SFB 1243 Cancer Evolution

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ChemBioChem research article on defined protein conjugates

Heinrich Leonhardt and Tubulis associates Jonas Helma and Dominik Schumacher team up with Berlin colleagues


Marc-André Kasper, Marcus Gerlach, Anselm F.L. Schneider, Christtiane Groneberg, Philipp Ochtrop, Stefanie Boldt, Dominik Schumacher, Jonas Helma, Heinrich Leonhardt, Mathias Christmann and Christian P.R. Hackenberger (in press) NHS-modified ethynylphosphonamidates enable the synthesis of configurationally defined protein conjugates. ChemBioChem 10.1002/cbic.201900587

Abstract cited from the publication:

"We describe the application of N-hydroxysuccinimide-(NHS-)-modified phosphonamidate building blocks for
the incorporation of Cysteine-selective ethynylphosphonamidates to lysine residues of proteins followed by thiol addition with small molecules and proteins. We demonstrate that our building blocks significantly lower undesired homo-crosslinking side-products that can occur with commonly applied succinimidyl 4-(Nmaleimidomethyl)
cyclohexane-1-carboxylate (SMCC) under physiological pH. The previously demonstrated stability of the
phosphonamidate moiety additionally solves the problem of premature maleimide hydrolysis, which can hamper the efficiency of the subsequent thiol addition. Furthermore, we developed a method to separate the phosphonamidate enantiomers to be able to synthesize protein-conjugates in a defined configuration. Finally, we apply our building blocks to the construction of functional Antibody Drug Conjugates (ADCs), analogously to the FDA-approved, SMCClinked
Kadcyla and to the synthesis of a functional antibody-protein conjugate."

See the feature interview in Pharma Technology Focus on drug delivery: "A safer ride: The latest innovation in targeted cancer treatment" by Abi Millar.

See also the main paper: Kasper MA, Stengl A, Ochtrop P, Gerlach M, Stoschek T, Schumacher D, Helma J, Penkert M, Krause E, Leonhardt H, Hackenberger CPR (2019) Ethynylphosphonamidates for the rapid and cysteine selective generation of efficacious Antibody-Drug-Conjugates. Angew. Chem. Int. Ed. Doi: 10.1002/anie.201904193