CA3045037A1 - Compositions and methods for treating cdk4/6-mediated cancer - Google Patents
Compositions and methods for treating cdk4/6-mediated cancer Download PDFInfo
- Publication number
- CA3045037A1 CA3045037A1 CA3045037A CA3045037A CA3045037A1 CA 3045037 A1 CA3045037 A1 CA 3045037A1 CA 3045037 A CA3045037 A CA 3045037A CA 3045037 A CA3045037 A CA 3045037A CA 3045037 A1 CA3045037 A1 CA 3045037A1
- Authority
- CA
- Canada
- Prior art keywords
- cancer
- cdk4
- alkyl
- amino
- compound
- 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.)
- Abandoned
Links
- 238000000034 method Methods 0.000 title claims abstract description 103
- 206010028980 Neoplasm Diseases 0.000 title claims abstract description 76
- 201000011510 cancer Diseases 0.000 title claims abstract description 63
- 230000001404 mediated effect Effects 0.000 title claims abstract description 29
- 239000000203 mixture Substances 0.000 title abstract description 59
- 101100005789 Caenorhabditis elegans cdk-4 gene Proteins 0.000 title 1
- 101000715943 Caenorhabditis elegans Cyclin-dependent kinase 4 homolog Proteins 0.000 claims abstract description 199
- 150000001875 compounds Chemical class 0.000 claims description 266
- AHJRHEGDXFFMBM-UHFFFAOYSA-N palbociclib Chemical compound N1=C2N(C3CCCC3)C(=O)C(C(=O)C)=C(C)C2=CN=C1NC(N=C1)=CC=C1N1CCNCC1 AHJRHEGDXFFMBM-UHFFFAOYSA-N 0.000 claims description 95
- 229960004390 palbociclib Drugs 0.000 claims description 95
- 108010025464 Cyclin-Dependent Kinase 4 Proteins 0.000 claims description 93
- 102000013698 Cyclin-Dependent Kinase 6 Human genes 0.000 claims description 80
- 108010025468 Cyclin-Dependent Kinase 6 Proteins 0.000 claims description 80
- 229910052739 hydrogen Inorganic materials 0.000 claims description 67
- 239000001257 hydrogen Substances 0.000 claims description 64
- 125000000623 heterocyclic group Chemical group 0.000 claims description 57
- 230000015556 catabolic process Effects 0.000 claims description 56
- 238000006731 degradation reaction Methods 0.000 claims description 56
- -1 RG7338 Chemical compound 0.000 claims description 52
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 51
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 48
- UZWDCWONPYILKI-UHFFFAOYSA-N n-[5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-yl]-5-fluoro-4-(7-fluoro-2-methyl-3-propan-2-ylbenzimidazol-5-yl)pyrimidin-2-amine Chemical compound C1CN(CC)CCN1CC(C=N1)=CC=C1NC1=NC=C(F)C(C=2C=C3N(C(C)C)C(C)=NC3=C(F)C=2)=N1 UZWDCWONPYILKI-UHFFFAOYSA-N 0.000 claims description 48
- 229950001573 abemaciclib Drugs 0.000 claims description 47
- 201000001441 melanoma Diseases 0.000 claims description 44
- 208000026310 Breast neoplasm Diseases 0.000 claims description 43
- 206010006187 Breast cancer Diseases 0.000 claims description 42
- 239000003446 ligand Substances 0.000 claims description 42
- 238000011282 treatment Methods 0.000 claims description 40
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 claims description 39
- 229940124297 CDK 4/6 inhibitor Drugs 0.000 claims description 39
- 101000776133 Viola hederacea Leaf cyclotide 1 Proteins 0.000 claims description 39
- 125000004649 C2-C8 alkynyl group Chemical group 0.000 claims description 37
- 229910052757 nitrogen Inorganic materials 0.000 claims description 34
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 31
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 30
- 125000001188 haloalkyl group Chemical group 0.000 claims description 30
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 30
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 29
- 125000000217 alkyl group Chemical group 0.000 claims description 26
- 102000006275 Ubiquitin-Protein Ligases Human genes 0.000 claims description 25
- 108010083111 Ubiquitin-Protein Ligases Proteins 0.000 claims description 25
- 229910052736 halogen Inorganic materials 0.000 claims description 24
- 150000002367 halogens Chemical class 0.000 claims description 24
- 125000003545 alkoxy group Chemical group 0.000 claims description 22
- PDGKHKMBHVFCMG-UHFFFAOYSA-N 2-[[5-(4-methylpiperazin-1-yl)pyridin-2-yl]amino]spiro[7,8-dihydropyrazino[5,6]pyrrolo[1,2-d]pyrimidine-9,1'-cyclohexane]-6-one Chemical compound C1CN(C)CCN1C(C=N1)=CC=C1NC1=NC=C(C=C2N3C4(CCCCC4)CNC2=O)C3=N1 PDGKHKMBHVFCMG-UHFFFAOYSA-N 0.000 claims description 19
- RHXHGRAEPCAFML-UHFFFAOYSA-N 7-cyclopentyl-n,n-dimethyl-2-[(5-piperazin-1-ylpyridin-2-yl)amino]pyrrolo[2,3-d]pyrimidine-6-carboxamide Chemical compound N1=C2N(C3CCCC3)C(C(=O)N(C)C)=CC2=CN=C1NC(N=C1)=CC=C1N1CCNCC1 RHXHGRAEPCAFML-UHFFFAOYSA-N 0.000 claims description 19
- 229950003687 ribociclib Drugs 0.000 claims description 19
- UVSMNLNDYGZFPF-UHFFFAOYSA-N pomalidomide Chemical compound O=C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O UVSMNLNDYGZFPF-UHFFFAOYSA-N 0.000 claims description 17
- 125000003118 aryl group Chemical group 0.000 claims description 15
- 229960000688 pomalidomide Drugs 0.000 claims description 14
- 125000003003 spiro group Chemical group 0.000 claims description 14
- 238000012360 testing method Methods 0.000 claims description 14
- 229910052720 vanadium Inorganic materials 0.000 claims description 13
- ORILYTVJVMAKLC-UHFFFAOYSA-N adamantane Chemical compound C1C(C2)CC3CC1CC2C3 ORILYTVJVMAKLC-UHFFFAOYSA-N 0.000 claims description 12
- 108010038795 estrogen receptors Proteins 0.000 claims description 12
- 125000001072 heteroaryl group Chemical group 0.000 claims description 12
- 210000001519 tissue Anatomy 0.000 claims description 12
- 230000006870 function Effects 0.000 claims description 10
- YPJRHEKCFKOVRT-UHFFFAOYSA-N lerociclib Chemical compound C1CN(C(C)C)CCN1C(C=N1)=CC=C1NC1=NC=C(C=C2N3C4(CCCCC4)CNC2=O)C3=N1 YPJRHEKCFKOVRT-UHFFFAOYSA-N 0.000 claims description 10
- 229950007127 trilaciclib Drugs 0.000 claims description 10
- SGJLSPUSUBJWHO-UHFFFAOYSA-N 6-acetyl-8-cyclopentyl-5-methyl-2-[(5-piperidin-4-ylpyridin-2-yl)amino]pyrido[2,3-d]pyrimidin-7-one Chemical compound N1=C2N(C3CCCC3)C(=O)C(C(=O)C)=C(C)C2=CN=C1NC(N=C1)=CC=C1C1CCNCC1 SGJLSPUSUBJWHO-UHFFFAOYSA-N 0.000 claims description 9
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 9
- 229940075611 SHR6390 Drugs 0.000 claims description 9
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 9
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 9
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 9
- UEJJHQNACJXSKW-UHFFFAOYSA-N 2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1C1CCC(=O)NC1=O UEJJHQNACJXSKW-UHFFFAOYSA-N 0.000 claims description 8
- 230000009467 reduction Effects 0.000 claims description 8
- 229960003433 thalidomide Drugs 0.000 claims description 8
- 230000002255 enzymatic effect Effects 0.000 claims description 7
- 125000001153 fluoro group Chemical group F* 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- 241000894007 species Species 0.000 claims description 7
- 102100032783 Protein cereblon Human genes 0.000 claims description 6
- 229960004942 lenalidomide Drugs 0.000 claims description 6
- GOTYRUGSSMKFNF-UHFFFAOYSA-N lenalidomide Chemical compound C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O GOTYRUGSSMKFNF-UHFFFAOYSA-N 0.000 claims description 6
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
- UFPFGVNKHCLJJO-SSKFGXFMSA-N (2s)-n-[(1s)-1-cyclohexyl-2-[(2s)-2-[4-(4-fluorobenzoyl)-1,3-thiazol-2-yl]pyrrolidin-1-yl]-2-oxoethyl]-2-(methylamino)propanamide Chemical compound C1([C@H](NC(=O)[C@H](C)NC)C(=O)N2[C@@H](CCC2)C=2SC=C(N=2)C(=O)C=2C=CC(F)=CC=2)CCCCC1 UFPFGVNKHCLJJO-SSKFGXFMSA-N 0.000 claims description 5
- DRLCSJFKKILATL-YWCVFVGNSA-N 2-[(3r,5r,6s)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-[(2s)-3-methyl-1-propan-2-ylsulfonylbutan-2-yl]-2-oxopiperidin-3-yl]acetic acid Chemical compound C1([C@@H]2[C@H](N(C([C@@](C)(CC(O)=O)C2)=O)[C@H](CS(=O)(=O)C(C)C)C(C)C)C=2C=CC(Cl)=CC=2)=CC=CC(Cl)=C1 DRLCSJFKKILATL-YWCVFVGNSA-N 0.000 claims description 5
- BDUHCSBCVGXTJM-WUFINQPMSA-N 4-[[(4S,5R)-4,5-bis(4-chlorophenyl)-2-(4-methoxy-2-propan-2-yloxyphenyl)-4,5-dihydroimidazol-1-yl]-oxomethyl]-2-piperazinone Chemical compound CC(C)OC1=CC(OC)=CC=C1C1=N[C@@H](C=2C=CC(Cl)=CC=2)[C@@H](C=2C=CC(Cl)=CC=2)N1C(=O)N1CC(=O)NCC1 BDUHCSBCVGXTJM-WUFINQPMSA-N 0.000 claims description 5
- VGGGPCQERPFHOB-MCIONIFRSA-N Bestatin Chemical compound CC(C)C[C@H](C(O)=O)NC(=O)[C@@H](O)[C@H](N)CC1=CC=CC=C1 VGGGPCQERPFHOB-MCIONIFRSA-N 0.000 claims description 5
- VGGGPCQERPFHOB-UHFFFAOYSA-N Bestatin Natural products CC(C)CC(C(O)=O)NC(=O)C(O)C(N)CC1=CC=CC=C1 VGGGPCQERPFHOB-UHFFFAOYSA-N 0.000 claims description 5
- YJCZPJQGFSSFOL-MNZPCBJKSA-N CCN1[C@H]([C@H](C2=CC=CC(Cl)=C2F)[C@]2(C(=O)NC3=CC(Cl)=CC=C23)C11CCCCC1)C(=O)NC12CCC(CC1)(CC2)C(O)=O Chemical compound CCN1[C@H]([C@H](C2=CC=CC(Cl)=C2F)[C@]2(C(=O)NC3=CC(Cl)=CC=C23)C11CCCCC1)C(=O)NC12CCC(CC1)(CC2)C(O)=O YJCZPJQGFSSFOL-MNZPCBJKSA-N 0.000 claims description 5
- 206010017993 Gastrointestinal neoplasms Diseases 0.000 claims description 5
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 5
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 5
- QBGKPEROWUKSBK-QPPIDDCLSA-N [(4s,5r)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis(4-chlorophenyl)-4,5-dimethylimidazol-1-yl]-[4-(3-methylsulfonylpropyl)piperazin-1-yl]methanone Chemical compound CCOC1=CC(C(C)(C)C)=CC=C1C(N([C@]1(C)C=2C=CC(Cl)=CC=2)C(=O)N2CCN(CCCS(C)(=O)=O)CC2)=N[C@@]1(C)C1=CC=C(Cl)C=C1 QBGKPEROWUKSBK-QPPIDDCLSA-N 0.000 claims description 5
- 201000005202 lung cancer Diseases 0.000 claims description 5
- 208000020816 lung neoplasm Diseases 0.000 claims description 5
- UUPZYAHONNHULX-CJBSCAABSA-N methyl 1-{(2S)-2-cyclohexyl-2-[(N-methyl-L-alanyl)amino]acetyl}-L-prolyl-beta-phenyl-L-phenylalaninate Chemical compound C1([C@H](NC(=O)[C@H](C)NC)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](C(C=2C=CC=CC=2)C=2C=CC=CC=2)C(=O)OC)CCCCC1 UUPZYAHONNHULX-CJBSCAABSA-N 0.000 claims description 5
- 229950009811 ubenimex Drugs 0.000 claims description 5
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 4
- 206010025323 Lymphomas Diseases 0.000 claims description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 4
- 208000006990 cholangiocarcinoma Diseases 0.000 claims description 4
- 125000001165 hydrophobic group Chemical group 0.000 claims description 4
- 208000032839 leukemia Diseases 0.000 claims description 4
- 229920006395 saturated elastomer Polymers 0.000 claims description 4
- 238000011285 therapeutic regimen Methods 0.000 claims description 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 3
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 3
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 3
- 208000006468 Adrenal Cortex Neoplasms Diseases 0.000 claims description 3
- 206010061424 Anal cancer Diseases 0.000 claims description 3
- 208000007860 Anus Neoplasms Diseases 0.000 claims description 3
- 206010005003 Bladder cancer Diseases 0.000 claims description 3
- 206010005949 Bone cancer Diseases 0.000 claims description 3
- 208000018084 Bone neoplasm Diseases 0.000 claims description 3
- 206010006143 Brain stem glioma Diseases 0.000 claims description 3
- 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 claims description 3
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 3
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 3
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 3
- 206010009944 Colon cancer Diseases 0.000 claims description 3
- 102000012199 E3 ubiquitin-protein ligase Mdm2 Human genes 0.000 claims description 3
- 108050002772 E3 ubiquitin-protein ligase Mdm2 Proteins 0.000 claims description 3
- 102100023431 E3 ubiquitin-protein ligase TRIM21 Human genes 0.000 claims description 3
- 208000001976 Endocrine Gland Neoplasms Diseases 0.000 claims description 3
- 206010014733 Endometrial cancer Diseases 0.000 claims description 3
- 206010014759 Endometrial neoplasm Diseases 0.000 claims description 3
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims description 3
- 201000001342 Fallopian tube cancer Diseases 0.000 claims description 3
- 208000013452 Fallopian tube neoplasm Diseases 0.000 claims description 3
- 201000008808 Fibrosarcoma Diseases 0.000 claims description 3
- 208000022072 Gallbladder Neoplasms Diseases 0.000 claims description 3
- 101000685877 Homo sapiens E3 ubiquitin-protein ligase TRIM21 Proteins 0.000 claims description 3
- 208000032271 Malignant tumor of penis Diseases 0.000 claims description 3
- 206010027406 Mesothelioma Diseases 0.000 claims description 3
- 206010029260 Neuroblastoma Diseases 0.000 claims description 3
- 206010030155 Oesophageal carcinoma Diseases 0.000 claims description 3
- 206010033128 Ovarian cancer Diseases 0.000 claims description 3
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 3
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 3
- 208000000821 Parathyroid Neoplasms Diseases 0.000 claims description 3
- 208000002471 Penile Neoplasms Diseases 0.000 claims description 3
- 206010034299 Penile cancer Diseases 0.000 claims description 3
- 208000007913 Pituitary Neoplasms Diseases 0.000 claims description 3
- 206010060862 Prostate cancer Diseases 0.000 claims description 3
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 3
- 208000015634 Rectal Neoplasms Diseases 0.000 claims description 3
- 201000000582 Retinoblastoma Diseases 0.000 claims description 3
- 206010039491 Sarcoma Diseases 0.000 claims description 3
- 208000000453 Skin Neoplasms Diseases 0.000 claims description 3
- 208000021712 Soft tissue sarcoma Diseases 0.000 claims description 3
- 108091007283 TRIM24 Proteins 0.000 claims description 3
- 208000024313 Testicular Neoplasms Diseases 0.000 claims description 3
- 206010057644 Testis cancer Diseases 0.000 claims description 3
- 208000024770 Thyroid neoplasm Diseases 0.000 claims description 3
- 206010046431 Urethral cancer Diseases 0.000 claims description 3
- 206010046458 Urethral neoplasms Diseases 0.000 claims description 3
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 3
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 3
- 208000002495 Uterine Neoplasms Diseases 0.000 claims description 3
- 206010047741 Vulval cancer Diseases 0.000 claims description 3
- 208000004354 Vulvar Neoplasms Diseases 0.000 claims description 3
- 125000002015 acyclic group Chemical group 0.000 claims description 3
- 150000001408 amides Chemical class 0.000 claims description 3
- 201000011165 anus cancer Diseases 0.000 claims description 3
- 239000004202 carbamide Substances 0.000 claims description 3
- 150000001721 carbon Chemical class 0.000 claims description 3
- 208000025997 central nervous system neoplasm Diseases 0.000 claims description 3
- 201000010881 cervical cancer Diseases 0.000 claims description 3
- 238000002512 chemotherapy Methods 0.000 claims description 3
- 208000029742 colonic neoplasm Diseases 0.000 claims description 3
- 125000004122 cyclic group Chemical group 0.000 claims description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 3
- 201000004101 esophageal cancer Diseases 0.000 claims description 3
- 201000010175 gallbladder cancer Diseases 0.000 claims description 3
- 201000010536 head and neck cancer Diseases 0.000 claims description 3
- 208000014829 head and neck neoplasm Diseases 0.000 claims description 3
- 125000005842 heteroatom Chemical group 0.000 claims description 3
- 238000001794 hormone therapy Methods 0.000 claims description 3
- 208000029559 malignant endocrine neoplasm Diseases 0.000 claims description 3
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 3
- 208000026045 malignant tumor of parathyroid gland Diseases 0.000 claims description 3
- SBOJXQVPLKSXOG-UHFFFAOYSA-N o-amino-hydroxylamine Chemical compound NON SBOJXQVPLKSXOG-UHFFFAOYSA-N 0.000 claims description 3
- 201000002528 pancreatic cancer Diseases 0.000 claims description 3
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 3
- 201000002511 pituitary cancer Diseases 0.000 claims description 3
- 238000001959 radiotherapy Methods 0.000 claims description 3
- 206010038038 rectal cancer Diseases 0.000 claims description 3
- 201000001275 rectum cancer Diseases 0.000 claims description 3
- 201000000849 skin cancer Diseases 0.000 claims description 3
- 238000001356 surgical procedure Methods 0.000 claims description 3
- 201000003120 testicular cancer Diseases 0.000 claims description 3
- 201000002510 thyroid cancer Diseases 0.000 claims description 3
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 3
- 206010046766 uterine cancer Diseases 0.000 claims description 3
- 206010046885 vaginal cancer Diseases 0.000 claims description 3
- 208000013139 vaginal neoplasm Diseases 0.000 claims description 3
- 201000005102 vulva cancer Diseases 0.000 claims description 3
- 208000034578 Multiple myelomas Diseases 0.000 claims description 2
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 2
- 208000006265 Renal cell carcinoma Diseases 0.000 claims description 2
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 2
- 201000005188 adrenal gland cancer Diseases 0.000 claims description 2
- 208000024447 adrenal gland neoplasm Diseases 0.000 claims description 2
- 206010017758 gastric cancer Diseases 0.000 claims description 2
- 206010073071 hepatocellular carcinoma Diseases 0.000 claims description 2
- 238000009169 immunotherapy Methods 0.000 claims description 2
- 208000014018 liver neoplasm Diseases 0.000 claims description 2
- 208000015347 renal cell adenocarcinoma Diseases 0.000 claims description 2
- 201000011549 stomach cancer Diseases 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 21
- 102000013701 Cyclin-Dependent Kinase 4 Human genes 0.000 claims 15
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims 1
- CAICZZJHNJHHDJ-UHFFFAOYSA-N 1-(4,4,5,5,5-pentafluoropentylsulfinyl)nonane Chemical compound CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F CAICZZJHNJHHDJ-UHFFFAOYSA-N 0.000 claims 1
- 102100038595 Estrogen receptor Human genes 0.000 claims 1
- 239000001064 degrader Substances 0.000 abstract description 54
- 150000003384 small molecules Chemical class 0.000 abstract description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 234
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 123
- 210000004027 cell Anatomy 0.000 description 114
- 239000007787 solid Substances 0.000 description 108
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 99
- 239000000243 solution Substances 0.000 description 81
- 102100036252 Cyclin-dependent kinase 4 Human genes 0.000 description 78
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 77
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 76
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 75
- 230000000694 effects Effects 0.000 description 65
- 238000005481 NMR spectroscopy Methods 0.000 description 55
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 53
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 51
- 230000014509 gene expression Effects 0.000 description 50
- 238000003786 synthesis reaction Methods 0.000 description 47
- 230000015572 biosynthetic process Effects 0.000 description 46
- 238000006243 chemical reaction Methods 0.000 description 45
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 45
- VLJNHYLEOZPXFW-UHFFFAOYSA-N pyrrolidine-2-carboxamide Chemical compound NC(=O)C1CCCN1 VLJNHYLEOZPXFW-UHFFFAOYSA-N 0.000 description 45
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 44
- 239000012317 TBTU Substances 0.000 description 43
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 description 43
- 230000002829 reductive effect Effects 0.000 description 41
- 238000002953 preparative HPLC Methods 0.000 description 40
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 38
- 201000010099 disease Diseases 0.000 description 35
- 238000002360 preparation method Methods 0.000 description 35
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 31
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 31
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 29
- 230000002401 inhibitory effect Effects 0.000 description 29
- 108010068192 Cyclin A Proteins 0.000 description 27
- 102100025191 Cyclin-A2 Human genes 0.000 description 27
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 27
- 238000003756 stirring Methods 0.000 description 26
- 102000007469 Actins Human genes 0.000 description 24
- 108010085238 Actins Proteins 0.000 description 24
- 102100031463 Serine/threonine-protein kinase PLK1 Human genes 0.000 description 24
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 24
- 239000008194 pharmaceutical composition Substances 0.000 description 24
- 108010056274 polo-like kinase 1 Proteins 0.000 description 24
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 23
- FPIRBHDGWMWJEP-UHFFFAOYSA-N 1-hydroxy-7-azabenzotriazole Chemical compound C1=CN=C2N(O)N=NC2=C1 FPIRBHDGWMWJEP-UHFFFAOYSA-N 0.000 description 22
- 108090000623 proteins and genes Proteins 0.000 description 21
- 239000003112 inhibitor Substances 0.000 description 20
- 102000004169 proteins and genes Human genes 0.000 description 20
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 19
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 description 19
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 18
- 125000000336 imidazol-5-yl group Chemical group [H]N1C([H])=NC([H])=C1[*] 0.000 description 18
- 230000026731 phosphorylation Effects 0.000 description 17
- 238000006366 phosphorylation reaction Methods 0.000 description 17
- 239000000047 product Substances 0.000 description 16
- 239000011541 reaction mixture Substances 0.000 description 16
- 239000002904 solvent Substances 0.000 description 16
- 238000001262 western blot Methods 0.000 description 16
- 102220497176 Small vasohibin-binding protein_T47D_mutation Human genes 0.000 description 15
- 239000002253 acid Substances 0.000 description 14
- 230000001965 increasing effect Effects 0.000 description 14
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 14
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 14
- 208000024891 symptom Diseases 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 13
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 13
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 13
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 13
- 239000003814 drug Substances 0.000 description 13
- 238000000132 electrospray ionisation Methods 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 230000003247 decreasing effect Effects 0.000 description 12
- 238000004949 mass spectrometry Methods 0.000 description 12
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 11
- 102000015694 estrogen receptors Human genes 0.000 description 11
- 235000002639 sodium chloride Nutrition 0.000 description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 10
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 10
- DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 description 10
- 235000019260 propionic acid Nutrition 0.000 description 10
- 230000004663 cell proliferation Effects 0.000 description 9
- 239000003795 chemical substances by application Substances 0.000 description 9
- 239000012528 membrane Substances 0.000 description 9
- 108020004999 messenger RNA Proteins 0.000 description 9
- 238000010992 reflux Methods 0.000 description 9
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 9
- 238000010798 ubiquitination Methods 0.000 description 9
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 230000009702 cancer cell proliferation Effects 0.000 description 8
- 229940079593 drug Drugs 0.000 description 8
- 201000007281 estrogen-receptor positive breast cancer Diseases 0.000 description 8
- 238000011865 proteolysis targeting chimera technique Methods 0.000 description 8
- 150000003839 salts Chemical class 0.000 description 8
- 108010026668 snake venom protein C activator Proteins 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- 230000008685 targeting Effects 0.000 description 8
- 230000034512 ubiquitination Effects 0.000 description 8
- 235000019253 formic acid Nutrition 0.000 description 7
- 230000000155 isotopic effect Effects 0.000 description 7
- 239000003921 oil Substances 0.000 description 7
- 235000019198 oils Nutrition 0.000 description 7
- KNCYXPMJDCCGSJ-UHFFFAOYSA-N piperidine-2,6-dione Chemical compound O=C1CCCC(=O)N1 KNCYXPMJDCCGSJ-UHFFFAOYSA-N 0.000 description 7
- 230000002265 prevention Effects 0.000 description 7
- NHOWDZOIZKMVAI-UHFFFAOYSA-N (2-chlorophenyl)(4-chlorophenyl)pyrimidin-5-ylmethanol Chemical compound C=1N=CN=CC=1C(C=1C(=CC=CC=1)Cl)(O)C1=CC=C(Cl)C=C1 NHOWDZOIZKMVAI-UHFFFAOYSA-N 0.000 description 6
- ZWVMLYRJXORSEP-LURJTMIESA-N (2s)-hexane-1,2,6-triol Chemical compound OCCCC[C@H](O)CO ZWVMLYRJXORSEP-LURJTMIESA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 101100134922 Gallus gallus COR5 gene Proteins 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 230000006369 cell cycle progression Effects 0.000 description 6
- 239000002552 dosage form Substances 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 6
- 229920000136 polysorbate Polymers 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 230000017854 proteolysis Effects 0.000 description 6
- 239000007858 starting material Substances 0.000 description 6
- 230000001225 therapeutic effect Effects 0.000 description 6
- OVHHNKPYYVQCLN-LJQANCHMSA-N (2r)-4-(6-chloronaphthalen-2-yl)sulfonyl-1-(5-methyl-6,7-dihydro-4h-[1,3]thiazolo[5,4-c]pyridine-2-carbonyl)piperazine-2-carboxamide Chemical compound C1=C(Cl)C=CC2=CC(S(=O)(=O)N3CCN([C@H](C3)C(N)=O)C(=O)C3=NC=4CCN(CC=4S3)C)=CC=C21 OVHHNKPYYVQCLN-LJQANCHMSA-N 0.000 description 5
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 5
- 239000004471 Glycine Substances 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 238000013459 approach Methods 0.000 description 5
- 239000000872 buffer Substances 0.000 description 5
- 230000002209 hydrophobic effect Effects 0.000 description 5
- 238000001727 in vivo Methods 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 5
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Substances [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 5
- 125000001325 propanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 description 5
- 210000004881 tumor cell Anatomy 0.000 description 5
- 239000003981 vehicle Substances 0.000 description 5
- WOVKYSAHUYNSMH-RRKCRQDMSA-N 5-bromodeoxyuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(Br)=C1 WOVKYSAHUYNSMH-RRKCRQDMSA-N 0.000 description 4
- 101150041968 CDC13 gene Proteins 0.000 description 4
- 101100295741 Gallus gallus COR4 gene Proteins 0.000 description 4
- 101100533874 Hypocrea jecorina (strain QM6a) sor5 gene Proteins 0.000 description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
- 102000004245 Proteasome Endopeptidase Complex Human genes 0.000 description 4
- 108090000708 Proteasome Endopeptidase Complex Proteins 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 108090000848 Ubiquitin Proteins 0.000 description 4
- 102000044159 Ubiquitin Human genes 0.000 description 4
- 239000002671 adjuvant Substances 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- 125000005605 benzo group Chemical group 0.000 description 4
- 230000000903 blocking effect Effects 0.000 description 4
- 230000003197 catalytic effect Effects 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 230000000875 corresponding effect Effects 0.000 description 4
- 239000002270 dispersing agent Substances 0.000 description 4
- 239000003937 drug carrier Substances 0.000 description 4
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 4
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 4
- 230000036961 partial effect Effects 0.000 description 4
- 229920001223 polyethylene glycol Polymers 0.000 description 4
- 239000000651 prodrug Substances 0.000 description 4
- 229940002612 prodrug Drugs 0.000 description 4
- 230000011664 signaling Effects 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- 125000003762 3,4-dimethoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 3
- WWZKQHOCKIZLMA-UHFFFAOYSA-N Caprylic acid Natural products CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 3
- 102000036364 Cullin Ring E3 Ligases Human genes 0.000 description 3
- 108091007045 Cullin Ring E3 Ligases Proteins 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 3
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 3
- 230000018199 S phase Effects 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 239000002246 antineoplastic agent Substances 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 230000010261 cell growth Effects 0.000 description 3
- 238000009643 clonogenic assay Methods 0.000 description 3
- 231100000096 clonogenic assay Toxicity 0.000 description 3
- 238000003235 crystal violet staining Methods 0.000 description 3
- 229940127089 cytotoxic agent Drugs 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 230000012010 growth Effects 0.000 description 3
- 230000001939 inductive effect Effects 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- 238000000111 isothermal titration calorimetry Methods 0.000 description 3
- 201000010893 malignant breast melanoma Diseases 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 235000013336 milk Nutrition 0.000 description 3
- 239000008267 milk Substances 0.000 description 3
- 210000004080 milk Anatomy 0.000 description 3
- 201000005962 mycosis fungoides Diseases 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 230000003000 nontoxic effect Effects 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 235000021317 phosphate Nutrition 0.000 description 3
- 235000015320 potassium carbonate Nutrition 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 239000012453 solvate Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- 230000035899 viability Effects 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- BHAZPMLHPHZMLG-UHFFFAOYSA-N 2-(4-methoxycarbonylpiperidin-1-yl)acetic acid Chemical compound COC(=O)C1CCN(CC(O)=O)CC1 BHAZPMLHPHZMLG-UHFFFAOYSA-N 0.000 description 2
- HCDMJFOHIXMBOV-UHFFFAOYSA-N 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-4,7-dihydropyrrolo[4,5]pyrido[1,2-d]pyrimidin-2-one Chemical compound C=1C2=C3N(CC)C(=O)N(C=4C(=C(OC)C=C(OC)C=4F)F)CC3=CN=C2NC=1CN1CCOCC1 HCDMJFOHIXMBOV-UHFFFAOYSA-N 0.000 description 2
- 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 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- 206010003571 Astrocytoma Diseases 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-NJFSPNSNSA-N Carbon-14 Chemical compound [14C] OKTJSMMVPCPJKN-NJFSPNSNSA-N 0.000 description 2
- 108020004635 Complementary DNA Proteins 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- 102000003903 Cyclin-dependent kinases Human genes 0.000 description 2
- 108090000266 Cyclin-dependent kinases Proteins 0.000 description 2
- 229920000858 Cyclodextrin Polymers 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 208000032612 Glial tumor Diseases 0.000 description 2
- 206010018338 Glioma Diseases 0.000 description 2
- 102100031181 Glyceraldehyde-3-phosphate dehydrogenase Human genes 0.000 description 2
- 101000941994 Homo sapiens Protein cereblon Proteins 0.000 description 2
- 101100533888 Hypocrea jecorina (strain QM6a) sor4 gene Proteins 0.000 description 2
- 101100533877 Hypocrea jecorina (strain QM6a) sor8 gene Proteins 0.000 description 2
- 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 2
- 208000031671 Large B-Cell Diffuse Lymphoma Diseases 0.000 description 2
- 102000003960 Ligases Human genes 0.000 description 2
- 108090000364 Ligases Proteins 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 206010027476 Metastases Diseases 0.000 description 2
- 101000881330 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) Dynein heavy chain, cytoplasmic Proteins 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 2
- 238000010222 PCR analysis Methods 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 238000011529 RT qPCR Methods 0.000 description 2
- SKZKKFZAGNVIMN-UHFFFAOYSA-N Salicilamide Chemical compound NC(=O)C1=CC=CC=C1O SKZKKFZAGNVIMN-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 108091027967 Small hairpin RNA Proteins 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 description 2
- 229910052776 Thorium Inorganic materials 0.000 description 2
- 239000007983 Tris buffer Substances 0.000 description 2
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 239000007900 aqueous suspension Substances 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 238000010804 cDNA synthesis Methods 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 208000002458 carcinoid tumor Diseases 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 239000002299 complementary DNA Substances 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 206010012818 diffuse large B-cell lymphoma Diseases 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 230000008034 disappearance Effects 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 230000009977 dual effect Effects 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 238000009261 endocrine therapy Methods 0.000 description 2
- 229940034984 endocrine therapy antineoplastic and immunomodulating agent Drugs 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 230000029142 excretion Effects 0.000 description 2
- 235000013861 fat-free Nutrition 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- 201000003444 follicular lymphoma Diseases 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 2
- 229960005277 gemcitabine Drugs 0.000 description 2
- 238000003209 gene knockout Methods 0.000 description 2
- 108020004445 glyceraldehyde-3-phosphate dehydrogenase Proteins 0.000 description 2
- 125000005456 glyceride group Chemical group 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 230000028993 immune response Effects 0.000 description 2
- 238000003119 immunoblot Methods 0.000 description 2
- 238000001114 immunoprecipitation Methods 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000010348 incorporation Methods 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 230000002503 metabolic effect Effects 0.000 description 2
- 230000009401 metastasis Effects 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 239000000346 nonvolatile oil Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 229960005141 piperazine Drugs 0.000 description 2
- IVXQBCUBSIPQGU-UHFFFAOYSA-N piperazine-1-carboxamide Chemical compound NC(=O)N1CCNCC1 IVXQBCUBSIPQGU-UHFFFAOYSA-N 0.000 description 2
- CXWQAPHDSYDHBR-UHFFFAOYSA-N piperidine-4-carboxamide Chemical compound NC(=O)C1CCNCC1.NC(=O)C1CCNCC1 CXWQAPHDSYDHBR-UHFFFAOYSA-N 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 229940124823 proteolysis targeting chimeric molecule Drugs 0.000 description 2
- 238000005956 quaternization reaction Methods 0.000 description 2
- 230000002285 radioactive effect Effects 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 230000008684 selective degradation Effects 0.000 description 2
- 238000009097 single-agent therapy Methods 0.000 description 2
- 239000004055 small Interfering RNA Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- 238000002198 surface plasmon resonance spectroscopy Methods 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 229960004964 temozolomide Drugs 0.000 description 2
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Natural products C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 2
- 208000008732 thymoma Diseases 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
- 238000013518 transcription Methods 0.000 description 2
- 230000035897 transcription Effects 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- 230000007704 transition Effects 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- 239000011534 wash buffer Substances 0.000 description 2
- NXLNNXIXOYSCMB-UHFFFAOYSA-N (4-nitrophenyl) carbonochloridate Chemical compound [O-][N+](=O)C1=CC=C(OC(Cl)=O)C=C1 NXLNNXIXOYSCMB-UHFFFAOYSA-N 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- WTXXSZUATXIAJO-OWBHPGMISA-N (Z)-14-methylpentadec-2-enoic acid Chemical compound CC(CCCCCCCCCC\C=C/C(=O)O)C WTXXSZUATXIAJO-OWBHPGMISA-N 0.000 description 1
- LQVYKEXVMZXOAH-OWOJBTEDSA-N (e)-oct-4-enedioic acid Chemical compound OC(=O)CC\C=C\CCC(O)=O LQVYKEXVMZXOAH-OWOJBTEDSA-N 0.000 description 1
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 1
- 125000001607 1,2,3-triazol-1-yl group Chemical group [*]N1N=NC([H])=C1[H] 0.000 description 1
- 125000001359 1,2,3-triazol-4-yl group Chemical group [H]N1N=NC([*])=C1[H] 0.000 description 1
- KZRAKSCBDFIHPR-UHFFFAOYSA-N 1,8-dihydropyrido[2,3-d]pyrimidine-2,7-dione Chemical compound C1=CC(=O)NC2=NC(O)=NC=C21 KZRAKSCBDFIHPR-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- CHHHXKFHOYLYRE-UHFFFAOYSA-M 2,4-Hexadienoic acid, potassium salt (1:1), (2E,4E)- Chemical compound [K+].CC=CC=CC([O-])=O CHHHXKFHOYLYRE-UHFFFAOYSA-M 0.000 description 1
- PMKKIDFHWBBGDA-UHFFFAOYSA-N 2-(2,5-dioxopyrrol-1-yl)ethyl methanesulfonate Chemical compound CS(=O)(=O)OCCN1C(=O)C=CC1=O PMKKIDFHWBBGDA-UHFFFAOYSA-N 0.000 description 1
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 1
- QKNFFJHHPCWXTH-UHFFFAOYSA-N 2-(methylamino)propanamide Chemical compound CNC(C)C(N)=O QKNFFJHHPCWXTH-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- SLWIPPZWFZGHEU-UHFFFAOYSA-N 2-[4-(carboxymethyl)phenyl]acetic acid Chemical compound OC(=O)CC1=CC=C(CC(O)=O)C=C1 SLWIPPZWFZGHEU-UHFFFAOYSA-N 0.000 description 1
- ZTTWQKYKGNLCCA-UHFFFAOYSA-N 2-methyl-10H-thieno[2,3-b][1,5]benzodiazepin-4-amine Chemical compound N1C2=CC=CC=C2N=C(N)C2=C1SC(C)=C2 ZTTWQKYKGNLCCA-UHFFFAOYSA-N 0.000 description 1
- 229940080296 2-naphthalenesulfonate Drugs 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- FOSIWKADJDNVMJ-UHFFFAOYSA-N 3-(2-carboxyethoxy)propanoic acid Chemical compound OC(=O)CCOCCC(O)=O FOSIWKADJDNVMJ-UHFFFAOYSA-N 0.000 description 1
- LYWTUUBOXDYLNV-UHFFFAOYSA-N 3-(4-bromo-3-oxo-1H-isoindol-2-yl)piperidine-2,6-dione Chemical compound BrC=1C=CC=C2CN(C(C=12)=O)C1C(NC(CC1)=O)=O LYWTUUBOXDYLNV-UHFFFAOYSA-N 0.000 description 1
- MNBBVQMRQVKNLZ-UHFFFAOYSA-N 3-[7-[tert-butyl(dimethyl)silyl]oxy-3-oxo-1H-isoindol-2-yl]piperidine-2,6-dione Chemical compound [Si](C)(C)(C(C)(C)C)OC1=C2CN(C(C2=CC=C1)=O)C1C(NC(CC1)=O)=O MNBBVQMRQVKNLZ-UHFFFAOYSA-N 0.000 description 1
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 description 1
- NVRVNSHHLPQGCU-UHFFFAOYSA-N 6-bromohexanoic acid Chemical compound OC(=O)CCCCCBr NVRVNSHHLPQGCU-UHFFFAOYSA-N 0.000 description 1
- BKJFDZSBZWHRNH-UHFFFAOYSA-N 8-bromooctanoic acid Chemical compound OC(=O)CCCCCCCBr BKJFDZSBZWHRNH-UHFFFAOYSA-N 0.000 description 1
- KOVPXZDUVJGGFU-UHFFFAOYSA-N 8-methoxy-8-oxooctanoic acid Chemical compound COC(=O)CCCCCCC(O)=O KOVPXZDUVJGGFU-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 1
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 1
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 1
- 102100022524 Alpha-1-antichymotrypsin Human genes 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 208000034048 Asymptomatic disease Diseases 0.000 description 1
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 1
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 1
- 206010004146 Basal cell carcinoma Diseases 0.000 description 1
- 206010004593 Bile duct cancer Diseases 0.000 description 1
- 108010017384 Blood Proteins Proteins 0.000 description 1
- 102000004506 Blood Proteins Human genes 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 238000010599 BrdU assay Methods 0.000 description 1
- 208000011691 Burkitt lymphomas Diseases 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 1
- 102000015367 CRBN Human genes 0.000 description 1
- 101100205030 Caenorhabditis elegans hars-1 gene Proteins 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 1
- 208000010833 Chronic myeloid leukaemia Diseases 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
- 108010024986 Cyclin-Dependent Kinase 2 Proteins 0.000 description 1
- 102100036239 Cyclin-dependent kinase 2 Human genes 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
- 239000012624 DNA alkylating agent Substances 0.000 description 1
- 229940126161 DNA alkylating agent Drugs 0.000 description 1
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 101100440695 Dictyostelium discoideum corB gene Proteins 0.000 description 1
- RPNUMPOLZDHAAY-UHFFFAOYSA-N Diethylenetriamine Chemical compound NCCNCCN RPNUMPOLZDHAAY-UHFFFAOYSA-N 0.000 description 1
- QEVGZEDELICMKH-UHFFFAOYSA-N Diglycolic acid Chemical compound OC(=O)COCC(O)=O QEVGZEDELICMKH-UHFFFAOYSA-N 0.000 description 1
- 101100338242 Drosophila virilis His1.1 gene Proteins 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 102000019274 E2F Family Human genes 0.000 description 1
- 108050006730 E2F Family Proteins 0.000 description 1
- 206010014967 Ependymoma Diseases 0.000 description 1
- 108700039887 Essential Genes Proteins 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 240000002989 Euphorbia neriifolia Species 0.000 description 1
- 208000006168 Ewing Sarcoma Diseases 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- AEMRFAOFKBGASW-UHFFFAOYSA-M Glycolate Chemical compound OCC([O-])=O AEMRFAOFKBGASW-UHFFFAOYSA-M 0.000 description 1
- 101710113864 Heat shock protein 90 Proteins 0.000 description 1
- 102100034051 Heat shock protein HSP 90-alpha Human genes 0.000 description 1
- 208000017604 Hodgkin disease Diseases 0.000 description 1
- 208000021519 Hodgkin lymphoma Diseases 0.000 description 1
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 1
- 101000678026 Homo sapiens Alpha-1-antichymotrypsin Proteins 0.000 description 1
- 101000777670 Homo sapiens Hsp90 co-chaperone Cdc37 Proteins 0.000 description 1
- 101001059454 Homo sapiens Serine/threonine-protein kinase MARK2 Proteins 0.000 description 1
- 102100031568 Hsp90 co-chaperone Cdc37 Human genes 0.000 description 1
- 102000008100 Human Serum Albumin Human genes 0.000 description 1
- 108091006905 Human Serum Albumin Proteins 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 1
- 101100203602 Hypocrea jecorina (strain QM6a) sor7 gene Proteins 0.000 description 1
- 206010021042 Hypopharyngeal cancer Diseases 0.000 description 1
- 206010056305 Hypopharyngeal neoplasm Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 208000025814 Inflammatory myopathy with abundant macrophages Diseases 0.000 description 1
- 208000007766 Kaposi sarcoma Diseases 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 206010023825 Laryngeal cancer Diseases 0.000 description 1
- 229910013470 LiC1 Inorganic materials 0.000 description 1
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 208000006644 Malignant Fibrous Histiocytoma Diseases 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 208000000172 Medulloblastoma Diseases 0.000 description 1
- 208000002030 Merkel cell carcinoma Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 108010006519 Molecular Chaperones Proteins 0.000 description 1
- 102000005431 Molecular Chaperones Human genes 0.000 description 1
- 101100240353 Mus musculus Nectin4 gene Proteins 0.000 description 1
- 101100539936 Mus musculus Utp20 gene Proteins 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 201000003793 Myelodysplastic syndrome Diseases 0.000 description 1
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 1
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 1
- 208000014767 Myeloproliferative disease Diseases 0.000 description 1
- 201000007224 Myeloproliferative neoplasm Diseases 0.000 description 1
- XOZQHKWULUWUMD-VPHXOMNUSA-N N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide Chemical compound N1C(CCC1)C(=O)N[C@@H](C)C1=CC=C(C=C1)C1=C(N=CS1)C XOZQHKWULUWUMD-VPHXOMNUSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- 208000001894 Nasopharyngeal Neoplasms Diseases 0.000 description 1
- 206010061306 Nasopharyngeal cancer Diseases 0.000 description 1
- 208000034176 Neoplasms, Germ Cell and Embryonal Diseases 0.000 description 1
- 206010029266 Neuroendocrine carcinoma of the skin Diseases 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 239000000020 Nitrocellulose Substances 0.000 description 1
- DRVDCRHDWPKWOS-VPHXOMNUSA-N ON1C(CCC1)C(=O)N[C@@H](C)C1=CC=C(C=C1)C1=C(N=CS1)C Chemical compound ON1C(CCC1)C(=O)N[C@@H](C)C1=CC=C(C=C1)C1=C(N=CS1)C DRVDCRHDWPKWOS-VPHXOMNUSA-N 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 108091034117 Oligonucleotide Proteins 0.000 description 1
- 206010031096 Oropharyngeal cancer Diseases 0.000 description 1
- 206010057444 Oropharyngeal neoplasm Diseases 0.000 description 1
- YIKSCQDJHCMVMK-UHFFFAOYSA-N Oxamide Chemical compound NC(=O)C(N)=O YIKSCQDJHCMVMK-UHFFFAOYSA-N 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 201000008199 Pleuropulmonary blastoma Diseases 0.000 description 1
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 102000007327 Protamines Human genes 0.000 description 1
- 108010007568 Protamines Proteins 0.000 description 1
- 229940079156 Proteasome inhibitor Drugs 0.000 description 1
- 238000011530 RNeasy Mini Kit Methods 0.000 description 1
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 1
- 208000004337 Salivary Gland Neoplasms Diseases 0.000 description 1
- 206010061934 Salivary gland cancer Diseases 0.000 description 1
- 102100028904 Serine/threonine-protein kinase MARK2 Human genes 0.000 description 1
- 208000009359 Sezary Syndrome Diseases 0.000 description 1
- 208000021388 Sezary disease Diseases 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 208000031673 T-Cell Cutaneous Lymphoma Diseases 0.000 description 1
- 201000009365 Thymic carcinoma Diseases 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- 208000015778 Undifferentiated pleomorphic sarcoma Diseases 0.000 description 1
- 208000033559 Waldenström macroglobulinemia Diseases 0.000 description 1
- 208000008383 Wilms tumor Diseases 0.000 description 1
- 230000001594 aberrant effect Effects 0.000 description 1
- 239000003070 absorption delaying agent Substances 0.000 description 1
- 229940124532 absorption promoter Drugs 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 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
- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000009056 active transport Effects 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- WNLRTRBMVRJNCN-UHFFFAOYSA-L adipate(2-) Chemical compound [O-]C(=O)CCCCC([O-])=O WNLRTRBMVRJNCN-UHFFFAOYSA-L 0.000 description 1
- 101150019302 alkA gene Proteins 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- OBETXYAYXDNJHR-UHFFFAOYSA-N alpha-ethylcaproic acid Natural products CCCCC(CC)C(O)=O OBETXYAYXDNJHR-UHFFFAOYSA-N 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- CEGOLXSVJUTHNZ-UHFFFAOYSA-K aluminium tristearate Chemical compound [Al+3].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CEGOLXSVJUTHNZ-UHFFFAOYSA-K 0.000 description 1
- 229940063655 aluminum stearate Drugs 0.000 description 1
- 230000001668 ameliorated effect Effects 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 238000009175 antibody therapy Methods 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 229940127079 antineoplastic immunimodulatory agent Drugs 0.000 description 1
- 239000003886 aromatase inhibitor Substances 0.000 description 1
- 229940046844 aromatase inhibitors Drugs 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 235000013871 bee wax Nutrition 0.000 description 1
- 239000012166 beeswax Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 description 1
- GONOPSZTUGRENK-UHFFFAOYSA-N benzyl(trichloro)silane Chemical compound Cl[Si](Cl)(Cl)CC1=CC=CC=C1 GONOPSZTUGRENK-UHFFFAOYSA-N 0.000 description 1
- 208000026900 bile duct neoplasm Diseases 0.000 description 1
- OWMVSZAMULFTJU-UHFFFAOYSA-N bis-tris Chemical compound OCCN(CCO)C(CO)(CO)CO OWMVSZAMULFTJU-UHFFFAOYSA-N 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000000133 brain stem Anatomy 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 201000002143 bronchus adenoma Diseases 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 150000003857 carboxamides Chemical class 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 238000000423 cell based assay Methods 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- 239000013592 cell lysate Substances 0.000 description 1
- 238000001516 cell proliferation assay Methods 0.000 description 1
- 238000002737 cell proliferation kit Methods 0.000 description 1
- 238000003570 cell viability assay Methods 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
- 235000010980 cellulose Nutrition 0.000 description 1
- 208000030239 cerebral astrocytoma Diseases 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 239000008119 colloidal silica Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 229940125833 compound 23 Drugs 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 210000004748 cultured cell Anatomy 0.000 description 1
- 201000007241 cutaneous T cell lymphoma Diseases 0.000 description 1
- 208000017763 cutaneous neuroendocrine carcinoma Diseases 0.000 description 1
- 229940044533 cyclin-dependent kinase 4/6 inhibitor Drugs 0.000 description 1
- 239000012643 cyclin-dependent kinase 4/6 inhibitor Substances 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 229940097362 cyclodextrins Drugs 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- OWZREIFADZCYQD-NSHGMRRFSA-N deltamethrin Chemical compound CC1(C)[C@@H](C=C(Br)Br)[C@H]1C(=O)O[C@H](C#N)C1=CC=CC(OC=2C=CC=CC=2)=C1 OWZREIFADZCYQD-NSHGMRRFSA-N 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 230000001066 destructive effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- GXGAKHNRMVGRPK-UHFFFAOYSA-N dimagnesium;dioxido-bis[[oxido(oxo)silyl]oxy]silane Chemical compound [Mg+2].[Mg+2].[O-][Si](=O)O[Si]([O-])([O-])O[Si]([O-])=O GXGAKHNRMVGRPK-UHFFFAOYSA-N 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 229910000396 dipotassium phosphate Inorganic materials 0.000 description 1
- 235000019797 dipotassium phosphate Nutrition 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000002612 dispersion medium Substances 0.000 description 1
- 208000002173 dizziness Diseases 0.000 description 1
- PMMYEEVYMWASQN-UHFFFAOYSA-N dl-hydroxyproline Natural products OC1C[NH2+]C(C([O-])=O)C1 PMMYEEVYMWASQN-UHFFFAOYSA-N 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 229940043264 dodecyl sulfate Drugs 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 230000002183 duodenal effect Effects 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 230000002124 endocrine Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 230000009088 enzymatic function Effects 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 238000000684 flow cytometry Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 229960002449 glycine Drugs 0.000 description 1
- 125000003630 glycyl group Chemical group [H]N([H])C([H])([H])C(*)=O 0.000 description 1
- 201000009277 hairy cell leukemia Diseases 0.000 description 1
- 235000015220 hamburgers Nutrition 0.000 description 1
- 230000003862 health status Effects 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229960002591 hydroxyproline Drugs 0.000 description 1
- 201000006866 hypopharynx cancer Diseases 0.000 description 1
- 230000002267 hypothalamic effect Effects 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 229940124622 immune-modulator drug Drugs 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 230000001976 improved effect Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000000415 inactivating effect Effects 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 229940102213 injectable suspension Drugs 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 238000001361 intraarterial administration Methods 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
- 238000007919 intrasynovial administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 206010023841 laryngeal neoplasm Diseases 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 108091053735 lin-4 stem-loop Proteins 0.000 description 1
- 108091032363 lin-4-1 stem-loop Proteins 0.000 description 1
- 108091028008 lin-4-2 stem-loop Proteins 0.000 description 1
- 208000012987 lip and oral cavity carcinoma Diseases 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000004324 lymphatic system Anatomy 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000000391 magnesium silicate Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229940099273 magnesium trisilicate Drugs 0.000 description 1
- 229910000386 magnesium trisilicate Inorganic materials 0.000 description 1
- 235000019793 magnesium trisilicate Nutrition 0.000 description 1
- 238000012423 maintenance Methods 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
- 208000030883 malignant astrocytoma Diseases 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- XZFYOUAJBCRNCF-UHFFFAOYSA-N methyl 2-bromo-6-(bromomethyl)benzoate Chemical compound COC(=O)C1=C(Br)C=CC=C1CBr XZFYOUAJBCRNCF-UHFFFAOYSA-N 0.000 description 1
- RKUPOLBFJIEWBZ-UHFFFAOYSA-N methyl 8-chloro-8-oxooctanoate Chemical compound COC(=O)CCCCCCC(Cl)=O RKUPOLBFJIEWBZ-UHFFFAOYSA-N 0.000 description 1
- 230000003278 mimic effect Effects 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- 206010051747 multiple endocrine neoplasia Diseases 0.000 description 1
- 208000025113 myeloid leukemia Diseases 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-M naphthalene-2-sulfonate Chemical compound C1=CC=CC2=CC(S(=O)(=O)[O-])=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-M 0.000 description 1
- 208000018795 nasal cavity and paranasal sinus carcinoma Diseases 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 239000006199 nebulizer Substances 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 229920001220 nitrocellulos Polymers 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 231100000344 non-irritating Toxicity 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 229960002446 octanoic acid Drugs 0.000 description 1
- 230000009437 off-target effect Effects 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 229920001542 oligosaccharide Polymers 0.000 description 1
- 150000002482 oligosaccharides Chemical class 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 201000006958 oropharynx cancer Diseases 0.000 description 1
- 201000008968 osteosarcoma Diseases 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 201000002530 pancreatic endocrine carcinoma Diseases 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 238000009520 phase I clinical trial Methods 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 230000000865 phosphorylative effect Effects 0.000 description 1
- 229940075930 picrate Drugs 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-M picrate anion Chemical compound [O-]C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-M 0.000 description 1
- 229950010765 pivalate Drugs 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 208000010626 plasma cell neoplasm Diseases 0.000 description 1
- 229920000058 polyacrylate Polymers 0.000 description 1
- 229940113116 polyethylene glycol 1000 Drugs 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 229920000053 polysorbate 80 Polymers 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
- 235000010241 potassium sorbate Nutrition 0.000 description 1
- 239000004302 potassium sorbate Substances 0.000 description 1
- 229940069338 potassium sorbate Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 208000025638 primary cutaneous T-cell non-Hodgkin lymphoma Diseases 0.000 description 1
- 208000029340 primitive neuroectodermal tumor Diseases 0.000 description 1
- XOJVVFBFDXDTEG-UHFFFAOYSA-N pristane Chemical compound CC(C)CCCC(C)CCCC(C)CCCC(C)C XOJVVFBFDXDTEG-UHFFFAOYSA-N 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229950008679 protamine sulfate Drugs 0.000 description 1
- 239000003207 proteasome inhibitor Substances 0.000 description 1
- 238000010379 pull-down assay Methods 0.000 description 1
- HKSQZEGSMBFHGC-UHFFFAOYSA-N pyrimidine-4-carboxamide Chemical compound NC(=O)C1=CC=NC=N1 HKSQZEGSMBFHGC-UHFFFAOYSA-N 0.000 description 1
- NPWMTBZSRRLQNJ-UHFFFAOYSA-N pyroglutamine Chemical compound NC1CCC(=O)NC1=O NPWMTBZSRRLQNJ-UHFFFAOYSA-N 0.000 description 1
- 238000010833 quantitative mass spectrometry Methods 0.000 description 1
- 238000003753 real-time PCR Methods 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000007115 recruitment Effects 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 230000014493 regulation of gene expression Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 201000009410 rhabdomyosarcoma Diseases 0.000 description 1
- 239000012146 running buffer Substances 0.000 description 1
- 235000002020 sage Nutrition 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 230000003381 solubilizing effect Effects 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 208000037969 squamous neck cancer Diseases 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 201000008205 supratentorial primitive neuroectodermal tumor Diseases 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 206010042863 synovial sarcoma Diseases 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- SJMDMGHPMLKLHQ-UHFFFAOYSA-N tert-butyl 2-aminoacetate Chemical compound CC(C)(C)OC(=O)CN SJMDMGHPMLKLHQ-UHFFFAOYSA-N 0.000 description 1
- BNWCETAHAJSBFG-UHFFFAOYSA-N tert-butyl 2-bromoacetate Chemical compound CC(C)(C)OC(=O)CBr BNWCETAHAJSBFG-UHFFFAOYSA-N 0.000 description 1
- NSCCYXHEZRMPPH-UHFFFAOYSA-N tert-butyl 3-(2-aminoethoxy)propanoate Chemical compound CC(C)(C)OC(=O)CCOCCN NSCCYXHEZRMPPH-UHFFFAOYSA-N 0.000 description 1
- XIVHGTLMLORWEP-UHFFFAOYSA-N tert-butyl 3-[2-(2-aminoethoxy)ethoxy]propanoate Chemical compound CC(C)(C)OC(=O)CCOCCOCCN XIVHGTLMLORWEP-UHFFFAOYSA-N 0.000 description 1
- CWFSAZJIJBTKRC-UHFFFAOYSA-N tert-butyl 3-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]propanoate Chemical compound CC(C)(C)OC(=O)CCOCCOCCOCCN CWFSAZJIJBTKRC-UHFFFAOYSA-N 0.000 description 1
- ZJXHVYSDMUKUCA-UHFFFAOYSA-N tert-butyl 3-aminopropanoate Chemical compound CC(C)(C)OC(=O)CCN ZJXHVYSDMUKUCA-UHFFFAOYSA-N 0.000 description 1
- XFZZZOMHBHBURH-UHFFFAOYSA-N tert-butyl 4-aminobutanoate Chemical compound CC(C)(C)OC(=O)CCCN XFZZZOMHBHBURH-UHFFFAOYSA-N 0.000 description 1
- ARKHCHKVZVMJRX-UHFFFAOYSA-N tert-butyl 6-aminohexanoate Chemical compound CC(C)(C)OC(=O)CCCCCN ARKHCHKVZVMJRX-UHFFFAOYSA-N 0.000 description 1
- IIALHJIMGXLAJI-UHFFFAOYSA-N tert-butyl 7-aminoheptanoate Chemical compound CC(C)(C)OC(=O)CCCCCCN IIALHJIMGXLAJI-UHFFFAOYSA-N 0.000 description 1
- CGXSJIQNNZPSCT-UHFFFAOYSA-N tert-butyl 8-aminooctanoate Chemical compound CC(C)(C)OC(=O)CCCCCCCN CGXSJIQNNZPSCT-UHFFFAOYSA-N 0.000 description 1
- TZRQZPMQUXEZMC-UHFFFAOYSA-N tert-butyl n-(2-bromoethyl)carbamate Chemical compound CC(C)(C)OC(=O)NCCBr TZRQZPMQUXEZMC-UHFFFAOYSA-N 0.000 description 1
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 description 1
- 230000037317 transdermal delivery Effects 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 206010044412 transitional cell carcinoma Diseases 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 208000029387 trophoblastic neoplasm Diseases 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 210000000239 visual pathway Anatomy 0.000 description 1
- 230000004400 visual pathway Effects 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 210000002268 wool Anatomy 0.000 description 1
- 229910052727 yttrium Inorganic materials 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
Classifications
-
- 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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed 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
- A61K31/435—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
- 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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/45—Transferases (2)
-
- 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
-
- 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
- A61K47/55—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 the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
-
- 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
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y203/00—Acyltransferases (2.3)
- C12Y203/02—Aminoacyltransferases (2.3.2)
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (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)
- Gastroenterology & Hepatology (AREA)
- General Engineering & Computer Science (AREA)
- Genetics & Genomics (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biochemistry (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Investigating Or Analysing Biological Materials (AREA)
- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicinal Preparation (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201662431806P | 2016-12-08 | 2016-12-08 | |
| US62/431,806 | 2016-12-08 | ||
| PCT/US2017/065027 WO2018106870A1 (en) | 2016-12-08 | 2017-12-07 | Compositions and methods for treating cdk4/6-mediated cancer |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA3045037A1 true CA3045037A1 (en) | 2018-06-14 |
Family
ID=62491322
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA3045037A Abandoned CA3045037A1 (en) | 2016-12-08 | 2017-12-07 | Compositions and methods for treating cdk4/6-mediated cancer |
Country Status (7)
| Country | Link |
|---|---|
| US (2) | US11541051B2 (enExample) |
| EP (1) | EP3551185A4 (enExample) |
| JP (1) | JP2020514252A (enExample) |
| CN (1) | CN110267659A (enExample) |
| AU (1) | AU2017370694A1 (enExample) |
| CA (1) | CA3045037A1 (enExample) |
| WO (1) | WO2018106870A1 (enExample) |
Families Citing this family (67)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9464092B2 (en) | 2013-03-15 | 2016-10-11 | G1 Therapeutics, Inc. | Transient protection of normal cells during chemotherapy |
| WO2018005863A1 (en) * | 2016-07-01 | 2018-01-04 | G1 Therapeutics, Inc. | Pyrimidine-based compounds for the treatment of cancer |
| WO2018005860A1 (en) | 2016-07-01 | 2018-01-04 | G1 Therapeutics, Inc. | Pyrimidine-based antiproliferative agents |
| MX2019004950A (es) | 2016-10-28 | 2019-09-26 | Icahn School Med Mount Sinai | Composiciones y metodos para tratar el cancer mediado por el potenciador del homologo zeste 2. |
| CA3045037A1 (en) | 2016-12-08 | 2018-06-14 | Icahn School Of Medicine At Mount Sinai | Compositions and methods for treating cdk4/6-mediated cancer |
| US11173211B2 (en) | 2016-12-23 | 2021-11-16 | Arvinas Operations, Inc. | Compounds and methods for the targeted degradation of rapidly accelerated Fibrosarcoma polypeptides |
| HRP20241553T1 (hr) | 2017-07-10 | 2025-01-17 | Celgene Corporation | 4-(4-(4-(((2-(2,6-dioksopiperidin-3-il)-l-oksoizoindolin-4-il)oksi)metil)benzil)piperazin-l-il)-3-fluorobenzonitril kao antiproliferativni spoj |
| CN109516989B (zh) * | 2017-09-17 | 2021-12-31 | 上海美志医药科技有限公司 | 一类抑制并降解cdk的化合物 |
| JP7569688B2 (ja) | 2017-12-22 | 2024-10-18 | ハイバーセル,インコーポレイテッド | ホスファチジルイノシトールリン酸キナーゼ阻害剤としてのアミノピリジン誘導体 |
| JP2021515013A (ja) | 2018-03-06 | 2021-06-17 | アイカーン スクール オブ メディスン アット マウント シナイ | セリンスレオニンキナーゼ(akt)分解/破壊化合物および使用方法 |
| CA3096404A1 (en) | 2018-04-23 | 2019-10-31 | Celgene Corporation | Substituted 4-aminoisoindoline-1,3-dione compounds and their use for treating lymphoma |
| CN110615779B (zh) * | 2018-06-20 | 2023-03-24 | 上海科技大学 | 制备来那度胺衍生物的方法 |
| WO2019246570A1 (en) | 2018-06-21 | 2019-12-26 | Icahn School Of Medicine At Mount Sinai | Wd40 repeat domain protein 5 (wdr5) degradation / disruption compounds and methods of use |
| JP2021529807A (ja) * | 2018-07-05 | 2021-11-04 | アイカーン スクール オブ メディスン アット マウント シナイ | タンパク質チロシンキナーゼ6(ptk6)分解/破壊化合物および使用方法 |
| WO2020023502A1 (en) * | 2018-07-23 | 2020-01-30 | Aileron Therapeutics, Inc. | Peptidomimetic macrocycles and uses thereof |
| CN108948136A (zh) * | 2018-08-06 | 2018-12-07 | 浙江华海药业股份有限公司 | 一种赖诺普利杂质及其制备方法 |
| CN110835345A (zh) * | 2018-08-17 | 2020-02-25 | 中国科学院上海药物研究所 | 一类细胞周期依赖性激酶的降解剂、其制备方法、药物组合物及其用途 |
| US11707452B2 (en) | 2018-08-20 | 2023-07-25 | Arvinas Operations, Inc. | Modulators of alpha-synuclein proteolysis and associated methods of use |
| US11046703B2 (en) * | 2018-10-08 | 2021-06-29 | The Regents Of The University Of Michigan | Small molecule MDM2 protein degraders |
| AU2019360928B2 (en) * | 2018-10-15 | 2023-11-09 | Nurix Therapeutics, Inc. | Bifunctional compounds for degrading BTK via ubiquitin proteosome pathway |
| CN113825752A (zh) * | 2018-11-02 | 2021-12-21 | 威斯特解剖及生物研究所 | 蛋白水解靶向嵌合体 |
| US20220016102A1 (en) * | 2018-11-21 | 2022-01-20 | Shanghaitech University | Er protein regulators and use thereof |
| CN113660937A (zh) * | 2019-02-08 | 2021-11-16 | 佛罗里达大学研究基金公司 | 治疗剂和治疗方法 |
| CN113646002A (zh) * | 2019-02-27 | 2021-11-12 | 上海睿跃生物科技有限公司 | 环amp反应元件结合蛋白(cbp)和/或300kda腺病毒e1a结合蛋白(p300)降解化合物和使用方法 |
| CN113747925B (zh) | 2019-03-21 | 2024-10-15 | 隆萨销售股份公司 | 胞外囊泡缀合物及其用途 |
| US12233356B2 (en) | 2019-03-21 | 2025-02-25 | Lonza Sales Ag | Process for preparing extracellular vesicles |
| JP2022521825A (ja) * | 2019-03-28 | 2022-04-12 | エッサ ファーマ,インコーポレイテッド | アンドロゲン受容体モジュレーター及びタンパク質分解誘導キメラリガンドとして使用するための方法 |
| US11485735B2 (en) * | 2019-04-25 | 2022-11-01 | Wuxi Shuangliang Biotechnology Co., Ltd. | Selective CDK4/6 inhibitor and preparation thereof |
| CN118908962A (zh) * | 2019-05-06 | 2024-11-08 | 西奈山伊坎医学院 | 作为hpk1的降解剂的异双功能化合物 |
| EP3976621A4 (en) * | 2019-06-03 | 2023-11-15 | Regents of the University of Minnesota | KINASE DEGRADING COMPOUNDS AND THEIR USE |
| TW202112767A (zh) | 2019-06-17 | 2021-04-01 | 美商佩特拉製藥公司 | 作為磷脂酸肌醇磷酸激酶抑制劑之胺基吡啶衍生物 |
| CN114867727B (zh) | 2019-07-17 | 2025-02-21 | 阿尔维纳斯运营股份有限公司 | Tau蛋白靶向化合物及相关使用方法 |
| EP4010336B1 (en) * | 2019-08-05 | 2025-04-02 | Dana-Farber Cancer Institute, Inc. | Degraders of cyclin-dependent kinase 7 (cdk7) and uses thereof |
| CN112457365B (zh) | 2019-09-09 | 2023-06-09 | 中国医学科学院药物研究所 | 一类靶向蛋白质水解通路的功能分子及其制备和应用 |
| EP4045496A1 (en) | 2019-10-17 | 2022-08-24 | Arvinas Operations, Inc. | Bifunctional molecules containing an e3 ubiquitine ligase binding moiety linked to a bcl6 targeting moiety |
| KR20220113986A (ko) | 2019-12-16 | 2022-08-17 | 루넬라 바이오테크 인코포레이티드 | 선택적 cdk 4/6 억제제 암 치료제 |
| JP7681599B2 (ja) | 2019-12-16 | 2025-05-22 | ルネラ・バイオテック・インコーポレーテッド | 選択的cdk4/6阻害剤のがん治療薬 |
| EP4076530A4 (en) * | 2019-12-17 | 2024-04-10 | Orionis Biosciences, Inc. | BIFUNCTIONAL AGENTS FOR RECRUITMENT AND/OR DEGRADATION OF PROTEINS |
| AU2020404956A1 (en) * | 2019-12-17 | 2022-07-07 | Orionis Biosciences, Inc. | Compounds modulating protein recruitment and/or degradation |
| CN115038697A (zh) | 2020-01-15 | 2022-09-09 | 佛罗里达大学研究基金公司 | 治疗剂和治疗方法 |
| WO2021150945A1 (en) * | 2020-01-23 | 2021-07-29 | Icahn School Of Medicine At Mount Sinai | Methods of diagnosing and treating cancer |
| EP4652997A2 (en) | 2020-05-19 | 2025-11-26 | Pharmacosmos Holding A/s | Cyclin-dependent kinase inhibiting compounds for the treatment of medical disorders |
| WO2021237100A1 (en) | 2020-05-21 | 2021-11-25 | Codiak Biosciences, Inc. | Methods of targeting extracellular vesicles to lung |
| US12103924B2 (en) | 2020-06-01 | 2024-10-01 | Icahn School Of Medicine At Mount Sinai | Mitogen-activated protein kinase kinase (MEK) degradation compounds and methods of use |
| AU2021287380A1 (en) * | 2020-06-11 | 2023-01-05 | Lunella Biotech, Inc. | Selective CDK4/6 inhibitor cancer therapeutics |
| KR102646850B1 (ko) * | 2020-07-21 | 2024-03-13 | 주식회사 유빅스테라퓨틱스 | 안드로겐 수용체 분해용 화합물 및 이들의 의약 용도 |
| KR102601028B1 (ko) * | 2020-08-18 | 2023-11-10 | 재단법인대구경북과학기술원 | 아베마시클립을 유효성분으로 포함하는 퇴행성 뇌질환의 예방 또는 치료용 약학적 조성물 |
| WO2022039421A1 (ko) * | 2020-08-18 | 2022-02-24 | 재단법인대구경북과학기술원 | 아베마시클립을 유효성분으로 포함하는 퇴행성 뇌질환의 예방 또는 치료용 약학적 조성물 |
| US12180193B2 (en) | 2020-08-28 | 2024-12-31 | Arvinas Operations, Inc. | Accelerating fibrosarcoma protein degrading compounds and associated methods of use |
| US20240241020A1 (en) | 2020-09-23 | 2024-07-18 | Lonza Sales Ag | Process for preparing extracellular vesicles |
| CN114349738B (zh) * | 2020-10-14 | 2023-05-05 | 清华大学 | 一类靶向降解cdk2的小分子缀合物及其应用 |
| AR124154A1 (es) | 2020-11-27 | 2023-02-22 | Rhizen Pharmaceuticals Ag | Inhibidores de cdk |
| WO2022149057A1 (en) | 2021-01-05 | 2022-07-14 | Rhizen Pharmaceuticals Ag | Cdk inhibitors |
| EP4277901A1 (en) | 2021-01-13 | 2023-11-22 | Monte Rosa Therapeutics, Inc. | Isoindolinone compounds |
| AU2022259683A1 (en) | 2021-04-16 | 2023-10-19 | Arvinas Operations, Inc. | Modulators of bcl6 proteolysis and associated methods of use |
| JP2024542984A (ja) | 2021-10-26 | 2024-11-19 | ニューリックス セラピューティクス,インコーポレイテッド | がんを治療および予防するためのピペリジニルピラジン-カルボキサミド化合物、およびbtkを分解するためのピペリジニルピラジン-カルボキサミド化合物 |
| CN116239566A (zh) * | 2021-12-08 | 2023-06-09 | 标新生物医药科技(上海)有限公司 | E3泛素连接酶配体化合物、基于该配体化合物开发的蛋白降解剂及它们的应用 |
| US20230295118A1 (en) * | 2022-03-18 | 2023-09-21 | EnhancedBio Inc. | Compounds and methods for the targeted degradation of cyclin dependent kinases |
| AU2023268542A1 (en) * | 2022-05-10 | 2024-11-14 | Biotheryx, Inc. | Cdk protein degraders, pharmaceutical compositions, and therapeutic applications |
| CN114957249B (zh) * | 2022-05-20 | 2023-04-21 | 东南大学 | 一种不可逆共价结合cdk抑制剂及其制备方法和应用 |
| US11957759B1 (en) | 2022-09-07 | 2024-04-16 | Arvinas Operations, Inc. | Rapidly accelerated fibrosarcoma (RAF) degrading compounds and associated methods of use |
| JP2025530372A (ja) * | 2022-09-15 | 2025-09-11 | クルゲン(シャンハイ),インク. | 修飾タンパク質ならびにタンパク質結合剤および分解剤 |
| EP4605088A1 (en) * | 2022-10-21 | 2025-08-27 | Novartis AG | Molecular glue degrader compounds and uses thereof |
| CN115650968B (zh) * | 2022-12-27 | 2023-03-21 | 英矽智能科技(上海)有限公司 | 作为cdk选择性抑制剂的新型哒嗪酮化合物 |
| WO2024229287A1 (en) * | 2023-05-03 | 2024-11-07 | St. Jude Children's Research Hospital, Inc. | A sequence selective dna binding molecule (syngrader) |
| AU2024276994A1 (en) | 2023-05-24 | 2025-10-23 | Kumquat Biosciences Inc. | Heterocyclic compounds and uses thereof |
| WO2024256569A1 (en) * | 2023-06-13 | 2024-12-19 | Rijksuniversiteit Groningen | Novel cdk degraders |
Family Cites Families (52)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5691147A (en) * | 1994-06-02 | 1997-11-25 | Mitotix, Inc. | CDK4 binding assay |
| US6486214B1 (en) | 1997-09-10 | 2002-11-26 | Rutgers, The State University Of New Jersey | Polyanhydride linkers for production of drug polymers and drug polymer compositions produced thereby |
| PT1255752E (pt) | 2000-02-15 | 2007-10-17 | Pharmacia & Upjohn Co Llc | Inibidores de proteína quinases: 2-indolinonas substituídas com pirrolo |
| TW200819435A (en) | 2006-09-15 | 2008-05-01 | Celgene Corp | N-methylaminomethyl isoindole compounds and compositions comprising and methods of using the same |
| WO2008109104A1 (en) | 2007-03-07 | 2008-09-12 | The Regents Of The University Of California | Bivalent inhibitors of akt protein kinase |
| SI2173723T1 (sl) | 2007-07-05 | 2011-12-30 | Array Biopharma Inc | Pirimidil ciklopentani kot inhibitorji AKT-protein-kinaze |
| US20110172107A1 (en) | 2008-04-30 | 2011-07-14 | Fox Chase Cancer Center | Assay for identifying agents that modulate epigenetic silencing, and agents identified thereby |
| WO2011029054A1 (en) | 2009-09-04 | 2011-03-10 | The Regents Of The University Of Michigan | Compositions and methods for treatment of leukemia |
| SG10201501062SA (en) | 2010-02-11 | 2015-04-29 | Celgene Corp | Arylmethoxy isoindoline derivatives and compositions comprising and methods of using the same |
| US20140031325A1 (en) | 2010-12-06 | 2014-01-30 | Celgene Corporation | Combination therapy with lenalidomide and a cdk inhibitor for treating multiple myeloma |
| EP3608317A1 (en) * | 2012-01-12 | 2020-02-12 | Yale University | Compounds & methods for the enhanced degradation of targeted proteins & other polypeptides by an e3 ubiquitin ligase |
| US20150119435A1 (en) | 2012-05-11 | 2015-04-30 | Yale University | Compounds useful for promoting protein degradation and methods using same |
| US9758522B2 (en) * | 2012-10-19 | 2017-09-12 | Dana-Farber Cancer Institute, Inc. | Hydrophobically tagged small molecules as inducers of protein degradation |
| WO2014100719A2 (en) | 2012-12-21 | 2014-06-26 | Epizyme, Inc. | Prmt5 inhibitors and uses thereof |
| WO2015101293A1 (zh) | 2013-12-31 | 2015-07-09 | 山东轩竹医药科技有限公司 | 激酶抑制剂及其用途 |
| WO2015104677A1 (en) | 2014-01-10 | 2015-07-16 | Piramal Enterprises Limited | Heterocyclic compounds as ezh2 inhibitors |
| KR20250127179A (ko) | 2014-04-14 | 2025-08-26 | 아비나스 오퍼레이션스, 인코포레이티드 | 단백질분해의 이미드-기초된 조절인자 및 연관된 이용 방법 |
| CN113786495A (zh) | 2014-06-13 | 2021-12-14 | 塔夫茨大学信托人 | Fap激活的治疗剂以及其相关用途 |
| US11236082B2 (en) | 2014-11-06 | 2022-02-01 | Dana-Farber Cancer Institute, Inc. | EZH2 inhibitors and uses thereof |
| EP3227446A1 (en) | 2014-12-01 | 2017-10-11 | Novartis AG | Compositions and methods for diagnosis and treatment of prostate cancer |
| JP6815318B2 (ja) * | 2014-12-23 | 2021-01-20 | ダナ−ファーバー キャンサー インスティテュート,インコーポレイテッド | 二官能性分子によって標的化タンパク質分解を誘導する方法 |
| WO2016106518A1 (zh) | 2014-12-29 | 2016-07-07 | 深圳市日上光电股份有限公司 | 导线集成式照明灯箱 |
| TWI770525B (zh) | 2014-12-30 | 2022-07-11 | 美商瓦洛健康公司 | 作為泛素特異性蛋白酶7抑制劑之吡咯并及吡唑并嘧啶 |
| US20180000906A1 (en) | 2015-01-16 | 2018-01-04 | Vedantra Pharmaceuticals, Inc. | Multilamellar lipid vesicle compositions including a conjugated anaplastic lymphoma kinase (alk) variant and uses thereof |
| EP3270917A4 (en) | 2015-03-18 | 2018-08-08 | Arvinas, Inc. | Compounds and methods for the enhanced degradation of targeted proteins |
| WO2016174130A1 (en) | 2015-04-28 | 2016-11-03 | Université De Strasbourg | Clinical gene signature-based human cell culture model and uses thereof |
| JP6819585B2 (ja) | 2015-06-22 | 2021-01-27 | 小野薬品工業株式会社 | Brk阻害化合物 |
| CN105085620B (zh) | 2015-06-25 | 2018-05-08 | 中山大学附属第一医院 | 一种靶向泛素化降解Smad3的化合物 |
| WO2017007612A1 (en) | 2015-07-07 | 2017-01-12 | Dana-Farber Cancer Institute, Inc. | Methods to induce targeted protein degradation through bifunctional molecules |
| US20170008904A1 (en) | 2015-07-10 | 2017-01-12 | Arvinas, Inc. | Mdm2-based modulators of proteolysis and associated methods of use |
| CA2988436A1 (en) | 2015-07-13 | 2017-01-19 | Arvinas, Inc. | Alanine-based modulators of proteolysis and associated methods of use |
| US9809603B1 (en) | 2015-08-18 | 2017-11-07 | Deuterx, Llc | Deuterium-enriched isoindolinonyl-piperidinonyl conjugates and oxoquinazolin-3(4H)-yl-piperidinonyl conjugates and methods of treating medical disorders using same |
| US20170114098A1 (en) | 2015-09-03 | 2017-04-27 | Aileron Therapeutics, Inc. | Peptidomimetic macrocycles and uses thereof |
| EP3423437A4 (en) | 2016-03-01 | 2019-07-24 | Propellon Therapeutics Inc. | INHIBITORS OF WDR5 PROTEIN PROTEIN BINDING |
| AU2017226004B2 (en) | 2016-03-01 | 2021-07-22 | Propellon Therapeutics Inc. | Inhibitors of WDR5 protein-protein binding |
| US10865204B2 (en) * | 2016-04-22 | 2020-12-15 | Dana-Farber Cancer Institute, Inc. | Degradation of cyclin-dependent kinase 4/6 (CDK4/6) by conjugation of CDK4/6 inhibitors with E3 ligase ligand and methods of use |
| EP3454856B1 (en) | 2016-05-10 | 2024-09-11 | C4 Therapeutics, Inc. | Heterocyclic degronimers for target protein degradation |
| WO2017197051A1 (en) | 2016-05-10 | 2017-11-16 | C4 Therapeutics, Inc. | Amine-linked c3-glutarimide degronimers for target protein degradation |
| US20180072741A1 (en) | 2016-09-09 | 2018-03-15 | Incyte Corporation | Pyrazolopyrimidine compounds and uses thereof |
| US10160763B2 (en) | 2016-09-13 | 2018-12-25 | Vanderbilt University | WDR5 inhibitors and modulators |
| MX2019004950A (es) | 2016-10-28 | 2019-09-26 | Icahn School Med Mount Sinai | Composiciones y metodos para tratar el cancer mediado por el potenciador del homologo zeste 2. |
| CA3045037A1 (en) | 2016-12-08 | 2018-06-14 | Icahn School Of Medicine At Mount Sinai | Compositions and methods for treating cdk4/6-mediated cancer |
| JP7047772B2 (ja) | 2016-12-21 | 2022-04-05 | 小野薬品工業株式会社 | Brk阻害化合物 |
| US20210283261A1 (en) | 2017-12-05 | 2021-09-16 | Icahn School Of Medicine At Mount Sinai | Compositions and Methods for Treating ALK-Mediated Cancer |
| CA3091041A1 (en) | 2018-02-22 | 2019-08-29 | Ichan School Of Medicine At Mount Sinai | Protein arginine methyltransferase 5 (prmt5) degradation / disruption compounds and methods of use |
| JP2021515013A (ja) | 2018-03-06 | 2021-06-17 | アイカーン スクール オブ メディスン アット マウント シナイ | セリンスレオニンキナーゼ(akt)分解/破壊化合物および使用方法 |
| JP7421499B2 (ja) | 2018-05-15 | 2024-01-24 | アメリカ合衆国 | 腫瘍転移および腫瘍発生の予防および治療のための製剤および方法 |
| WO2019246570A1 (en) | 2018-06-21 | 2019-12-26 | Icahn School Of Medicine At Mount Sinai | Wd40 repeat domain protein 5 (wdr5) degradation / disruption compounds and methods of use |
| US20220242871A1 (en) | 2019-06-10 | 2022-08-04 | Sutro Biopharma, Inc. | 5H-PYRROLO[3,2-d]PYRIMIDINE-2,4-DIAMINO COMPOUNDS AND ANTIBODY CONJUGATES THEREOF |
| US20220274980A1 (en) | 2019-07-30 | 2022-09-01 | The Scripps Research Institute | Pharmacological inhibitors of the enl yeats domain |
| US12103924B2 (en) | 2020-06-01 | 2024-10-01 | Icahn School Of Medicine At Mount Sinai | Mitogen-activated protein kinase kinase (MEK) degradation compounds and methods of use |
| CN112778303A (zh) | 2020-12-31 | 2021-05-11 | 武汉九州钰民医药科技有限公司 | Cdk4/6激酶抑制剂shr6390的制备方法 |
-
2017
- 2017-12-07 CA CA3045037A patent/CA3045037A1/en not_active Abandoned
- 2017-12-07 AU AU2017370694A patent/AU2017370694A1/en not_active Abandoned
- 2017-12-07 JP JP2019530811A patent/JP2020514252A/ja active Pending
- 2017-12-07 CN CN201780085879.6A patent/CN110267659A/zh active Pending
- 2017-12-07 US US16/467,888 patent/US11541051B2/en active Active
- 2017-12-07 EP EP17877800.7A patent/EP3551185A4/en active Pending
- 2017-12-07 WO PCT/US2017/065027 patent/WO2018106870A1/en not_active Ceased
-
2021
- 2021-11-04 US US17/453,619 patent/US20220054488A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| CN110267659A (zh) | 2019-09-20 |
| AU2017370694A1 (en) | 2019-07-25 |
| EP3551185A4 (en) | 2021-07-14 |
| US20220054488A1 (en) | 2022-02-24 |
| JP2020514252A (ja) | 2020-05-21 |
| WO2018106870A1 (en) | 2018-06-14 |
| US20190336503A1 (en) | 2019-11-07 |
| US11541051B2 (en) | 2023-01-03 |
| EP3551185A1 (en) | 2019-10-16 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA3045037A1 (en) | Compositions and methods for treating cdk4/6-mediated cancer | |
| US11285218B2 (en) | Degradation of bromodomain-containing protein 9 (BRD9) by conjugation of BRD9 inhibitors with E3 ligase ligand and methods of use | |
| AU2017201536B2 (en) | Pyrimidinyl Tyrosine Kinase Inhibitors | |
| TWI639427B (zh) | Tank-結合激酶抑制劑化合物 | |
| JP7717125B2 (ja) | α4β7インテグリンの阻害のための化合物 | |
| WO2019113071A1 (en) | Compositions and methods for treating alk-mediated cancer | |
| JP2022531446A (ja) | Hpk1の分解剤としてのヘテロ二官能性化合物 | |
| JP2023540270A (ja) | 複素環式化合物およびその使用 | |
| AU2013296627B2 (en) | Deuterated ibrutinib | |
| KR20250021402A (ko) | 헤테로환 화합물 및 이의 용도 | |
| CA3091041A1 (en) | Protein arginine methyltransferase 5 (prmt5) degradation / disruption compounds and methods of use | |
| EP3532464A1 (en) | Compositions and methods for treating ezh2-mediated cancer | |
| CA2865875A1 (en) | Piperidine compound or salt thereof | |
| JPWO2019189732A1 (ja) | 光学活性な架橋型環状2級アミン誘導体 | |
| US11174243B2 (en) | Succinate forms and compositions of Bruton's tyrosine kinase inhibitors | |
| KR20250004810A (ko) | 대환식 헤테로환 및 이의 용도 | |
| CA2973773A1 (en) | 2-phenyl-3h-imidazo[4,5-b]pyridine derivatives useful as inhibitors of mammalian tyrosine kinase ror1 activity | |
| EP4426286A1 (en) | Bifunctional pi3k-alpha inhibitors and uses thereof | |
| WO2018187294A1 (en) | Pyrimido-pyridazinone compound combinations, methods, kits and formulations thereof | |
| WO2023183652A1 (en) | Dual cxcr4-btk inhibitors | |
| JPWO2018186366A1 (ja) | 新規サイクリン依存性キナーゼ8及び/又は19阻害剤 | |
| BR112018009880B1 (pt) | Compostos e composições farmacêuticas moduladores dos receptores de quimiocina e seus usos |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |
Effective date: 20240320 |