Generation and structure-activity relationships of novel imidazo-thienopyridine based TLR7 agonists: application as payloads for immunostimulatory antibody drug-conjugates.

Autor: Brant MG; ADC Therapeutic Development, Zymeworks Inc., Vancouver, BC, Canada. Electronic address: michael.brant@zymeworks.com., Garnett GAE; ADC Therapeutic Development, Zymeworks Inc., Vancouver, BC, Canada., Guedia J; ADC Therapeutic Development, Zymeworks Inc., Vancouver, BC, Canada., Lasalle M; ADC Therapeutic Development, Zymeworks Inc., Vancouver, BC, Canada., Lawn S; ADC Therapeutic Development, Zymeworks Inc., Vancouver, BC, Canada., Petersen ME; ADC Therapeutic Development, Zymeworks Inc., Vancouver, BC, Canada., Duan R; ADC Therapeutic Development, Zymeworks Inc., Vancouver, BC, Canada., Mendez-Campos J; ADC Therapeutic Development, Zymeworks Inc., Vancouver, BC, Canada., Hirkala-Schaefer T; ADC Therapeutic Development, Zymeworks Inc., Vancouver, BC, Canada., Winters GC; ADC Therapeutic Development, Zymeworks Inc., Vancouver, BC, Canada., Barnscher SD; ADC Therapeutic Development, Zymeworks Inc., Vancouver, BC, Canada. Electronic address: stuart.barnscher@zymeworks.com.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2023 Jul 15; Vol. 91, pp. 129348. Date of Electronic Publication: 2023 May 20.
DOI: 10.1016/j.bmcl.2023.129348
Abstrakt: Pairing immunostimulatory small molecules with the targeting capability of an antibody has emerged as a novel therapeutic modality with the potential to treat a variety of solid tumors. A series of compounds based on an imidazo-thienopyridine scaffold were synthesized and tested for their ability to agonize the innate immune sensors toll-like receptor 7 and 8 (TLR7/8). Structure-activity relationship (SAR) studies revealed that certain simple amino-substituents could enable TLR7 agonism at low nanomolar concentrations. Drug-linkers containing either payload 1 or 20h were conjugated to the HER2-targeting antibody trastuzumab at the interchain disulfide cysteine residues using a cleavable valine-citrulline dipeptide linker and stochastic thiol-maleimide chemistry. In vitro, these immune-stimulating antibody drug-conjugates (ADCs) were found to induce cytokine release in a murine splenocyte assay when co-cultured with the HER2-high NCI-N87 cancer cell line. In vivo, tumor regression was observed with a single dose in an NCI-N87 gastric carcinoma xenograft model in BALB/c nude mice.
Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The authors are current/former employees of Zymeworks Inc. and are shareholders in the company.
(Copyright © 2023 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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