Wei, BinQing published the artcileDiscovery of Peptidomimetic Antibody-Drug Conjugate Linkers with Enhanced Protease Specificity, Quality Control of 2418-95-3, the publication is Journal of Medicinal Chemistry (2018), 61(3), 989-1000, database is CAplus and MEDLINE.
Antibody-drug conjugates (ADCs) have become an important therapeutic modality for oncol., with three approved by the FDA and over 60 others in clin. trials. Despite the progress, improvements in ADC therapeutic index are desired. Peptide-based ADC linkers that are cleaved by lysosomal proteases have shown sufficient stability in serum and effective payload-release in targeted cells. If the linker can be preferentially hydrolyzed by tumor-specific proteases, safety margin may improve. However, the use of peptide-based linkers limits our ability to modulate protease specificity. Here we report the structure-guided discovery of novel, nonpeptidic ADC linkers. We show that a cyclobutane-1,1-dicarboxamide-containing linker is hydrolyzed predominantly by cathepsin B while the valine-citrulline dipeptide linker is not. ADCs bearing the nonpeptidic linker are as efficacious and stable in vivo as those with the dipeptide linker. Our results strongly support the application of the peptidomimetic linker and present new opportunities for improving the selectivity of ADCs.
Journal of Medicinal Chemistry published new progress about 2418-95-3. 2418-95-3 belongs to amides-buliding-blocks, auxiliary class Chiral,Carboxylic acid,Amine,Aliphatic hydrocarbon chain,Ester,Amino acide derivatives, name is H-Lys(Boc)-OH, and the molecular formula is C7H8BNO4, Quality Control of 2418-95-3.
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