Halogenation at the Phenylalanine Residue of Monomethyl Auristatin F Leads to a Favorable cis/trans Equilibrium and Retained Cytotoxicity

Show simple item record

dc.contributor.author Sokka, Iris K.
dc.contributor.author Imlimthan, Surachet
dc.contributor.author Sarparanta, Mirkka
dc.contributor.author Maaheimo, Hannu
dc.contributor.author Johansson, Mikael P.
dc.contributor.author Ekholm, Filip S.
dc.date.accessioned 2021-08-31T06:10:01Z
dc.date.available 2021-08-31T06:10:01Z
dc.date.issued 2021-08-02
dc.identifier.citation Sokka , I K , Imlimthan , S , Sarparanta , M , Maaheimo , H , Johansson , M P & Ekholm , F S 2021 , ' Halogenation at the Phenylalanine Residue of Monomethyl Auristatin F Leads to a Favorable cis/trans Equilibrium and Retained Cytotoxicity ' , Molecular Pharmaceutics , vol. 18 , no. 8 , pp. 3125-3131 . https://doi.org/10.1021/acs.molpharmaceut.1c00342
dc.identifier.other PURE: 168014267
dc.identifier.other PURE UUID: d1a682be-c153-41dc-9fb1-1a4824e459ea
dc.identifier.other WOS: 000683329000022
dc.identifier.other ORCID: /0000-0002-2956-4366/work/99271736
dc.identifier.other ORCID: /0000-0002-4461-2215/work/99271786
dc.identifier.other ORCID: /0000-0003-2520-2146/work/99273412
dc.identifier.other ORCID: /0000-0002-9793-8235/work/99273538
dc.identifier.uri http://hdl.handle.net/10138/333790
dc.description.abstract Halogenation can be utilized for the purposes of labeling and molecular imaging, providing a means to, e.g., follow drug distribution in an organism through positron emission tomography (PET) or study the molecular recognition events unfolding by nuclear magnetic resonance (NMR) spectroscopy. For cancer therapeutics, where often highly toxic substances are employed, it is of importance to be able to track the distribution of the drugs and their metabolites in order to ensure minimal side effects. Labeling should ideally have a negligible disruptive effect on the efficacy of a given drug. Using a combination of NMR spectroscopy and cytotoxicity assays, we identify a site susceptible to halogenation in monomethyl auristatin F (MMAF), a widely used cytotoxic agent in the antibody-drug conjugate (ADC) family of cancer drugs, and study the effects of fluorination and chlorination on the physiological solution structure of the auristatins and their cytotoxicity. We find that the cytotoxicity of the parent drug is retained, while the conformational equilibrium is shifted significantly toward the biologically active trans isomer, simultaneously decreasing the concentration of the inactive and potentially disruptive cis isomer by up to 50%. Our results may serve as a base for the future assembly of a multifunctional toolkit for the assessment of linker technologies and exploring bystander effects from the warhead perspective in auristatin-derived ADCs. en
dc.format.extent 7
dc.language.iso eng
dc.relation.ispartof Molecular Pharmaceutics
dc.rights cc_by
dc.rights.uri info:eu-repo/semantics/openAccess
dc.subject 317 Pharmacy
dc.subject antibody-drug conjugates
dc.subject auristatins
dc.subject cancer therapeutics
dc.subject structural characterization
dc.subject NMR-spectroscopy
dc.subject ANTIBODY
dc.subject DRUG
dc.subject DOLASTATIN-10
dc.subject LINKER
dc.subject PET
dc.subject DISCOVERY
dc.subject VEDOTIN
dc.subject NMR
dc.title Halogenation at the Phenylalanine Residue of Monomethyl Auristatin F Leads to a Favorable cis/trans Equilibrium and Retained Cytotoxicity en
dc.type Article
dc.contributor.organization Department of Chemistry
dc.contributor.organization Doctoral Programme in Chemistry and Molecular Sciences
dc.contributor.organization Helsinki Institute of Sustainability Science (HELSUS)
dc.description.reviewstatus Peer reviewed
dc.relation.doi https://doi.org/10.1021/acs.molpharmaceut.1c00342
dc.relation.issn 1543-8384
dc.rights.accesslevel openAccess
dc.type.version publishedVersion

Files in this item

Total number of downloads: Loading...

Files Size Format View
acs.molpharmaceut.1c00342.pdf 3.298Mb PDF View/Open

This item appears in the following Collection(s)

Show simple item record