLIKAWJENQZMHA-UHFFFAOYSA-N 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- 208000003174 Brain Neoplasms Diseases 0.000 description 2
- 210000001266 CD8-positive T-lymphocyte Anatomy 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 206010008342 Cervix carcinoma Diseases 0.000 description 2
- 206010009944 Colon cancer Diseases 0.000 description 2
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 2
- 238000002965 ELISA Methods 0.000 description 2
- 102000005593 Endopeptidases Human genes 0.000 description 2
- 108010059378 Endopeptidases Proteins 0.000 description 2
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 2
- 201000008808 Fibrosarcoma Diseases 0.000 description 2
- 239000007821 HATU Substances 0.000 description 2
- 101000738771 Homo sapiens Receptor-type tyrosine-protein phosphatase C Proteins 0.000 description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 2
- 108010013709 Leukocyte Common Antigens Proteins 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 208000001894 Nasopharyngeal Neoplasms Diseases 0.000 description 2
- 206010061306 Nasopharyngeal cancer Diseases 0.000 description 2
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 2
- 102100026547 Platelet-derived growth factor receptor beta Human genes 0.000 description 2
- 101710164680 Platelet-derived growth factor receptor beta Proteins 0.000 description 2
- 208000015634 Rectal Neoplasms Diseases 0.000 description 2
- 206010038389 Renal cancer Diseases 0.000 description 2
- 208000006265 Renal cell carcinoma Diseases 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 208000000453 Skin Neoplasms Diseases 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 2
- 208000002495 Uterine Neoplasms Diseases 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 210000002798 bone marrow cell Anatomy 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- 239000013553 cell monolayer Substances 0.000 description 2
- 201000010881 cervical cancer Diseases 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 208000024207 chronic leukemia Diseases 0.000 description 2
- ONCCWDRMOZMNSM-FBCQKBJTSA-N compound Z Chemical compound N1=C2C(=O)NC(N)=NC2=NC=C1C(=O)[C@H]1OP(O)(=O)OC[C@H]1O ONCCWDRMOZMNSM-FBCQKBJTSA-N 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- 238000005520 cutting process Methods 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 230000029087 digestion Effects 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 201000004101 esophageal cancer Diseases 0.000 description 2
- 230000003203 everyday effect Effects 0.000 description 2
- 239000012091 fetal bovine serum Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 230000014509 gene expression Effects 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 201000005787 hematologic cancer Diseases 0.000 description 2
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000002955 immunomodulating agent Substances 0.000 description 2
- 230000001506 immunosuppresive effect Effects 0.000 description 2
- 230000001024 immunotherapeutic effect Effects 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 201000010982 kidney cancer Diseases 0.000 description 2
- 208000003747 lymphoid leukemia Diseases 0.000 description 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 229950003968 motesanib Drugs 0.000 description 2
- 208000025113 myeloid leukemia Diseases 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 238000012758 nuclear staining Methods 0.000 description 2
- UQPUONNXJVWHRM-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 UQPUONNXJVWHRM-UHFFFAOYSA-N 0.000 description 2
- 201000002528 pancreatic cancer Diseases 0.000 description 2
- 208000008443 pancreatic carcinoma Diseases 0.000 description 2
- 230000035515 penetration Effects 0.000 description 2
- 230000003285 pharmacodynamic effect Effects 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 229920001184 polypeptide Polymers 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 206010038038 rectal cancer Diseases 0.000 description 2
- 201000001275 rectum cancer Diseases 0.000 description 2
- 201000000849 skin cancer Diseases 0.000 description 2
- 238000010186 staining Methods 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- BSCMJQUASNXFIA-UHFFFAOYSA-N tert-butyl 4-chloropyridine-2-carboxylate Chemical compound CC(C)(C)OC(=O)C1=CC(Cl)=CC=N1 BSCMJQUASNXFIA-UHFFFAOYSA-N 0.000 description 2
- QYJVBVKFXDHFPQ-UHFFFAOYSA-N tert-butyl n-(2-aminoethyl)-n-methylcarbamate Chemical compound NCCN(C)C(=O)OC(C)(C)C QYJVBVKFXDHFPQ-UHFFFAOYSA-N 0.000 description 2
- 125000000341 threoninyl group Chemical group [H]OC([H])(C([H])([H])[H])C([H])(N([H])[H])C(*)=O 0.000 description 2
- 210000001685 thyroid gland Anatomy 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- DBGVGMSCBYYSLD-UHFFFAOYSA-N tributylstannane Chemical compound CCCC[SnH](CCCC)CCCC DBGVGMSCBYYSLD-UHFFFAOYSA-N 0.000 description 2
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical class [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 2
- 230000004614 tumor growth Effects 0.000 description 2
- 206010046766 uterine cancer Diseases 0.000 description 2
- 125000002987 valine group Chemical group [H]N([H])C([H])(C(*)=O)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- BJHCYTJNPVGSBZ-YXSASFKJSA-N 1-[4-[6-amino-5-[(Z)-methoxyiminomethyl]pyrimidin-4-yl]oxy-2-chlorophenyl]-3-ethylurea Chemical compound CCNC(=O)Nc1ccc(Oc2ncnc(N)c2\C=N/OC)cc1Cl BJHCYTJNPVGSBZ-YXSASFKJSA-N 0.000 description 1
- 102100027324 2-hydroxyacyl-CoA lyase 1 Human genes 0.000 description 1
- MNPLTKHJEAFOCA-UHFFFAOYSA-N 4-amino-3-fluorophenol Chemical compound NC1=CC=C(O)C=C1F MNPLTKHJEAFOCA-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 229920001824 Barex® Polymers 0.000 description 1
- 241001456553 Chanodichthys dabryi Species 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- MWWSFMDVAYGXBV-RUELKSSGSA-N Doxorubicin hydrochloride Chemical compound Cl.O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 MWWSFMDVAYGXBV-RUELKSSGSA-N 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 208000010201 Exanthema Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 102100031547 HLA class II histocompatibility antigen, DO alpha chain Human genes 0.000 description 1
- 101001009252 Homo sapiens 2-hydroxyacyl-CoA lyase 1 Proteins 0.000 description 1
- 101000866278 Homo sapiens HLA class II histocompatibility antigen, DO alpha chain Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-L L-tartrate(2-) Chemical compound [O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O FEWJPZIEWOKRBE-JCYAYHJZSA-L 0.000 description 1
- 239000002138 L01XE21 - Regorafenib Substances 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 206010024264 Lethargy Diseases 0.000 description 1
- 210000004322 M2 macrophage Anatomy 0.000 description 1
- 102000007651 Macrophage Colony-Stimulating Factor Human genes 0.000 description 1
- 108010046938 Macrophage Colony-Stimulating Factor Proteins 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- HSHXDCVZWHOWCS-UHFFFAOYSA-N N'-hexadecylthiophene-2-carbohydrazide Chemical compound CCCCCCCCCCCCCCCCNNC(=O)c1cccs1 HSHXDCVZWHOWCS-UHFFFAOYSA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 239000004677 Nylon Substances 0.000 description 1
- HHAIXNHKPAADOF-UHFFFAOYSA-N ONC(CO)(CO)CO.[Na] Chemical compound ONC(CO)(CO)CO.[Na] HHAIXNHKPAADOF-UHFFFAOYSA-N 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 206010057249 Phagocytosis Diseases 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 102000001253 Protein Kinase Human genes 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- 101150040459 RAS gene Proteins 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 108091008605 VEGF receptors Proteins 0.000 description 1
- 108010053096 Vascular Endothelial Growth Factor Receptor-1 Proteins 0.000 description 1
- 108010053099 Vascular Endothelial Growth Factor Receptor-2 Proteins 0.000 description 1
- 108010053100 Vascular Endothelial Growth Factor Receptor-3 Proteins 0.000 description 1
- 102000009484 Vascular Endothelial Growth Factor Receptors Human genes 0.000 description 1
- 102100033178 Vascular endothelial growth factor receptor 1 Human genes 0.000 description 1
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 description 1
- 102100033179 Vascular endothelial growth factor receptor 3 Human genes 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 230000003281 allosteric effect Effects 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000005809 anti-tumor immunity Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 125000000613 asparagine group Chemical group N[C@@H](CC(N)=O)C(=O)* 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000007640 basal medium Substances 0.000 description 1
- SQVRNKJHWKZAKO-UHFFFAOYSA-N beta-N-Acetyl-D-neuraminic acid Natural products CC(=O)NC1C(O)CC(O)(C(O)=O)OC1C(O)C(O)CO SQVRNKJHWKZAKO-UHFFFAOYSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000000601 blood cell Anatomy 0.000 description 1
- 238000004820 blood count Methods 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 230000023402 cell communication Effects 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 239000013592 cell lysate Substances 0.000 description 1
- 210000003855 cell nucleus Anatomy 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000701 coagulant Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000011284 combination treatment Methods 0.000 description 1
- 238000001218 confocal laser scanning microscopy Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 229940099112 cornstarch Drugs 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 235000019700 dicalcium phosphate Nutrition 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229960002918 doxorubicin hydrochloride Drugs 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 238000009513 drug distribution Methods 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 230000000235 effect on cancer Effects 0.000 description 1
- 230000012202 endocytosis Effects 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 201000005884 exanthem Diseases 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000000799 fluorescence microscopy Methods 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical compound [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 229940014259 gelatin Drugs 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 230000003760 hair shine Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 210000002216 heart Anatomy 0.000 description 1
- 238000007490 hematoxylin and eosin (H&E) staining Methods 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- 231100000171 higher toxicity Toxicity 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 238000003125 immunofluorescent labeling Methods 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical class CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 210000005229 liver cell Anatomy 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 239000002932 luster Substances 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 230000002934 lysing effect Effects 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Substances [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 229960002900 methylcellulose Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 201000008026 nephroblastoma Diseases 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 238000007344 nucleophilic reaction Methods 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- 229920001778 nylon Polymers 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000008782 phagocytosis Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 229940116317 potato starch Drugs 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- CAEWJEXPFKNBQL-UHFFFAOYSA-N prop-2-enyl carbonochloridate Chemical compound ClC(=O)OCC=C CAEWJEXPFKNBQL-UHFFFAOYSA-N 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108700042226 ras Genes Proteins 0.000 description 1
- 206010037844 rash Diseases 0.000 description 1
- FNHKPVJBJVTLMP-UHFFFAOYSA-N regorafenib Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=C(F)C(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 FNHKPVJBJVTLMP-UHFFFAOYSA-N 0.000 description 1
- 229960004836 regorafenib Drugs 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 229940100486 rice starch Drugs 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 125000003607 serino group Chemical group [H]N([H])[C@]([H])(C(=O)[*])C(O[H])([H])[H] 0.000 description 1
- SQVRNKJHWKZAKO-OQPLDHBCSA-N sialic acid Chemical compound CC(=O)N[C@@H]1[C@@H](O)C[C@@](O)(C(O)=O)OC1[C@H](O)[C@H](O)CO SQVRNKJHWKZAKO-OQPLDHBCSA-N 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000009987 spinning Methods 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 238000010257 thawing Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 235000019731 tricalcium phosphate Nutrition 0.000 description 1
- 229940078499 tricalcium phosphate Drugs 0.000 description 1
- 229910000391 tricalcium phosphate Inorganic materials 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 230000005760 tumorsuppression Effects 0.000 description 1
- 230000002100 tumorsuppressive effect Effects 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229940100445 wheat starch Drugs 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0802—Tripeptides with the first amino acid being neutral
- C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
- C07K5/0806—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/549—Sugars, nucleosides, nucleotides or nucleic acids
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
- A61K47/65—Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K19/00—Hybrid peptides, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0802—Tripeptides with the first amino acid being neutral
- C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
- C07K5/0808—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0802—Tripeptides with the first amino acid being neutral
- C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
- C07K5/081—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing O or S as heteroatoms, e.g. Cys, Ser
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Oncology (AREA)
- Hematology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
公开了分子定点靶向和激活的激酶抑制剂的制备和用途。具体而言,公开了下式A所示的化合物或其药学上可接受的盐,式中,X为极性和非极性不带电荷的氨基酸,如丙氨酸、缬氨酸或苏氨酸;A为丙氨酸;N为天冬酰胺;PABC为‑NH‑苯基‑CH2‑O‑;和Z为药物分子;其中,乳糖酸残基、XAN以及PABC相互间通过酰胺键相连;PABC与Z以酯基,即‑O‑C(O)‑相连。乳糖酸残基‑XAN‑PABC‑Z (式A)。
Description
技术领域
本发明涉及分子定点靶向和激活的激酶抑制剂的制备和用途。
背景技术
糖类物质是多羟基(2个或以上)的醛类()或酮类()化合物,在水解后能变成以上两者之一的有机化合物。糖分子在免疫细胞和肿瘤细胞上有着不同的受体。例如,乳糖(Lacto)在人体细胞中具有多种作用受体,其中包括唾液酸糖蛋白受体。糖分子与受体间相互作用起到了细胞间识别和生物分子间的识别,参与细胞通信等重要用途。
索拉菲尼(Sorafenib)是一种新型多靶向性的治疗肿瘤的口服药物,其结构式如下所示:
2005年12月20日,美国FDA快速批准了索拉菲尼作为晚期肾细胞癌的一线治疗药物,用于治疗不能手术的晚期肾细胞癌。索拉菲尼还可用于治疗无法手术或远处转移的原发肝细胞癌,以及治疗对放射性碘治疗不再有效的局部复发或转移性、逐步分化型甲状腺患者。此外,该药对非小细胞肺癌以及黑色素瘤也有一定疗效。索拉菲尼是一种小分子靶向药物,具有双重抗肿瘤作用。主要作用机制是:1)索拉菲尼是丝、苏氨酸蛋白激酶(RAF)和酪氨酸激酶抑制剂,通过抑制Ras基因的表达,抑制RAF/MEK/ERK信号传导通路直接抑制肿瘤生长;2)通过抑制血管内皮生长因子受体(VEGFR-1,VEGFR-2,VEGFR-3)和血小板源性生长因子受体β(PDGFR-β)而阻断肿瘤新生血管的形成,切断肿瘤细胞的营养供应而达到抑制肿瘤生长的目的。但是索拉菲尼具有严重的不良反应,包括皮疹、腹泻、血压升高以及手掌或足底部发红、疼痛、肿胀或出现水疱,长期服用淋巴细胞下降,并且不适用于本身具有基础肝脏疾病的患者和抑制人体免疫力。
发明内容
本公开提供具有以下结构的化合物或其药学上可接受的盐:
乳糖酸残基-XAN-PABC-Z (式A)
式中,
X为极性和非极性不带电荷的氨基酸,如丙氨酸、缬氨酸或苏氨酸;
A为丙氨酸;
N为天冬酰胺;
PABC为-NH-苯基-CH2-O-;
Z为药物分子。
在一个或多个实施方案中,乳糖酸残基与X以酰胺键(-C(O)-NH-)相连。
在一个或多个实施方案中,X与A以酰胺键相连。
在一个或多个实施方案中PABC与N通过酰胺键相连。
在一个或多个实施方案中,PABC与Z以酯基(-O-C(O)-)相连。
在一个或多个实施方案中,Z选自阿霉素、达拉非尼、多韦替尼、莫特塞尼和本公开式B所示的索拉菲尼衍生物。
在一个或多个实施方案中,式A化合物具有下式I所示的结构:
式中,X和Z如前文所定义。
在一个或多个实施方案中,X为丙氨酸,所述式I化合物具有下式II所示的结构:
在一个具体实施例中,所述式II化合物选自:
S1:Lacto-AAN-PABC-化合物a
S2:Lacto-AAN-PABC-化合物b
S3:Lacto-AAN-PABC-阿霉素
S4:Lacto-AAN-PABC-达拉非尼
S5:Lacto-AAN-PABC-多韦替尼
S6:Lacto-AAN-PABC-莫特塞尼
在一个具体实施例中,X为缬氨酸,所述式I化合物具有下式III结构:
在一个具体实施例中,所述式III化合物选自:
S7:Lacto-VAN-PABC-化合物a
S8:Lacto-VAN-PABC-化合物b
S9:Lacto-VAN-PABC-阿霉素
S10:Lacto-VAN-PABC-达拉非尼
S11:Lacto-AAN-PABC-多韦替尼
S 12:Lacto-VAN-PABC-莫特塞尼
在一个具体实施例中,X为苏氨酸,所述式I化合物具有下式IV结构:
在一个具体实施例中,所述式IV化合物选自:
S13:Lacto-TAN-PABC-化合物a
S14:Lacto-TAN-PABC-化合物b
S15:Lacto-TAN-PABC-阿霉素
S16:Lacto-TAN-PABC-达拉非尼
S17:Lacto-TAN-PABC-多韦替尼
S18:Lacto-TAN-PABC-莫特塞尼
本公开还提供一种药物组合物,所述药物组合物含有本文所公开的式A化合物或其药学上可接受的盐,和药学上可接受的载体。
在一个或多个实施方案中,所述药物组合物含有式I所示的化合物或其药学上可接受的盐。
在一个或多个实施方案中,所述药物组合物含有本文所公开的化合物S1-S18中的任意一种或多种或其药学上可接受的盐。
本公开还提供所述式A化合物或其药学上可接受的盐在制备治疗癌症或癌细胞转移用的药物中的应用。
在一个或多个实施方案中,所述癌症选自:肝癌、肾癌、甲状腺癌、结肠直肠癌、膀胱癌、脑癌、乳腺癌、宫颈癌、直肠癌、食管癌、肺癌(例如支气管肺癌,包括未分化小细胞性和非小细胞性)、鼻咽癌、胰腺癌、前列腺癌、皮肤癌、胃癌、子宫癌、卵巢癌、睾丸癌、血癌(例如慢性或急性白血病,包括淋巴细胞性和粒细胞性白血病)、恶性淋巴瘤、纤维素肉瘤、软组织肉瘤、成骨肉瘤、横纹肌肉瘤、尤文肉瘤、肾母细胞瘤、神经母细胞瘤、甲状腺癌和头颈部鳞癌。
本公开还提供所述式A化合物或其药学上可接受的盐在制备免疫治疗药物中的应用。
在一个或多个实施方案中,所述免疫治疗药物可用于刺激T细胞的繁殖和对病灶的侵入、抑制肿瘤相关巨噬细胞和/或促进刺激免疫反应。
本文还提供下式B所示的化合物:
式中,R为H或卤素。
在一个或多个实施方案中,式B化合物选自化合物a和化合物b,即:
本文还提供下式C所示的化合物:
乳糖酸残基-XAN-PABC’ (式C)
式中,
X为极性和非极性不带电荷的氨基酸,如丙氨酸、缬氨酸或苏氨酸;
A为丙氨酸;
N为天冬酰胺;
PABC’为-NH-苯基-CH2-OH。
在一个或多个实施方案中,乳糖酸残基与X以酰胺键(-C(O)-NH-)相连。
在一个或多个实施方案中,X与A以酰胺键相连。
在一个或多个实施方案中,式C具有下式C-1所示结构:
本文还提供式C化合物在提高抗癌药物的抗癌活性中的应用。
附图说明
图1:分子定点靶向导致高激活和高效的分子受体在肿瘤细胞表面分布相同。荧光共聚焦显微镜检测对应抗体标记的MDA-MB435肿瘤细胞,天冬氨酸肽链内切酶(左1,绿色),唾液酸糖蛋白受体(左2,红色),细胞核染色用DAPI(蓝色),两图合并共同分布为黄色(左3)。
图2:与Succinyl-AANL-DOX相比,S3静脉注射后具有更多的肿瘤组织分布和渗透。
图3:S1、索拉菲尼和化合物a对Heg2肿瘤细胞的毒性效应。
图4:分子定点靶向导致高激活和高效化合物S1、S2、S3和C11相对于索拉菲尼的肿瘤组织分布。
图5:肿瘤治疗中分子定点靶向导致高激活和高效化合物S1、S2、S3、S4、S5、S6、索拉菲尼和阿霉素的肿瘤大小变化曲线。
图6:通过细胞分化骨髓细胞为M1、M2型巨噬细胞,天冬酰胺肽链内切酶在M2型上高表达和分泌。左图显示为肿瘤诱导的M2巨噬细胞,右图显示M1-炎症型巨噬细胞。亮点(绿色荧光)为天冬酰胺肽链内切酶的染色。
图7:药物对M2肿瘤相关巨噬细胞的毒性比较。
图8:本文化合物的作用机制示意图。
具体实施方式
本文发现,唾液酸糖蛋白受体与天冬氨酸肽链内切酶分子受体在肿瘤细胞表面具有共分布的特点,双靶点的同分布可能是定点靶向导致高激活化合物高效激活的原因;可利用这种共分布的特点设计药物,使其在共分布位置积累和滞留,从而提高其对肿瘤细胞的识别和激活效率。基于这一发现,本发明人通过将特定的天冬酰胺肽链内切酶(Legumain)酶切底物肽与不同种类的糖类进行连接,并测试该连接体的稳定性和酶切效率,筛选到具有预测之外的强激活效果和稳定性相对高的连接体。进一步地,本发明人利用所筛选得到的连接体连接不同的药物分子,从而获得本公开式A所示的化合物。这些化合物是分子定点靶向导致高激活和高效的化合物,其作用机制如图8所示:本公开的分子定点靶向导致高激活和高效化合物既有被同分布双靶点高效激活以杀死癌细胞的特性,同时也具有通过内吞激活抑制M2型肿瘤相关巨噬细胞、而后激活抗肿瘤免疫的特点,最终产生具有治愈肿瘤,产生机体免疫力,导致肿瘤不再复发的活性。
因此,本公开首先提供式C所示的化合物:
乳糖酸残基-XAN-PABC’ (式C)
式中,X为极性和非极性不带电荷的氨基酸,如丙氨酸、缬氨酸或苏氨酸;A为丙氨酸;N为天冬酰胺;PABC’为-NH-苯基-CH2-OH。
式C以及含有本文式C结构的其它化合物中,乳糖酸残基(Lacto)、X和N酰胺键相连,而PABC’也通过酰胺键与天冬酰胺残基(N)相连。
应理解的是,作为基团的“-NH-”中的“N”指氮原子,而作为氨基酸残基的“N”则指天冬酰胺。此外,本文中,酰胺键指“-C(O)-NH-”。
在某些实施方案中,式C具有下式C-1所示结构:
式C化合物可作为本公开分子定点靶向导致高激活和高效化合物中的连接体部分,用于与活性药物分子进行连接。具体而言,本发明的分子定点靶向导致高激活和高效化合物具有下式A所示的结构:
乳糖酸残基-XAN-PABC-Z (式A)
式中,X为极性和非极性不带电荷的氨基酸,如丙氨酸、缬氨酸或苏氨酸;A为丙氨酸;N为天冬酰胺;PABC为-NH-苯基-CH2-O-;Z为感兴趣的药物分子。
通常,乳糖酸残基、XAN和PABC均通过酰胺键相互连接,而PABC与Z以酯基(-O-C(O)-)相连。
在某些实施方案中,式A化合物的结构进一步如本文所公开的式I所示。
感兴趣的药物分子Z可选自下式B所示的索拉菲尼衍生物:
式中,R为H或卤素。
本文中,“卤素”包括F、Cl、Br和I。
在某些实施方案中,式B化合物选自本文所公开的化合物a和化合物b。
感兴趣的药物分子Z还可以是,例如阿霉素、达拉非尼、多韦替尼和莫特塞尼。
可根据感兴趣药物分子的药效结构确定与PABC连接的位点。通常是在远离其活性位点的位置上与PABC连接。连接的方式可以是各种合适的方式。本文中,药物分子与PABC通过酯基,即-O-C(O)-相连。
在本公开的某些实施方案中,X为丙氨酸、缬氨酸或苏氨酸,因此式A可以是乳糖酸残基-AAN-PABC-Z、乳糖酸残基-VAN-PABC-Z或乳糖酸残基-TAN-PABC-Z。
在本公开的某些实施方案中,X为丙氨酸,因此,本文式I化合物的结构可如式II所示。在其它实施方案中,X为缬氨酸,因此,本文式I化合物的结构可如式III所示。在其它实施方案中,X为苏氨酸,因此本文式I化合物的结构可如式IV所示。
示范性的本文式A或式I化合物可如前文所述的S1-S18所示。
本文也包括本文式A或式I化合物的药学上可接受的盐。药学上可接受的盐的例子包括但不限于无机酸盐和有机酸盐,例如盐酸盐、氢溴酸盐、磷酸盐、硫酸盐、柠檬酸盐、乳酸盐、酒石酸盐、马来酸盐、富马酸盐、甲磺酸盐、扁桃酸盐和草酸盐;以及与碱例如钠羟基、三(羟基甲基)胺基甲烷(TRIS,胺丁三醇)和N-甲基葡糖胺形成的无机碱盐和有机碱盐。例如,在某些实施方案中,式A中的药物分子Z为达拉非尼、式B化合物的甲磺酸盐,或者为多韦替尼的羟基丙酸盐等。
本文也包括式A或式I化合物的立体异构体,也包括立体异构体的外消旋体。可以根据本领域技术人员众所周知的方法分离出单独的对映体。但应理解的是,本文所述的化合物中,乳糖酸以及X、A和N优选为其天然存在的异构体形式。
本文部分化合物的制备流程可如本文实施例1-3所示。例如,可先行合成式A化合物中的XAN-PABC-Z部分,然后在于乳糖酸相连;或者,可先行合成式A化合物中的乳糖酸残基-XAN-PABC部分,然后在于感兴趣的药物分子Z相连。
因此,本文提供一种药物组合物,该药物组合物含有式A化合物或其药学上可接受的盐和药学上可接受的载体。
药学上可接受的载体通常是安全、无毒的,且广义上可包括制药产业中用于制备药物组合物的任何已知物质,如填充剂、稀释剂、凝结剂、黏合剂、润滑剂、助流剂、稳定剂、着色剂、润湿剂、崩解剂等。合适的药学上可接受的载体包括糖类,如乳糖或蔗糖、甘露醇或山梨醇;纤维素制剂和/或钙磷酸盐,例如磷酸三钙或磷酸氢钙;淀粉糊,包括玉米淀粉、小麦淀粉、大米淀粉、马铃薯淀粉、明胶、黄芪胶、甲基纤维素、羟丙基甲基纤维素、羧甲基纤维素钠和/或聚乙烯吡咯烷酮;硅石、滑石、硬脂酸或其盐,如硬脂酸镁或硬脂酸钙和/或聚乙二醇;等等。在选择药学上可接受的载体时,主要需考虑此药物组合物的给药方式,这为本领域技术人员所熟知。
药物组合物中可含有治疗有效量的式A化合物或其药学上可接受的盐。“有效量”指某成分的用量足以产生所期望的反应。具体的有效量取决于多种因素,诸如欲治疗的特定病症、患者的身体条件(如患者体重、年龄或性别)、治疗持续时间、共同施与的疗法(如果有的话)以及所用的具体配方。“有效量”也指在该用量下,本申请多肽的毒性或负面效果不及于其所带来的正面疗效。在本公开中,式A化合物或其药学上可接受的盐的治疗有效量可与常规的药物分子Z的治疗有效量相当。在某些情况下,由于偶联了本公开的连接体(即式C化合物),具有更高的激活效率和抗肿瘤效果,因此,本公开式A化合物或其药学上可接受的盐的治疗有效量低于常规的药物分子Z的治疗有效量。
可根据已知的药学程序来制备上述药物组合物,譬如《雷明顿制药科学》(Remington’s Pharmaceutical Sciences)(第17版,Alfonoso R.Gennaro编,麦克出版公司(Mack Publishing Company),伊斯顿,宾夕法尼亚(1985))一书中有详细的记载。
本公开的药物组合物可以是各种合适的剂型,包括但不限于药片、胶囊、注射剂等,并可通过任何合适的途径给药,以达到其预期目的。例如,可以通过肠外、皮下、静脉、肌肉、腹腔内、透皮、口腔、鞘内、颅内、鼻腔或外用途径给药。药的剂量可根据病人的年龄、健康与体重、并行治疗的种类和治疗的频率等来决定。
本公开的药物组合物可以给予任何哺乳动物,尤其是人。
本文式A化合物或其药学上可接受的盐或药物组合物尤其可用于治疗癌症或癌细胞转移。可采用本文式A化合物或其药学上可接受的盐或药物组合物治疗的癌症可根据感兴趣的药物分子Z本身所具有的治疗活性而定。例如,本领域已知,索拉菲尼是多靶向性肿瘤治疗药物,其适应症包括但不限于无法手术或远处转移的肝肿瘤细胞、不能手术的肾肿瘤细胞和对放射性碘治疗不再有效的局部复发或转移性、逐步分化型甲状腺患者等。阿霉素抗瘤谱较广,适用于急性白血病(淋巴细胞性和粒细胞性)、恶性淋巴瘤、乳腺癌、支气管肺癌(未分化小细胞性和非小细胞性)、卵巢癌、软组织肉瘤、成骨肉瘤、横纹肌肉瘤、尤文肉瘤、肾母细胞瘤、神经母细胞瘤、膀胱癌、甲状腺癌、前列腺癌、头颈部鳞癌、睾丸癌、胃癌和肝癌等。
因此,本文式A化合物或其药学上可接受的盐或药物组合物可用于治疗的癌症包括但不限于肝癌、肾癌、甲状腺癌、结肠直肠癌、膀胱癌、脑癌、乳腺癌、宫颈癌、直肠癌、食管癌、肺癌(例如支气管肺癌,包括未分化小细胞性和非小细胞性)、鼻咽癌、胰腺癌、前列腺癌、皮肤癌、胃癌、子宫癌、卵巢癌、睾丸癌、血癌(例如慢性或急性白血病,包括淋巴细胞性和粒细胞性白血病)、恶性淋巴瘤、纤维素肉瘤、软组织肉瘤、成骨肉瘤、横纹肌肉瘤、尤文肉瘤、肾母细胞瘤、神经母细胞瘤、甲状腺癌和头颈部鳞癌。本文的式A化合物或其药学上可接受的盐或药物组合物也可用于治疗这些伴随这些癌症发生的癌细胞转移。
在某些方面,本公开式A化合物或其药学上可接受的盐或药物组合物还可刺激T细胞的繁殖和对病灶的侵入、抑制肿瘤相关巨噬细胞和/或促进刺激免疫反应。
因此,本公开提供一种治疗癌症或癌细胞转移的方法,所述方法包括给予有此需要的对象治疗有效量的本文所公开的式A化合物或其药学上可接受的盐或药物组合物。所述癌症或癌细胞转移如前文所述。
在某些方面,本公开还提供一种刺激T细胞的繁殖和对病灶的侵入、抑制肿瘤相关巨噬细胞和/或促进刺激免疫反应的方法,所述方法包括给予有此需要的对象治疗有效量的本文所公开的式A化合物或其药学上可接受的盐或药物组合物。
感兴趣的“对象”可以是任何哺乳动物,尤其是人。
还提供的是本公开式A化合物或其药学上可接受的盐在制备治疗癌症或癌细胞转移用的药物中的应用,或在制备免疫治疗药物中的应用。所述癌症或癌细胞转移如前文所述;所述免疫治疗药物可用于刺激T细胞的繁殖和对病灶的侵入、抑制肿瘤相关巨噬细胞和/或促进刺激免疫反应。
还提供的是本公开的式A化合物或其药学上可接受的盐,用于治疗癌症或癌细胞转移,或用于刺激T细胞的繁殖和对病灶的侵入、抑制肿瘤相关巨噬细胞和/或促进刺激免疫反应。
应理解的是,本文所述各方面、各实施方案以及下述各具体实施例中的各特征可任意组合,构成优选的实施方案。因此,例如,虽然上述公开仅体积式A化合物或其药学上可接受的盐,但本文所公开的任一落入式A范围内的具体化合物,例如式I、II、III和IV化合物,或化合物S1-S18均可用于上述具体公开的任意一种癌症或癌细胞转移的治疗。
下面结合具体实施例,进一步阐述本申请。除非另外说明,下述实施例将使用本领域技术人员已知的化学、生物化学和免疫学的常规方法。这些技术在文献中有完整的解释。此外,实施例中所用到的各种材料和试剂,除非另有说明,否则均为已知的和/或常规的材料和试剂。
实施例1:化合物S1、S7和S13的合成
采用以下流程合成化合物S1、S7和S13,其中,X为丙氨酸:
QHL001的合成
在100ml的单口瓶中,依次加入DMF(40ml),对氨基苯酚(5g,45.8mmol),叔丁醇钾(5.35g,47.7mmol)。搅拌30分钟后,加入4-氯吡啶-2-羧酸叔丁酯(11.75g,55mmol)。室温搅拌5分钟后,升温至80℃,反应过夜。减压蒸除DMF,残留物用二氯甲烷溶解,水洗,萃取,分液。有机相干燥,旋干,硅胶柱层析分离纯化(按体积比计,二氯甲烷:甲醇=80:1~10:1),得到白色固体QHL001(7.86g,收率:60%)。
QHL002的合成
在100ml的单口瓶中,依次加入DCM(30ml),QHL001(7.80g,27.3mmol),搅拌5分钟后,用冰盐浴将体系降温至0℃,分批加入4-氯-3-三氟甲基异氰酸苯酯(7.0g,32.8mmol)。加完后,撤去冰盐浴,升至室温,反应过夜。加入50ml水,萃取,分液。有机相干燥,旋干,硅胶柱层析分离纯化(按体积比计,二氯甲烷:甲醇=50:1~10:1),得到棕色固体QHL002(10.54g,收率76%)。
QHL003的合成
在100ml的单口瓶中,依次加入DCM(15ml),三氟醋酸(15ml),QHL002(10.5g,20.7mmol),三乙基硅烷(2.5ml),室温搅拌至QHL002完全反应。反应结束后,将反应液旋干,粗品用硅胶柱层析分离纯化(按体积比计,二氯甲烷:甲醇=50:1~5:1),得到白色固体QHL003(7.47g,收率80%)。
QHL004的合成
在50ml的单口瓶中,依次加入DMF(10ml),QHL003(417mg,0.92m mol),N-BOC-N-甲基乙二胺(200mg,1.25mmol),HATU(420mg,1.10mmol)。搅拌5分钟后,滴入DIPEA(0.5ml,2.76mmol)。室温搅拌至QHL003完全反应。减压蒸除DMF,粗产品用乙酸乙酯溶解,水洗1次。有机相干燥,旋干,硅胶柱层析分离纯化(按体积比计,二氯甲烷:甲醇=50:1~20:1),得到淡黄色固体QHL004(454mg,收率83%)。
QHL005的合成
将化合物QHL004(450mg,0.764mmol)溶于DCM(10ml)中,加入三氟乙酸(10ml)。室温下搅拌至QHL004完全反应。蒸除溶剂,残留固体用硅胶柱层析分离纯化(按体积比计,二氯甲烷:甲醇=30:1~10:1),得到淡黄色固体QHL005(340mg,,收率:90%)。
QHL006的合成
在100ml单口瓶中,依次加入L-Ala-L-Ala-L-Asn(Trt)-PABC(6.21g,10mmol),DMF(20ml),DIPEA(1.29g,10mmol)。室温搅拌5分钟后,冰盐浴将体系降温至0℃。缓慢加入氯甲酸烯丙酯(1.21g,10mmol).室温搅拌过夜。反应结束后,减压蒸馏除去DMF,残留物经硅胶柱层析分离纯化(按体积比计,二氯甲烷:甲醇=50:1~10:1),得到白色固体QHL006(5.0g,收率71%)。
QHL007的合成
在100ml单口瓶中,依次加入DCM(15ml),三氟乙酸(15ml),QHL006(5.0g),室温搅拌至QHL012反应完全。然后旋蒸除去DCM和三氟乙酸,残留物用甲基叔丁基醚打浆1h。过滤,收集固体。再将固体溶于甲醇(30ml)中,加入DIPEA(15ml),室温搅拌2h后,旋干溶剂,得到粗品。粗品再次用甲基叔丁基醚打浆1h,过滤,干燥,得到QHL007(2.75g,收率92%)。
QHL008的合成
在100ml单口瓶中,依次加入DMF(15ml),QHL007(2.75g,5.94mmol),4,4-二硝基碳酸二苯酯(3.54g,11.6mmol),DIPEA(1.13g,8.76mmol),室温搅拌至QHL007反应完全。反应结束后,减压蒸馏除去DMF,残留物经硅胶柱层析分离纯化(按体积比计,二氯甲烷:甲醇=50:1~10:1),得到白色固体QHL008(2.43g,收率65%)。
QHL009的合成
在50ml的单口瓶中,依次加入DMF(10ml),QHL005(508mg,1mmol),QHL008(629mg,1mmol)。搅拌5分钟后,滴入DIPEA(387mg,3mmol),继续室温搅拌2h。减压蒸除DMF,粗产品用硅胶柱层析分离纯化(按体积比计,二氯甲烷:甲醇=50:1~10:1),得到白色固体QHL009(698mg,收率:70%)。
QHL010的合成
在50ml的单口瓶中,依次加入DMF(10ml),QHL009(310mg,0.31mmol),乙酸(274mg,4.65mmol),三苯基膦钯(72mg,0.062mmol),三正丁基氢化锡(1.17g,4.03mmol),置换氮气后,室温搅拌至QHL009反应完全。反应结束后,减压蒸除DMF,粗产品用硅胶柱层析分离纯化(按体积比计,二氯甲烷:甲醇=50:1~10:1),得到白色固体QHL010(175mg,收率:62%)。
S1(Lacto-AAN-PABC-化合物a)的合成
将乳糖酸(3.8g,10mmol)溶于无水甲醇(100ml)中,升温至回流,反应24小时后,冷却至室温。将QHL010(175mg,0.192mmol)溶解于无水甲醇(10ml)中,室温滴加至上述乳糖酸的甲醇溶液中。滴加完毕后,将体系升温至60℃,反应过夜。减压蒸干溶剂,粗品用反相制备纯化,得到白色固体即化合物S1(91mg,收率36%)。
采用与S1合成类似的方法,用不同的氨基酸残基进行连接,制备得到化合物S7(Lacto-VAN-PABC-化合物a)和S13(Lacto-TAN-PABC-化合物a)。
实施例2:化合物S2、S8和S14的合成
采用以下流程合成化合物S2、S8和S14,其中X为丙氨酸:
QHL012的合成
在100ml的单口瓶中,依次加入DMF(40ml),4-氨基-3-氟-苯酚(5.8g,45.8mmol),叔丁醇钾(5.35g,47.7mmol)。搅拌30分钟后,加入4-氯吡啶-2-羧酸叔丁酯(11.75g,55mmol)。室温搅拌5分钟后,升温至80℃,反应过夜。减压蒸除DMF,残留物用二氯甲烷溶解,水洗,萃取,分液。有机相干燥,旋干,硅胶柱层析分离纯化(按体积比计,二氯甲烷:甲醇=80:1~10:1),得到白色固体QHL012(9.7g,收率:70%)。
QHL013的合成
在100ml的单口瓶中,依次加入DCM(30ml),QHL012(8.30g,27.3mmol),搅拌5分钟后,用冰盐浴将体系降温至0℃,分批加入4-氯-3-三氟甲基异氰酸苯酯(7.0g,32.8mmol)。加完后,撤去冰盐浴,升至室温,反应过夜。加入50ml水,萃取,分液。有机相干燥,旋干,硅胶柱层析分离纯化(按体积比计,二氯甲烷:甲醇=50:1~10:1),得到棕色固体QHL013(11.2g,收率75%)。
QHL014的合成
在100ml的单口瓶中,依次加入DCM(15ml),三氟醋酸(15ml),QHL013(11.2g,20.7mmol),三乙基硅烷(2.5ml),室温搅拌至QHL013完全反应。反应结束后,将反应液旋干,粗品用硅胶柱层析分离纯化(按体积比计,二氯甲烷:甲醇=50:1~5:1),得到白色固体QHL014(7.92g,收率80%)。
QHL015的合成
在50ml的单口瓶中,依次加入DMF(20ml),QHL014(4.42g,9.2mmol),N-BOC-N-甲基乙二胺(2.00g,12.5mmol),HATU(4.20g,11mmol)。搅拌5分钟后,滴入DIPEA(5ml,27.6mmol)。室温搅拌至QHL014完全反应。减压蒸除DMF,粗产品用乙酸乙酯溶解,水洗1次。有机相干燥,旋干,硅胶柱层析分离纯化(按体积比计,二氯甲烷:甲醇=50:1~20:1),得到淡黄色固体QHL015(4.81g,收率80%)。
QHL016的合成
将化合物QHL015(4.80g,7.64mmol)溶于DCM(10ml)中,加入三氟乙酸(10ml)。室温下搅拌至QHL015完全反应。蒸除溶剂,残留固体用硅胶柱层析分离纯化(按体积比计,二氯甲烷:甲醇=30:1~10:1),得到淡黄色固体QHL016(3.60g,收率:90%)。
QHL017的合成
在50ml的单口瓶中,依次加入DMF(10ml),QHL016(670mg,1.28mmol),QHL008(965mg,1.54mmol)。搅拌5分钟后,滴入DIPEA(1.4ml,7.68mmol),置换氮气后,继续室温搅拌3h。减压蒸除DMF,粗产品用硅胶柱层析分离纯化(按体积比计,二氯甲烷:甲醇=50:1~15:1),得到白色固体QHL017(1.0g,收率:77%)。
QHL018的合成
在50ml的单口瓶中,依次加入DMF(10ml),QHL017(500mg,0.49mmol),乙酸(0.42ml,7.39mmol),三苯基膦钯(116mg,0.10mmol),三正丁基氢化锡(1.75ml,6.37mmol),置换氮气后,室温搅拌至QHL017反应完全。反应结束后,减压蒸除DMF,粗产品用硅胶柱层析分离纯化(按体积比计,二氯甲烷:甲醇=50:1~10:1),得到白色固体QHL018(300mg,收率:65%)。
S2的合成
将乳糖酸(3.8g,10mmol)溶于无水甲醇(100ml)中,升温至回流,反应24小时后,冷至室温。将QHL018(175mg,0.188mmol)溶解于无水甲醇(10ml)中,室温滴加至上述乳糖酸的甲醇溶液中。滴加完毕后,将体系升温至60℃,反应过夜。减压蒸干溶剂,粗品用反相制备纯化,得到白色固体,即S2(102mg,收率42%)。
采用与S2合成类似的方法,用不同的氨基酸残基进行连接,制备得到化合物S8(Lacto-VAN-PABC-化合物b)和S14(Lacto-TAN-PABC-化合物b)。
实施例3:化合物S3-S6、S9-S11和S15-S18的合成
采用以下流程合成化合物S3-S6、S9-S11和S15-S18,通式中,X为丙氨酸、苏氨酸或缬氨酸。
具体而言,先以XAN-PABC中X的氨基端与乳糖酸的羧基进行反应,生成定点靶向连接体(Lacto-XAN-PABC)。然后对Lacto-XAN-PABC进行活化,生成Lacto-XAN-PABC-PNP。化合物Z以其结构上含有的氨基对Lacto-XAN-PABC-PNP进行亲核反应,即得到化合物Lacto-XAN-PABC-Z。
以下以化合物S3为例阐述这些化合物的合成:
QHL020的合成
将乳糖酸(3.8g,10mmol)溶于无水甲醇(100ml)中,升温至回流,反应24小时后,冷至室温。将L-Ala-L-Ala-L-Asn-PABC(760mg,2.0mmol)溶解于无水甲醇(10ml)中,室温滴加至上述乳糖酸的甲醇溶液中。滴加完毕后,将体系升温至60℃,反应过夜。减压蒸干溶剂,粗品用反相制备纯化,得到白色固体QHL020(650mg,收率45%)。
QHL021的合成
在100ml单口瓶中,依次加入DMF(15ml),QHL020(650mg,0.90mmol),4,4-二硝基碳酸二苯酯(354mg,1.16mmol),DIPEA(113mg,0.88mmol),室温搅拌过夜。反应结束后,减压蒸馏除去DMF,残留物经硅胶柱层析分离纯化(按体积比计,二氯甲烷:甲醇=25:1~3:1),得到白色固体QHL021(243mg,收率30%)。
S3的合成
在50ml的单口瓶中,依次加入DMF(10ml),QHL021(180mg,0.2mmol),盐酸阿霉素(192mg,0.33mmol)。搅拌5分钟后,滴入DIPEA(194mg,1.5mmol),继续室温搅拌5h。减压蒸除DMF,粗产品用反相制备纯化,得到QHL022红色固体(127mg,收率:49%)即化合物S3。
当Z为阿霉素时,改变连接的氨基酸,分别得到实施例S9,S15;
当Z为达拉非尼时,改变连接的氨基酸,分别得到实施例S4,S10,S16;
当Z为多韦替尼时,改变连接的氨基酸,分别得到实施例S5,S11,S17;
当Z为莫特塞尼时,改变连接的氨基酸,分别得到实施例S6,S12,S18。
质谱(MS)检测结果确认S1-S18化合物,分子量依次如下表1所示,与结构计算预测的分子量相一致。
表1
实施例4:分子定点靶向导致高激活连接体组分合成筛选
肿瘤组织特异性的激活位点是短肽,因为天冬氨酸肽链内切酶的酶活中心位于球囊状内陷的底部,切割位点需要接近酶活中心,这时化合物对切割位点是否有空间位阻变为非常重要。
通过特定的天冬酰胺肽链内切酶(Legumain)酶切底物肽与不同种类的糖类进行连接,并测试所得连接体的稳定性和酶切效率,筛选到具有预测之外的强激活效果和稳定性相对高的连接体,结果如下表2所示。
表2
上述结果说明:本发明的乳糖酸-AAN-对氨基苯甲醇不但不影响激活效率,与PEG-Ala-Ala-ASN-对氨基苯甲醇相比反而促进了激活效率和稳定性。
实施例5:唾液酸糖蛋白受体与天冬氨酸肽链内切酶的细胞分布特性
本发明人深入研究发现,唾液酸糖蛋白受体与天冬氨酸肽链内切酶分子受体在肿瘤细胞表面具有共分布的特点。具体而言,在MDA-MB435乳腺癌肿瘤细胞的免疫荧光染色中,用荧光共聚焦显微镜检测对应抗体标记的唾液酸糖蛋白受体与天冬氨酸肽链内切酶,细胞核染色用DAPI。结果如图1所示,显示唾液酸糖蛋白受体和天冬氨酸肽链内切酶的位点分布相同。这种共分布的特点可以使本发明化合物在共分布位置积累和滞留,从而提高其对肿瘤细胞的识别和激活效率。
实施例6:本发明化合物的的组织分布特性
由于DOX、Succinyl-AANL-DOX和S3具有自发荧光,因此可用荧光显微镜检测肿瘤组织中它们的分布情况。静脉注射10umol/kg的DOX、Succinyl-AANL-DOX和S3。12小时后检测肿瘤组织切片的药物分布图像和肿瘤组织匀浆荧光强度。细胞核染色用DAPI。结果如图2所示。结果显示,与Succinyl-AANL-DOX相比,S3静脉注射后具有更多的肿瘤组织分布和渗透,说明S3所具有的分子定点靶向功能使其能够同时双靶向于唾液酸糖蛋白受体与天冬氨酸肽链内切酶,从而比Succinyl-AANL-DOX具有很强的肿瘤部位的滞留效应。
实施例7:索拉菲尼衍生物的合成
索拉菲尼不具备与本发明式II化合物偶联的可能性。为了解决这一困境,本文对索拉菲尼分子中的吡啶环邻位的甲酰胺基团进行了变构合成和筛选,得到既满足构效关系,又能增加释放药效的特殊化合物(即化合物a和化合物b)。对化合物a和化合物b进行了稳定性及细胞活性实验,结果表明化合物a和化合物b在弱酸、弱碱及中性缓冲体系中稳定性良好,不会发生降解,并且对癌细胞的抑制效果均优于阳性对照药索拉菲尼及瑞戈非尼(图3)。
实施例8:S1和化合物a的抗肿瘤细胞毒性
收集对数期Heg2细胞,调整细胞悬液浓度,每孔加入140ul,铺板使待测细胞调密度~5000个/孔;5%CO2,37℃孵育过夜,至细胞单层铺满孔底(96孔平底板),再加入连续浓度梯度的给予不同浓度的化合物S1、化合物a和索拉菲尼,药物设置9个浓度梯度,每孔10ul,设3个复孔;5%CO2,37℃PH6.5孵育48小时,倒置显微镜下观察;每孔加入20ulMTT溶液(5mg/ml,即0.5%MTT),继续培养4h。终止培养,小心吸去孔内培养液;每孔加入100ul二甲基亚砜,置摇床上低速振荡10min,使结晶物充分溶解。在酶联免疫检测仪OD490nm处测量各孔的吸光值。同时设置调零孔(培养基、MTT、二甲基亚砜),对照组(细胞、相同浓度的药物溶解介质、培养基、MTT、二甲基亚砜)。检测后对化合物对正常肝细胞的毒性进行分析,结果见图3。图3显示给予不同浓度的化合物2天后,化合物a相对索拉菲尼具有更高的毒性。而S1通过偶联连接体变为一个对正常细胞无毒性的药物。
实施例9:化合物的相对激活特性
将样品化合物和部分对照化合物(本文中,所有对照化合物可采用类似于实施例1-3所述的方法进行合成)统一用酶切溶液稀释10倍到1毫克/毫升。在本实验中,在37℃、2小时条件下在天冬氨酸肽链内切酶(1umol/L,pH6.0)中加入1毫克/毫升的样品化合物,反应后酶能够导致释放出酶切产物,通过HPLC检测化合物的减少和产物的增加,从而比较酶激活效率〔指被酶剪切而释放出来的产物产生相对于原化合物比率〕。结果如下表3所示。
表3:本发明化合物和部分对照化合物的激活效率
化合物 | 激活效率(%) |
C1:AANL-化合物a | 1.8(不激活) |
C2:AAN-PABC-化合物a | 46.7 |
C3:PEG-AAN-PABC-化合物a | 51.4 |
C4:葡萄糖-AAN-PABC-化合物a | 46.7 |
C5:Lacto-AAN-PABC-紫杉醇 | 59.3 |
S3:Lacto-AAN-PABC-阿霉素 | 82.6 |
S1:Lacto-AAN-PABC-化合物a | 86.7 |
S7:Lacto-VAN-PABC-化合物a | 90.5 |
S13:Lacto-TAN-PABC-化合物a | 98.6 |
C6:AANL-化合物b | 1.6(不激活) |
C7:AAN-PABC-化合物b | 38.4 |
C8:PEG-AAN-PABC-化合物b | 51.4 |
C9:葡萄糖-l-PEG-AAN-PABC-化合物b | 16.7 |
S2:Lacto-AAN-PABC-化合物b | 88.4 |
S8:Lacto-VAN-PABC-化合物b | 93.7 |
S14:Lacto-VAN-PABC-化合物b | 99.5 |
C10:Lacto-LAN-PABC-化合物b | 2.7 |
C11:EMC-AANL-阿霉素 | 54.5 |
上述结果说明:天冬酰胺肽链内切酶对底物肽和底物肽两端的基团有结构要求,药物与不同的连接体连接对药物激活具有不同的影响:C1,C6不被激活说明,AANL连接体对化合物a,b激活无效。C2,C3,C4,C7,C8,C9激活效率比S1,S2低很多,说明与不存在Lacto相比或与PEG和Succinyl相比Lacto具有特殊构效关系,促进了整体化合物的激活。S1比C5相比,具有更高的激活效率,说明化合物a,b比紫杉醇更适用于Lacto-AAN-PABC-连接体。S1,S7,S13激活效率依次提高,而C10等其他氨基酸替代无激活,说明氨基酸筛选优化的连接体对整体药物激活具有优化的重要作用。S3与C11相比激活效率提高,说明与本发明的连接体能提高药物的激活效率。
实施例10:化合物对成药性评价中的关键数据(固体稳定性)的影响
在60℃避光放置10天,进行稳定性检测。通过HPLC检测化合物的含量变化与时间0时的化合物比例,计为稳定性数值(%)。结果如下表4所示。
表4
化合物 | 稳定性(%) |
C1:AANL-化合物a | 96.8,稳定 |
C2:AAN-PABC-化合物a | 89.4,不稳定 |
C3:PEG-AAN-PABC-化合物a | 87.2,不稳定 |
C4:葡萄糖-AAN-PABC-化合物a | 85.7,不稳定 |
C5:Lacto-AAN-PABC-紫杉醇 | 89.3,不稳定 |
S3:Lacto-AAN-PABC-阿霉素 | 99.8,稳定 |
S1:Lacto-AAN-PABC-化合物a | 96.7,稳定 |
S7:Lacto-VAN-PABC-化合物a | 97.2,稳定 |
S13:Lacto-TAN-PABC-化合物a | 98.6,稳定 |
C6:AANL-化合物b | 91.6,稳定 |
C7:AAN-PABC-化合物b | 85.6,不稳定 |
C8:PEG-AAN-PABC-化合物b | 86.5,不稳定 |
C9:葡萄糖-AAN-PABC-化合物b | 90.7,稳定 |
S2:Lacto-AAN-PABC-化合物b | 99.6,稳定 |
S8:Lacto-VAN-PABC-化合物b | 98.4,稳定 |
S14:Lacto-VAN-PABC-化合物b | 97.8,稳定 |
C10:Lacto-LAN-PABC-化合物b | 92.2,稳定 |
C11:EMC-AANL-阿霉素 | 96.5,稳定 |
上述结果说明:本公开通过将药物分子与本公开的连接体进行连接,大大提高了药物的稳定性。
实施例11:本文化合物相对于索拉菲尼和其他连接方式的药物的代谢分布
通过静脉注射10微摩每公斤剂量的药物到荷瘤小鼠中,手术获取肿瘤组织匀浆,通过HPCL方法并检测药物含量。结果如图4所示,证明化合物S1和S2相比索拉菲尼在肿瘤中的分布成倍提高,化合物S3相比C11也具有提高在肿瘤中分布的特性。
实施例12:本文化合物相对于索拉菲尼和其他连接方式的毒理
试验目的:通过测定小鼠静脉用药MTD(最大耐受剂量)实验,了解本发明分子定点靶向导致高激活化合物的急性毒性。
试验药物:试验药物如下表3所示,各药物的注射液和对照药物使用注射用水统一溶解,试验时用生理盐水稀释到相应剂量。
动物:一级巴比赛(BALB/C)小鼠(购自上海史莱克生物科技有限公司),体重19-21g,雌性。
方法和结果:受试BALB/C小鼠36只,体重19-21g,雌性,按体重随机分组,每组10只。如表3所示,按表3中不同剂量药物溶于生理盐水中,静脉注射,并纪录出现死亡时剂量和获得最大耐受剂量(MTD)。并进行生理盐水组、阿霉素组注射液(市售,北京悦康)的对照试验,每个小鼠给药体积0.2ml。连续观察17天,每日观察动物是否出现立毛树立、糟乱无光泽、昏睡、弯腰驼背、过激反应等,记录体重和死亡情况。在第3、5、14天采血样进行全血球计数,在第14天解剖动物采取心脏、肝脏、肾脏、肺、脾脏、胰腺HE染色观察。死亡率结果如下表5所示。
表5:受试小鼠分别接受不同剂量的S1,S2,S3,S4,S5和S6注射液以及生理盐水、阿霉素注射液的死亡率结果
实施例13:本文化合物相对于索拉菲尼和其他连接方式的药效
在人肝癌HepG2移植瘤模型中给予等摩尔(30umol/kg)的各药物(S1-S6、阿霉素和索拉菲尼,对照组给予生理盐水),在不同时间点测试给药后肿瘤体积大小。结果如图5所示,与阳性对照药(阿霉素和索拉菲尼)相比,化合物S1-S6给药组对肿瘤的治疗能力大大提高。这和药物设计理念中的靶向机制有关,药物在肿瘤微环境中的双靶向局部释放,因此对肿瘤的治疗能力远远优于阳性对照药。同时,S1-S6在肿瘤局部靶向释放,迅速减小荷瘤鼠的肿瘤体积,并在给药两次后,出现肿瘤消失现象。随着给药次数的增加,S1-S6给药组的荷瘤鼠均被治愈,并在停药后,没有出现肿瘤重新生长的现象。
实施例14:本文化合物相对于索拉菲尼等对照组的免疫治疗
(1)将来源于美国模式培养物集存库ATCC的D121肺癌细胞培养于含10%胎牛血清的DMEM培养基中,细胞按照常规使用含有EDTA胰蛋白酶消化,每周传代两到三次,放置于37℃,5%的CO2培养箱中培养。
(2)动物:C57BALB/C小鼠,6-8周龄,雌性,体重约18-22g,购自上海史莱克生物科技有限公司。
(3)免疫:小鼠腹腔注射100μL,数量为5×105经反复冻融死亡的D121肺癌细胞,免疫3次,每次间隔2周。
(4)细胞接种:收集对数生长期肿瘤细胞,用DMEM基础培养基调整D121细胞浓度为(1×107/ml),用1ml注射器将0.1ml细胞悬液接种于每只小鼠右侧靠近背部皮下。观察和测量肿瘤体积,平均肿瘤体积在接种后约7天达到100-200mm3,即对肿瘤细胞荷瘤鼠进行分组和给药。表9中的免疫组就是用D121肺癌细胞免疫,而无D121死肿瘤细胞免疫组注射生理盐水为对照。
(5)治疗过程:i.v.,S1~S8都使用1/6MTD的剂量,每周一次,共4周。免疫抑制调节点蛋白Anti-Pd L1抗体注射治疗每周两次。共两周。
(6)实验观察:在整个实验过程中,对实验动物的使用和观察均按照AAALAC的规定进行。实验动物在接种肿瘤细胞后,每天进行观察,记录其发病和死亡等。在常规实验过程中,对所有的实验动物进行行为、进食、摄水、体重改变、毛发光泽和其他一些异常情况的监测和记录。
(7)肿瘤CD8+T细胞(T淋巴细胞亚群)分析。肿瘤组织经过研磨,用Cell starainer40μm Nylon细胞滤网过滤分离出单个肿瘤细胞,用血细胞裂解液裂解两次,每次20min,再用1%BSA-PBS缓冲液洗两次,离心,重悬后进行细胞计数。取1×105个细胞用白细胞共同抗原CD45-PE和CD8-FITC标记的抗体在室温避光孵育1小时,然后用流式细胞仪分析白细胞共同抗原(CD45)阳性细胞中T淋巴细胞抗原(CD8)阳性细胞的比例。
(8)分组与结果测量如下表6所示。
表6
(9)结果与讨论:根据表9的数据,S1-S6化合物与溶媒和阳性对照组相比均显示出良好的抑瘤作用。而且,通过与Anti-Pd L1抗体联合治疗,都显示出了100%的抑瘤作用,优于单药治疗组,表现出非常好的协同药效。并且,联合治疗具有良好的促进免疫作用。流式细胞术分析结果显示,联合治疗组中的CD8+T细胞比例上升,导致CD8+CD45+细胞数量增多。而对照组不改变免疫治疗的效果,非靶向的阿霉素和索拉菲尼对T细胞有抑制作用。
实施例15:本文化合物相对于索拉菲尼在CT26免疫治疗模型中的新进展
1)CT26肿瘤细胞从美国模式培养物保藏所ATCC购买,细胞使用含有10%胎牛血清DMEM培养液在37℃,5%的二氧化碳条件下培养。每3天传代一次,细胞使用在15代以内。动物:C57小鼠,6-8周龄,全为雌性,购自上海斯莱克实验动物有限公司。
2)肿瘤产生:将106个活的CT26肿瘤细胞皮下注射到肿瘤免疫的C57小鼠背部,待肿瘤长至0.3~0.4cm左右时开始治疗,记录计小鼠肿瘤大小(mm3),并与溶媒对照组相比计算第42天的抑瘤率。
4)治疗过程:使用IV注射,药物都使用1/3MTD的剂量,每周一次。免疫抑IV注射治疗每周一次,共6周疗程。
5)统计每组10只中的治愈率,治愈的小鼠和野生组在50天后,再接种2*105,检测复发生长情况。
6)分组与结果测量如下表7所示。
表7
7)结果与讨论:与各对照组相比,S1,S2,S3,S7,S13,S8,S14组都出现了较高的治愈率,即将肿瘤治疗到完全消失。而后再接种CT26肿瘤细胞,野生组能够复发生长肿瘤,而S1,S2,S3,S7,S13,S8,S14治愈组肿瘤不再复发生长,说明老鼠通过药物治疗已经产生对肿瘤细胞的免疫力。S1,S7,S13治愈率提高,说明氨基酸筛选优化的连接体对整体药效具有优化的重要作用。
实施例16:本文化合物构效关系刺激免疫的机制
肿瘤相关巨噬细胞(M2型)是肿瘤生长和复发的帮凶。诱导产生炎症型巨噬细胞(M1型)和肿瘤相关巨噬细胞(M2型),并用荧光染色证明肿瘤相关巨噬细胞(M2型)高表达天冬酰胺肽链内切酶(图6)。
收集通过M-CSF(10ng/ml)由单核骨髓细胞诱导形成的肿瘤相关巨噬细胞(M2型),调整细胞悬液浓度,每孔加入140ul,铺板使待测细胞调密度~3000个/孔;5%CO2,37℃孵育过夜,至细胞单层铺满孔底(96孔平底板),再加入连续浓度梯度的给予不同浓度的药物,药物设置9个浓度梯度,每孔10ul,设3个复孔;5%CO2,37℃、pH6.5孵育48小时,倒置显微镜下观察;每孔加入20ul MTT溶液(5mg/ml,即0.5%MTT),继续培养4h。终止培养,小心吸去孔内培养液;每孔加入100ul二甲基亚砜,置摇床上低速振荡10min,使结晶物充分溶解。在酶联免疫检测仪OD490nm处测量各孔的吸光值。同时设置调零孔(培养基、MTT、二甲基亚砜),对照组(细胞、相同浓度的药物溶解介质、培养基、MTT、二甲基亚砜)。检测后对化合物对肿瘤相关巨噬细胞(M2型)的毒性进行分析。比较不同的药物对肿瘤相关巨噬细胞(M2型)的抑制,结果见图7。图7显示,含有乳糖基的药物(S1)相对其他的连接方式更容易被巨噬细胞吞噬和激活。而化合物a索拉菲尼因为不是靶向激活药物,也具有毒性。
由此可见,分子定点靶向导致高激活和高效连接体具有特殊的促进肿瘤相关巨噬细胞(M2型)吞噬和激活药物的作用,从而抑制肿瘤相关巨噬细胞(M2型)。
实施例17:化合物S4-S6、S9-S12和S15-S18在CT26治疗模型中的药效和免疫治疗
按照实施例15构建CT26免疫治疗模型,并测试化合物S4-S6、S9-S12和S15-S18在CT26治疗模型中的药效和免疫治疗效果,结果如下表8所示。
表8
结果与讨论:在CT26治疗模型中,考察了其他化合物的肿瘤抑制作用以及免疫治疗特性。从数据可以看出,与溶媒和阳性对照组相比,其他化合物也具有良好的抑瘤作用和抑制复发作用。在流式细胞术分析结果中,S7-S18化合物给药组中的CD8+T cell比例较阳性对照组也有明显上升的现象,说明分子定点靶向导致高激活和高效具有使机体免疫力增加,刺激免疫的作用。
Claims (7)
6.一种药物组合物,其特征在于,所述药物组合物含有权利要求1-5中任一项所述的化合物或其药学上可接受的盐,和药学上可接受的载体。
7.权利要求1-5中任一项所述的化合物或其药学上可接受的盐在制备治疗癌症用的药物中的应用,其中:
所述化合物中,所述药物分子为阿霉素,所述癌症选自急性白血病、恶性淋巴瘤、乳腺癌、支气管肺癌、卵巢癌、软组织肉瘤、成骨肉瘤、横纹肌肉瘤、尤文肉瘤、肾母细胞瘤、神经母细胞瘤、膀胱癌、甲状腺癌、前列腺癌、头颈部鳞癌、睾丸癌、胃癌和肝癌;或
所述化合物中,所述药物分子为达拉非尼,所述癌症为非小细胞肺癌;或
所述化合物中,所述药物分子为多韦替尼,所述癌症为肝癌、乳腺癌或前列腺癌;或
所述化合物中,所述药物分子为莫特塞尼,所述癌症为非小细胞肺癌或甲状腺癌;或
所述化合物中,所述药物分子为所述式B所示的索拉菲尼衍生物,所述癌症的患者为无法手术或肝肿瘤细胞远处转移的肝肿瘤患者、不能手术的肾肿瘤患者、或对放射性碘治疗不再有效的局部复发或转移性、逐步分化型甲状腺癌患者。
Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201710037230.9A CN108314703B (zh) | 2017-01-17 | 2017-01-17 | 分子定点靶向和激活的激酶抑制剂的制备和用途 |
EP18741988.2A EP3572420B1 (en) | 2017-01-17 | 2018-01-16 | Preparation and use of molecular site targeted and activated kinase inhibitor |
CA3050345A CA3050345A1 (en) | 2017-01-17 | 2018-01-16 | Preparation and application of molecular site-directed and activated kinase inhibitors |
AU2018209534A AU2018209534B2 (en) | 2017-01-17 | 2018-01-16 | Preparation and use of molecular site targeted and activated kinase inhibitor |
US16/478,826 US11078232B2 (en) | 2017-01-17 | 2018-01-16 | Preparation and use of molecular site targeted and activated kinase inhibitor |
PCT/CN2018/072766 WO2018133766A1 (zh) | 2017-01-17 | 2018-01-16 | 分子定点靶向和激活的激酶抑制剂的制备和用途 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201710037230.9A CN108314703B (zh) | 2017-01-17 | 2017-01-17 | 分子定点靶向和激活的激酶抑制剂的制备和用途 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN108314703A CN108314703A (zh) | 2018-07-24 |
CN108314703B true CN108314703B (zh) | 2022-02-01 |
Family
ID=62891360
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201710037230.9A Active CN108314703B (zh) | 2017-01-17 | 2017-01-17 | 分子定点靶向和激活的激酶抑制剂的制备和用途 |
Country Status (6)
Country | Link |
---|---|
US (1) | US11078232B2 (zh) |
EP (1) | EP3572420B1 (zh) |
CN (1) | CN108314703B (zh) |
AU (1) | AU2018209534B2 (zh) |
CA (1) | CA3050345A1 (zh) |
WO (1) | WO2018133766A1 (zh) |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004113274A2 (en) * | 2003-05-20 | 2004-12-29 | Bayer Pharmaceuticals Corporation | Diaryl ureas with kinase inhibiting activity |
WO2007018431A2 (en) * | 2005-08-05 | 2007-02-15 | Syntarga B.V. | Triazole-containing releasable linkers and conjugates comprising the same |
CN101259284A (zh) * | 2008-04-15 | 2008-09-10 | 华东师范大学 | 一种基于树形聚合物肝靶向抗癌纳米前药系统、制备及用途 |
CN104147612A (zh) * | 2014-08-22 | 2014-11-19 | 亚飞(上海)生物医药科技有限公司 | 一种肿瘤微环境特异激活的小分子靶向偶联体及其用途 |
WO2015189478A1 (en) * | 2014-06-13 | 2015-12-17 | Glykos Finland Oy | Payload-polymer-protein conjugates |
WO2016026458A1 (zh) * | 2014-08-22 | 2016-02-25 | 亚飞(上海)生物医药科技有限公司 | 一种肿瘤微环境特异激活的小分子靶向偶联体及其用途 |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6218519B1 (en) * | 1996-04-12 | 2001-04-17 | Pro-Neuron, Inc. | Compounds and methods for the selective treatment of cancer and bacterial infections |
EP1787661A1 (en) | 2004-09-10 | 2007-05-23 | Toray Industries, Inc. | Medicinal preparation |
WO2008115263A2 (en) * | 2007-03-20 | 2008-09-25 | Curis, Inc. | Raf kinase inhibitors containing a zinc binding moiety |
CN101732721B (zh) * | 2009-01-15 | 2012-06-13 | 中国科学技术大学 | 一种生物相容性纳米颗粒及其作为药物输送载体的应用 |
CN102863557A (zh) * | 2012-10-12 | 2013-01-09 | 苏州大学 | 乳糖酸修饰的脂肪酸-三甲基壳聚糖聚合物制备方法及应用 |
WO2015085173A1 (en) | 2013-12-05 | 2015-06-11 | Wu Nian | Polymer-carbohydrate conjugates for drug delivery technology |
CN106456799B (zh) * | 2014-06-03 | 2020-05-22 | 江苏佳瑞生物技术有限公司 | 肽-药物偶联物 |
CN104800845B (zh) * | 2015-01-28 | 2017-12-29 | 东华大学 | 一种具有肝癌细胞靶向性的二硫化钼载药纳米片的制备方法 |
CN106344930B (zh) | 2015-07-16 | 2021-08-17 | 亚飞(上海)生物医药科技有限公司 | 分子定点靶向和激活的短肽阿霉素的制备和用途 |
-
2017
- 2017-01-17 CN CN201710037230.9A patent/CN108314703B/zh active Active
-
2018
- 2018-01-16 CA CA3050345A patent/CA3050345A1/en active Pending
- 2018-01-16 EP EP18741988.2A patent/EP3572420B1/en active Active
- 2018-01-16 WO PCT/CN2018/072766 patent/WO2018133766A1/zh unknown
- 2018-01-16 AU AU2018209534A patent/AU2018209534B2/en active Active
- 2018-01-16 US US16/478,826 patent/US11078232B2/en active Active
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004113274A2 (en) * | 2003-05-20 | 2004-12-29 | Bayer Pharmaceuticals Corporation | Diaryl ureas with kinase inhibiting activity |
WO2007018431A2 (en) * | 2005-08-05 | 2007-02-15 | Syntarga B.V. | Triazole-containing releasable linkers and conjugates comprising the same |
CN101259284A (zh) * | 2008-04-15 | 2008-09-10 | 华东师范大学 | 一种基于树形聚合物肝靶向抗癌纳米前药系统、制备及用途 |
WO2015189478A1 (en) * | 2014-06-13 | 2015-12-17 | Glykos Finland Oy | Payload-polymer-protein conjugates |
CN104147612A (zh) * | 2014-08-22 | 2014-11-19 | 亚飞(上海)生物医药科技有限公司 | 一种肿瘤微环境特异激活的小分子靶向偶联体及其用途 |
WO2016026458A1 (zh) * | 2014-08-22 | 2016-02-25 | 亚飞(上海)生物医药科技有限公司 | 一种肿瘤微环境特异激活的小分子靶向偶联体及其用途 |
Non-Patent Citations (2)
Title |
---|
Site-Specific Antibody−Drug Conjugation through Glycoengineering;Qun Zhou等;《Bioconjugate Chemistry》;20140217;第25卷;第510-520页 * |
去唾液酸糖蛋白受体介导的肝肿瘤靶向载药系统研究进展;高媛悦等;《中国药科大学学报》;20161025;第47卷(第5期);第537-542页 * |
Also Published As
Publication number | Publication date |
---|---|
EP3572420A4 (en) | 2020-11-04 |
EP3572420A1 (en) | 2019-11-27 |
AU2018209534A1 (en) | 2019-08-29 |
US20200140485A1 (en) | 2020-05-07 |
AU2018209534B2 (en) | 2022-03-17 |
CA3050345A1 (en) | 2018-07-26 |
CN108314703A (zh) | 2018-07-24 |
EP3572420B1 (en) | 2022-03-09 |
US11078232B2 (en) | 2021-08-03 |
WO2018133766A1 (zh) | 2018-07-26 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN106715457B (zh) | 一种肿瘤微环境特异激活的小分子靶向偶联体及其用途 | |
WO2021164765A1 (zh) | 靶向递送和激活的免疫刺激性偶联复合物的制备和用途 | |
JP2013529218A (ja) | デューアル機能性の抱合体の化学合成及び抗腫瘍及び抗腫瘍転移作用 | |
KR20210118764A (ko) | 암의 예방 또는 치료용 약학적 조성물 | |
CN108314703B (zh) | 分子定点靶向和激活的激酶抑制剂的制备和用途 | |
US11319341B2 (en) | Immune-stimulating soluble doxorubicin-conjugated complex | |
CN109053782B (zh) | 多功能靶向免疫小分子抗癌药枸橼酸Bestazomib及其制备方法与应用 | |
JPH09511761A (ja) | 抗癌−、抗ウィルス−および植物生長抑制作用をもつ治療用カシノイド製剤 | |
CN116726192A (zh) | N-烷氧烷基取代的喜树碱衍生物的抗体偶联药物 | |
CN113603743B (zh) | 一类具有联合治疗作用的cddo/川芎嗪醇杂合物及其制备方法和用途 | |
WO2022100535A1 (zh) | 一种抗肿瘤药物组合物及其应用 | |
CN104262455B (zh) | 肿瘤微环境靶向激活的紫杉醇衍生物及其制备和用途 | |
RU2697551C2 (ru) | Новые производные peg | |
JP2016037472A (ja) | 新規セマフォリン3a阻害剤 | |
CN106344930B (zh) | 分子定点靶向和激活的短肽阿霉素的制备和用途 | |
CN111732631B (zh) | 一种多肽及其在制备治疗和预防肿瘤的药物中的应用 | |
CN114437151A (zh) | 白蛋白结合型喜树碱衍生物前药及其制备方法与应用 | |
EP4265274A1 (en) | B7-h3 targeting antibody-drug conjugate, and preparation method therefor and use thereof | |
CN117126072A (zh) | 一种含酯链pd-1/pd-l1小分子抑制剂及其制备方法和应用 | |
JP2024516217A (ja) | 腫瘍疾患の治療における医薬の使用 | |
CN117959459A (zh) | 肿瘤微环境激活的药物偶联物及抗体药物偶联物 | |
CN118252945A (zh) | 肿瘤微环境激活的药物偶联物及抗体药物偶联物 | |
KR20220131739A (ko) | 암의 예방 또는 치료용 약학적 조성물 | |
CN114642739A (zh) | 一种靶向b7-h3的抗体药物偶联物、其制备方法及应用 | |
CN116462681A (zh) | 一种光热-免疫联合治疗肿瘤的化合物及其应用 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |