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Bioorg Med Chem Lett ; 98: 129589, 2024 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-38097140

RESUMEN

Elevated levels of receptor tyrosine kinase-like orphan receptor 1 (RORl) expression are observed in multiple hematological and solid tumors, but not in most of the healthy adult tissues, identifying ROR1 as an attractive target for tumor-specific therapy. Herein we will describe the discovery of macrocyclic peptides as binders of the extracellular Cysteine-Rich Domain (CRD) of human ROR1 via mRNA in vitro selection technology using the PDPS platform, followed by exploration of sidechain SAR of parent macrocycle peptides, fluorescently labeled analogs, and a Peptide Drug Conjugate (PDC). The parent macrocyclic peptides represented by Compound 1 and Compound 14 displayed nanomolar cell-based binding to ROR1 and relatively good internalization in 786-O and MDA-MB-231 tumor cell lines. However, these peptides were not observed to induce apoptosis in Mia PaCa-2 cells, a model pancreatic tumor cell line with a relatively low level of cell surface expression of ROR1.


Asunto(s)
Péptidos Cíclicos , Receptores Huérfanos Similares al Receptor Tirosina Quinasa , Adulto , Humanos , Línea Celular Tumoral , Receptores Huérfanos Similares al Receptor Tirosina Quinasa/efectos de los fármacos , Receptores Huérfanos Similares al Receptor Tirosina Quinasa/metabolismo , Péptidos Cíclicos/química , Péptidos Cíclicos/farmacología
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