CA2682174C - Stitched polypeptides - Google Patents
Stitched polypeptides Download PDFInfo
- Publication number
- CA2682174C CA2682174C CA2682174A CA2682174A CA2682174C CA 2682174 C CA2682174 C CA 2682174C CA 2682174 A CA2682174 A CA 2682174A CA 2682174 A CA2682174 A CA 2682174A CA 2682174 C CA2682174 C CA 2682174C
- Authority
- CA
- Canada
- Prior art keywords
- substituted
- unsubstituted
- acyclic
- cyclic
- unbranched
- 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.)
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- 108090000765 processed proteins & peptides Proteins 0.000 title claims abstract description 318
- 102000004196 processed proteins & peptides Human genes 0.000 title claims abstract description 236
- 229920001184 polypeptide Polymers 0.000 title claims abstract description 205
- 238000000034 method Methods 0.000 claims abstract description 59
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 33
- 125000002015 acyclic group Chemical group 0.000 claims description 290
- 125000004122 cyclic group Chemical group 0.000 claims description 289
- 150000001413 amino acids Chemical class 0.000 claims description 180
- 125000001072 heteroaryl group Chemical group 0.000 claims description 112
- 125000003118 aryl group Chemical group 0.000 claims description 106
- 229920005989 resin Polymers 0.000 claims description 98
- 239000011347 resin Substances 0.000 claims description 98
- 239000001257 hydrogen Substances 0.000 claims description 90
- 229910052739 hydrogen Inorganic materials 0.000 claims description 90
- 125000001931 aliphatic group Chemical group 0.000 claims description 87
- 125000002252 acyl group Chemical group 0.000 claims description 83
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 74
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 58
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 50
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 claims description 48
- 150000003839 salts Chemical class 0.000 claims description 48
- 239000003054 catalyst Substances 0.000 claims description 46
- 125000000623 heterocyclic group Chemical group 0.000 claims description 46
- 125000002947 alkylene group Chemical group 0.000 claims description 42
- 125000005843 halogen group Chemical group 0.000 claims description 42
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 42
- 125000005647 linker group Chemical group 0.000 claims description 39
- 125000003275 alpha amino acid group Chemical group 0.000 claims description 36
- 125000006239 protecting group Chemical group 0.000 claims description 32
- 125000004419 alkynylene group Chemical group 0.000 claims description 29
- 125000004474 heteroalkylene group Chemical group 0.000 claims description 29
- 125000004450 alkenylene group Chemical group 0.000 claims description 28
- 125000004432 carbon atom Chemical group C* 0.000 claims description 27
- 125000000732 arylene group Chemical group 0.000 claims description 26
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 26
- 125000005549 heteroarylene group Chemical group 0.000 claims description 26
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 26
- 229910052757 nitrogen Inorganic materials 0.000 claims description 26
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 25
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 24
- 125000002462 isocyano group Chemical group *[N+]#[C-] 0.000 claims description 22
- 238000005859 coupling reaction Methods 0.000 claims description 16
- 238000010168 coupling process Methods 0.000 claims description 13
- 125000003396 thiol group Chemical class [H]S* 0.000 claims description 13
- 230000008878 coupling Effects 0.000 claims description 12
- 238000004519 manufacturing process Methods 0.000 claims description 10
- 238000006798 ring closing metathesis reaction Methods 0.000 claims description 9
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical group [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims description 8
- 229910052707 ruthenium Inorganic materials 0.000 claims description 8
- 230000004071 biological effect Effects 0.000 claims description 6
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- 229930195733 hydrocarbon Natural products 0.000 claims description 5
- 150000002430 hydrocarbons Chemical class 0.000 claims description 5
- 150000002431 hydrogen Chemical class 0.000 claims 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims 3
- 238000002983 circular dichroism Methods 0.000 claims 1
- -1 hydrogen radicals Chemical class 0.000 description 232
- 235000001014 amino acid Nutrition 0.000 description 154
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- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 72
- 239000000203 mixture Substances 0.000 description 63
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 57
- 125000000217 alkyl group Chemical group 0.000 description 55
- 150000003573 thiols Chemical class 0.000 description 50
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- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 46
- 230000015572 biosynthetic process Effects 0.000 description 45
- 125000001424 substituent group Chemical group 0.000 description 40
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- 238000003786 synthesis reaction Methods 0.000 description 27
- 125000003710 aryl alkyl group Chemical group 0.000 description 26
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- 125000002877 alkyl aryl group Chemical group 0.000 description 22
- 239000003795 chemical substances by application Substances 0.000 description 22
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
- 125000003282 alkyl amino group Chemical group 0.000 description 21
- 125000005377 alkyl thioxy group Chemical group 0.000 description 21
- 125000001769 aryl amino group Chemical group 0.000 description 21
- 125000005165 aryl thioxy group Chemical group 0.000 description 21
- 125000004104 aryloxy group Chemical group 0.000 description 21
- 210000004027 cell Anatomy 0.000 description 21
- 238000009472 formulation Methods 0.000 description 21
- 125000005241 heteroarylamino group Chemical group 0.000 description 21
- 125000005553 heteroaryloxy group Chemical group 0.000 description 21
- 125000005378 heteroarylthioxy group Chemical group 0.000 description 21
- 125000003545 alkoxy group Chemical group 0.000 description 20
- 125000001841 imino group Chemical group [H]N=* 0.000 description 20
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- 125000000464 thioxo group Chemical group S=* 0.000 description 20
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 19
- 239000000047 product Substances 0.000 description 19
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- 102000004169 proteins and genes Human genes 0.000 description 19
- 235000002639 sodium chloride Nutrition 0.000 description 19
- 239000000243 solution Substances 0.000 description 19
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
- 239000013543 active substance Substances 0.000 description 18
- 206010028980 Neoplasm Diseases 0.000 description 17
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- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 14
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- 230000004048 modification Effects 0.000 description 12
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- 229920002472 Starch Polymers 0.000 description 11
- 229940079593 drug Drugs 0.000 description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 11
- 230000002062 proliferating effect Effects 0.000 description 11
- 235000019698 starch Nutrition 0.000 description 11
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- 150000001412 amines Chemical class 0.000 description 10
- 230000030833 cell death Effects 0.000 description 10
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- 238000004128 high performance liquid chromatography Methods 0.000 description 10
- GTCAXTIRRLKXRU-UHFFFAOYSA-N methyl carbamate Chemical compound COC(N)=O GTCAXTIRRLKXRU-UHFFFAOYSA-N 0.000 description 10
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 102000012199 E3 ubiquitin-protein ligase Mdm2 Human genes 0.000 description 9
- 108050002772 E3 ubiquitin-protein ligase Mdm2 Proteins 0.000 description 9
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 9
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- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 9
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 9
- 229910052799 carbon Inorganic materials 0.000 description 9
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- 125000004404 heteroalkyl group Chemical group 0.000 description 9
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- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 8
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 8
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- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
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- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 description 8
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- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 6
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
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| RU2016111360A (ru) | 2010-08-13 | 2018-11-27 | Эйлерон Терапьютикс, Инк. | Пептидомиметические макроциклы |
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| RU2017145921A (ru) | 2012-02-15 | 2019-02-21 | Эйлерон Терапьютикс, Инк. | Пептидомиметические макроциклы |
| HK1205454A1 (en) | 2012-02-15 | 2015-12-18 | Aileron Therapeutics, Inc. | Triazole-crosslinked and thioether-crosslinked peptidomimetic macrocycles |
| US9044421B2 (en) | 2012-03-28 | 2015-06-02 | Genus Oncology, Llc | Treating MUC1-expressing cancers with combination therapies |
| US9878056B2 (en) | 2012-04-02 | 2018-01-30 | Modernatx, Inc. | Modified polynucleotides for the production of cosmetic proteins and peptides |
| EP2920197B1 (en) | 2012-09-26 | 2021-03-17 | President and Fellows of Harvard College | Proline-locked stapled peptides and uses thereof |
| US20150225471A1 (en) | 2012-10-01 | 2015-08-13 | President And Fellows Of Harvard College | Stabilized polypeptide insulin receptor modulators |
| CN104812384B (zh) | 2012-11-01 | 2020-09-18 | 爱勒让治疗公司 | 二取代的氨基酸及其制备和使用方法 |
| WO2014138429A2 (en) | 2013-03-06 | 2014-09-12 | Aileron Therapeutics, Inc. | Peptidomimetic macrocycles and use thereof in regulating hif1alpha |
| JP6568515B2 (ja) * | 2013-03-13 | 2019-08-28 | プレジデント アンド フェローズ オブ ハーバード カレッジ | ステープルドおよびステッチドポリペプチドならびにその使用 |
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