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Rational Design of ...
Rational Design of Azastatin as a Potential ADC Payload with Reduced Bystander Killing.
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- Hartmann, Rafael (författare)
- Uppsala universitet,Preparativ läkemedelskemi
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Fahrner, Raphael (författare)
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Shevshenko, Denys (författare)
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- Fryknäs, Mårten (författare)
- Uppsala universitet,Cancerfarmakologi och beräkningsmedicin
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- Larsson, Rolf (författare)
- Uppsala universitet,Cancerfarmakologi och beräkningsmedicin
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Lehmann, Fredrik (författare)
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- Odell, Luke R. (författare)
- Uppsala universitet,Preparativ läkemedelskemi
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(creator_code:org_t)
- 2020-10-16
- 2020
- Engelska.
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Ingår i: ChemMedChem. - : Wiley. - 1860-7179 .- 1860-7187. ; 15:24, s. 2500-2512
- Relaterad länk:
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https://doi.org/10.1...
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https://uu.diva-port... (primary) (Raw object)
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https://doi.org/10.1...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- Auristatins are a class of ultrapotent microtubule inhibitors, whose growing clinical popularity in oncology is based upon their use as payloads in antibody-drug conjugates (ADCs). The most widely utilized auristatin, MMAE, has however been shown to cause apoptosis in non-pathological cells proximal to the tumour ("bystander killing"). Herein, we introduce azastatins, a new class of auristatin derivatives encompassing a side chain amine for antibody conjugation. The synthesis of Cbz-azastatin methyl ester, which included the C2-elongation and diastereoselective reduction of two proteinogenic amino acids as key transformations, was accomplished in 22 steps and 0.76 % overall yield. While Cbz-protected azastatin methyl ester (0.13-3.0 nM) inhibited proliferation more potently than MMAE (0.47-6.5 nM), removal of the Cbz-group yielded dramatically increased IC50 -values (9.8-170 nM). We attribute the reduced apparent cytotoxicity of the deprotected azastatin methyl esters to a lack of membrane permeability. These results clearly establish the azastatins as a novel class of cytotoxic payloads ideally suited for use in next-generation ADC development.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Läkemedelskemi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medicinal Chemistry (hsv//eng)
Nyckelord
- Antibodies
- Cytotoxicity
- Diastereoselectivity
- Medicinal chemistry
- Total synthesis
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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