CA2762877A1 - Polyal drug conjugates comprising variable rate-releasing linkers - Google Patents
Polyal drug conjugates comprising variable rate-releasing linkers Download PDFInfo
- Publication number
- CA2762877A1 CA2762877A1 CA2762877A CA2762877A CA2762877A1 CA 2762877 A1 CA2762877 A1 CA 2762877A1 CA 2762877 A CA2762877 A CA 2762877A CA 2762877 A CA2762877 A CA 2762877A CA 2762877 A1 CA2762877 A1 CA 2762877A1
- Authority
- CA
- Canada
- Prior art keywords
- conjugate
- phf
- polyal
- drug
- gly
- 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
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- 229940079593 drug Drugs 0.000 title claims abstract description 133
- 238000000034 method Methods 0.000 claims abstract description 50
- 229940127093 camptothecin Drugs 0.000 claims description 83
- 125000005647 linker group Chemical group 0.000 claims description 60
- 125000000217 alkyl group Chemical group 0.000 claims description 52
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 51
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 claims description 48
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 47
- 229940122803 Vinca alkaloid Drugs 0.000 claims description 45
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 claims description 43
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 claims description 43
- 229910052757 nitrogen Inorganic materials 0.000 claims description 36
- 206010028980 Neoplasm Diseases 0.000 claims description 34
- 125000004429 atom Chemical group 0.000 claims description 33
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 33
- 150000003839 salts Chemical class 0.000 claims description 30
- 125000001142 dicarboxylic acid group Chemical group 0.000 claims description 28
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 27
- 201000011510 cancer Diseases 0.000 claims description 25
- 125000003118 aryl group Chemical group 0.000 claims description 24
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- 125000005842 heteroatom Chemical group 0.000 claims description 17
- 229930182556 Polyacetal Natural products 0.000 claims description 15
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 15
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- 125000000623 heterocyclic group Chemical group 0.000 claims description 14
- 229920001855 polyketal Polymers 0.000 claims description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims description 13
- 239000001257 hydrogen Substances 0.000 claims description 13
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 11
- 239000000872 buffer Substances 0.000 claims description 10
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 9
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical group CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 claims description 8
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- FJHBVJOVLFPMQE-QFIPXVFZSA-N 7-Ethyl-10-Hydroxy-Camptothecin Chemical compound C1=C(O)C=C2C(CC)=C(CN3C(C4=C([C@@](C(=O)OC4)(O)CC)C=C33)=O)C3=NC2=C1 FJHBVJOVLFPMQE-QFIPXVFZSA-N 0.000 claims description 7
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims description 7
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 239000000178 monomer Substances 0.000 claims description 5
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- CEVCTNCUIVEQOY-UHFFFAOYSA-N Fumagillol Natural products O1C(CC=C(C)C)C1(C)C1C(OC)C(O)CCC21CO2 CEVCTNCUIVEQOY-UHFFFAOYSA-N 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- CEVCTNCUIVEQOY-STXHBLNNSA-N fumagillol Chemical compound C([C@@H](O)[C@H](C1[C@]2(C)[C@H](O2)CC=C(C)C)OC)C[C@@]21CO2 CEVCTNCUIVEQOY-STXHBLNNSA-N 0.000 claims description 4
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 3
- 150000004985 diamines Chemical class 0.000 claims description 3
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- RSPCKAHMRANGJZ-UHFFFAOYSA-N thiohydroxylamine Chemical compound SN RSPCKAHMRANGJZ-UHFFFAOYSA-N 0.000 claims description 3
- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 claims 2
- 239000000562 conjugate Substances 0.000 description 129
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- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 17
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- 239000000203 mixture Substances 0.000 description 11
- 238000011282 treatment Methods 0.000 description 11
- 239000011780 sodium chloride Substances 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 241000699670 Mus sp. Species 0.000 description 8
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- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- 230000000694 effects Effects 0.000 description 7
- 230000007062 hydrolysis Effects 0.000 description 7
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 6
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 6
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 241000699666 Mus <mouse, genus> Species 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 150000001412 amines Chemical class 0.000 description 6
- 230000007246 mechanism Effects 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 5
- 150000001241 acetals Chemical class 0.000 description 5
- 230000021615 conjugation Effects 0.000 description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 5
- 150000003443 succinic acid derivatives Chemical class 0.000 description 5
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 5
- 230000004614 tumor growth Effects 0.000 description 5
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 4
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 4
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 4
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 4
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- 210000004027 cell Anatomy 0.000 description 4
- 238000006731 degradation reaction Methods 0.000 description 4
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- 238000012377 drug delivery Methods 0.000 description 4
- 229910052736 halogen Inorganic materials 0.000 description 4
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- 238000000338 in vitro Methods 0.000 description 4
- 238000001802 infusion Methods 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
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- 230000004962 physiological condition Effects 0.000 description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
- FSYKKLYZXJSNPZ-UHFFFAOYSA-N sarcosine Chemical compound C[NH2+]CC([O-])=O FSYKKLYZXJSNPZ-UHFFFAOYSA-N 0.000 description 4
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- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 4
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Classifications
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Landscapes
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Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
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| US18192609P | 2009-05-28 | 2009-05-28 | |
| US61/181,926 | 2009-05-28 | ||
| PCT/US2010/036413 WO2010138719A1 (en) | 2009-05-28 | 2010-05-27 | Polyal drug conjugates comprising variable rate-releasing linkers |
Publications (1)
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| CA2762877A1 true CA2762877A1 (en) | 2010-12-02 |
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| TW (1) | TW201102089A (OSRAM) |
| WO (1) | WO2010138719A1 (OSRAM) |
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| NZ585547A (en) * | 2007-11-28 | 2012-12-21 | Mersana Therapeutics Inc | Biocompatible biodegradable fumagillin analog conjugates |
| US8349308B2 (en) * | 2010-03-26 | 2013-01-08 | Mersana Therapeutics, Inc. | Modified polymers for delivery of polynucleotides, method of manufacture, and methods of use thereof |
| WO2012092339A2 (en) * | 2010-12-28 | 2012-07-05 | The Children's Hospital Of Philadelphia | The design of hydrolytically releasable prodrugs for sustained release nanoparticle formulations |
| US8815226B2 (en) | 2011-06-10 | 2014-08-26 | Mersana Therapeutics, Inc. | Protein-polymer-drug conjugates |
| RU2617402C2 (ru) | 2011-06-10 | 2017-04-25 | Мерсана Терапьютикс, Инк. | Конъюгаты белок-полимер-лекарственное средство |
| AU2012332588B2 (en) | 2011-11-01 | 2017-09-07 | Bionomics, Inc. | Methods of blocking cancer stem cell growth |
| CN104024236A (zh) * | 2011-12-23 | 2014-09-03 | 摩萨那医疗公司 | 烟曲霉素衍生物-phf结合物的药物配制品 |
| EP2928503B1 (en) | 2012-12-10 | 2019-02-20 | Mersana Therapeutics, Inc. | Conjugates of auristatin compounds |
| AU2013359506B2 (en) * | 2012-12-10 | 2018-05-24 | Mersana Therapeutics, Inc. | Protein-polymer-drug conjugates |
| WO2014093640A1 (en) | 2012-12-12 | 2014-06-19 | Mersana Therapeutics,Inc. | Hydroxy-polmer-drug-protein conjugates |
| MY174813A (en) | 2013-03-15 | 2020-05-16 | Zymeworks Inc | Cytotoxic and anti-mitotic compounds, and methods of using the same |
| CA2925132C (en) | 2013-10-04 | 2021-11-30 | Prolynx Llc | Slow-release conjugates of sn-38 |
| CA2926586C (en) | 2013-10-11 | 2020-04-07 | Mersana Therapeutics, Inc. | Polymeric scaffold based on phf for targeted drug delivery |
| WO2015054669A1 (en) | 2013-10-11 | 2015-04-16 | Asana Biosciences, Llc | Protein-polymer-drug conjugates |
| CA2935077C (en) | 2013-12-27 | 2022-03-15 | Geoffrey C. Winters | Sulfonamide-containing linkage systems for drug conjugates |
| CA2960899C (en) | 2014-09-17 | 2021-08-17 | Zymeworks Inc. | Cytotoxic and anti-mitotic compounds, and methods of using the same |
| WO2016070089A2 (en) | 2014-10-31 | 2016-05-06 | Abbvie Biotherapeutics Inc. | Anti-cs1 antibodies and antibody drug conjugates |
| MX2017006167A (es) | 2014-11-12 | 2018-03-23 | Siamab Therapeutics Inc | Compuestos que interactúan con glicanos y métodos de uso. |
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- 2010-05-27 WO PCT/US2010/036413 patent/WO2010138719A1/en not_active Ceased
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| WO2010138719A1 (en) | 2010-12-02 |
| EP2435053A4 (en) | 2016-03-16 |
| AR078510A1 (es) | 2011-11-16 |
| AU2010254013A1 (en) | 2011-11-24 |
| EP2435053A1 (en) | 2012-04-04 |
| US8524214B2 (en) | 2013-09-03 |
| IL216325A0 (en) | 2012-01-31 |
| EP2435053B1 (en) | 2018-11-14 |
| JP2012528240A (ja) | 2012-11-12 |
| CN102448469A (zh) | 2012-05-09 |
| TW201102089A (en) | 2011-01-16 |
| US20100305149A1 (en) | 2010-12-02 |
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