A general approach for the site-selective modification of native proteins, enabling the generation of stable and functional antibody–drug conjugates

Walsh, Stephen J.; Omarjee, Soleilmane; Galloway, Warren R. J. D.; Kwan, Terence T.-L.; Sore, Hannah F.; Parker, Jeremy S.; Hyvönen, Marko; Carroll, Jason S.; Spring, David R.

doi:10.1039/c8sc04645j

Cited by 95 publications

(91 citation statements)

References 46 publications

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“…25,26 Recently, novel divinylpyrimidine linkers have also been developed for selective bioconjugation through re-bridging of reduced disulfide bonds in native antibodies. 27 In this study, we report our efforts towards the synthesis and evaluation of a series of novel heterocyclic warheads capable of cysteine capture. Reactivity of warhead fragments was assessed using glutathione reactivity and quantum mechanical (QM) calculations.…”

Section: Introductionmentioning

confidence: 99%

Alkynyl Benzoxazines and Dihydroquinazolines as Cysteine Targeting Covalent Warheads and Their Application in Identification of Selective Irreversible Kinase Inhibitors

et al. 2020

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With a resurgence in interest in covalent drugs, there is need to identify new moieties capable of cysteine bond formation that are differentiated from commonly employed systems such as acrylamide. Herein, we report on the discovery of new alkynyl benzoxazine and dihydroquinazoline moieties capable of covalent reaction with cysteine. Their utility as alternative electrophilic warheads for chemical biological probes and drug molecules is demonstrated through site-selective protein modification and incorporation into kinase drug scaffolds. A potent covalent inhibitor of JAK3 kinase was identified with superior selectivity across the kinome and improvements in in vitro pharmacokinetic profile relative to the related acrylamide-based inhibitor. In addition, the use of a novel heterocycle as cysteine reactive warhead is employed to target Cys788 in c-KIT where acrylamide has previously failed to form covalent interactions. These new reactive and selective heterocyclic warheads supplement the current repertoire for cysteine covalent modification whilst avoiding some of the limitations generally associated with established moieties.

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Section: Introductionmentioning

confidence: 99%

Alkynyl Benzoxazines and Dihydroquinazolines as Cysteine Targeting Covalent Warheads and Their Application in Identification of Selective Irreversible Kinase Inhibitors

et al. 2020

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“…[11][12][13] In parallel, site-selective chemical strategies for the conjugation of native and natural proteins have also flourishedo ver the past few years, giving rise to methods targeting varioust ypes of amino acids (for example, lysine, cysteine, tryptophan, tyrosine) that proved to be effective on proteins of all sizes, including antibodies. [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28] With the aim of pursuing the efforts in this field, we could not help but notice that the vast majority of previously reported strategies for the site-selective conjugation of native proteins were focusedo nt he modificationo faunique residue. We hypothesized that targeting two different amino acid side chainss imultaneously would lower the enormouss ubset of possibilities given by single-residue bioconjugation techniques, thus increasing our chances of developing as ite-selective method by minimising the number of potentially reactive sites;apath that has also been successfully explored by others in the meantime.…”

Section: Introductionmentioning

confidence: 99%

Investigating Ugi/Passerini Multicomponent Reactions for the Site‐Selective Conjugation of Native Trastuzumab**

Sornay

Hessmann

Erb

et al. 2020

Chemistry A European J

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Site-selective modificationo fp roteins hasb een the object of intense studies over the past decades, especially in the therapeutic field. Prominent resultsh ave been obtained with recombinant proteins,f or which site-specific conjugation is made possible by the incorporation of particular aminoa cid residues or peptides equences. In parallel, methods for the site-selective and site-specific conjugation of native andn atural proteins are starting to thrive, allowing the controlled functionalization of various types of amino acid residues.P ursuingt he efforts in this field, we planned to develop an ew typeo fs ite-selective method, aiming at the simultaneous conjugation of two amino acid residues. We reasonedt hat this should give higher chances of developing as ite-selective strategy compared to the great majority of existing methods that solely target as ingle residue. We opted for the Ugi four-centre three-component reaction to implement this idea, with the aim of conjugating the sidechain amine and carboxylate groups of two neighbouring lysine and aspartate/glutamate. Herein,w es how that this strategyc an give access to valuable antibody conjugates bearings everald ifferent payloads;f urthermore, the approach limits the potential conjugation sites to only six on the model antibody trastuzumab.

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“…Expected improvements in this field rely on the design of novel drug-linker technologies that strongly influence the physicochemical properties of the conjugates 4–6. Key parameters such as (i) plasmatic stability of the drug-linker,7,8 (ii) Drug-Antibody-Ratio (DAR),9,10 (iii) conjugation position on the antibody component,11,12 (iv) overall hydrophobicity13 and homogeneity14,15 of the conjugates dictates pharmacokinetics (PK) properties, efficacy and tolerability of ADCs.…”

Section: Introductionmentioning

confidence: 99%

Monodisperse polysarcosine-based highly-loaded antibody-drug conjugates

et al. 2019

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A general approach for the site-selective modification of native proteins, enabling the generation of stable and functional antibody–drug conjugates

Abstract: Divinylpyrimidine (DVP) linkers enable access to highly stable and functional antibody–drug conjugates.

Cited by 95 publications

References 46 publications

Alkynyl Benzoxazines and Dihydroquinazolines as Cysteine Targeting Covalent Warheads and Their Application in Identification of Selective Irreversible Kinase Inhibitors

Alkynyl Benzoxazines and Dihydroquinazolines as Cysteine Targeting Covalent Warheads and Their Application in Identification of Selective Irreversible Kinase Inhibitors

Investigating Ugi/Passerini Multicomponent Reactions for the Site‐Selective Conjugation of Native Trastuzumab**

Monodisperse polysarcosine-based highly-loaded antibody-drug conjugates

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