{"entity": "publication", "iuid": "833bd35c6f9343eca70e9d216f2dac9a", "timestamp": "2026-07-17T04:42:37.472Z", "links": {"self": {"href": "https://publications.scilifelab.se/publication/833bd35c6f9343eca70e9d216f2dac9a.json"}, "display": {"href": "https://publications.scilifelab.se/publication/833bd35c6f9343eca70e9d216f2dac9a"}}, "title": "Rational Design of Azastatin as a Potential ADC Payload with Reduced Bystander Killing.", "authors": [{"family": "Hartmann", "given": "Rafael W", "initials": "RW", "orcid": "0000-0002-5520-0179", "researcher": {"href": "https://publications.scilifelab.se/researcher/7c8d3d38aa874be68232147db4b1dde0.json"}}, {"family": "Fahrner", "given": "Raphael", "initials": "R", "orcid": "0000-0002-6737-0917", "researcher": {"href": "https://publications.scilifelab.se/researcher/4bff9aa2f39b428599d006065f0400d9.json"}}, {"family": "Shevshenko", "given": "Denys", "initials": "D", "orcid": "0000-0001-8779-0153", "researcher": {"href": "https://publications.scilifelab.se/researcher/fe6b3911262c4355af202746e3be90b7.json"}}, {"family": "Fyrkn\u00e4s", "given": "M\u00e5rten", "initials": "M"}, {"family": "Larsson", "given": "Rolf", "initials": "R"}, {"family": "Lehmann", "given": "Fredrik", "initials": "F", "orcid": "0000-0001-7385-3870", "researcher": {"href": "https://publications.scilifelab.se/researcher/822d2043ec8c4d3bb5341a1dfd007d4e.json"}}, {"family": "Odell", "given": "Luke R", "initials": "LR", "orcid": "0000-0001-7658-5103", "researcher": {"href": "https://publications.scilifelab.se/researcher/7653ba79ce9d4e4a80be4b42f516680b.json"}}], "type": "journal article", "published": "2020-12-15", "journal": {"title": "ChemMedChem", "issn": "1860-7187", "volume": "15", "issue": "24", "pages": "2500-2512", "issn-l": "1860-7179"}, "abstract": "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.", "doi": "10.1002/cmdc.202000497", "pmid": "33063934", "labels": {"Drug Discovery and Development": null}, "xrefs": [{"db": "pmc", "key": "PMC7756782"}], "notes": [], "created": "2021-12-08T12:26:21.225Z", "modified": "2025-10-17T13:05:07.940Z"}