Products Cited in Publications Worldwide Cell-active peptide inhibitors of the FANCM-RMI interaction

Cell-active peptide inhibitors of the FANCM-RMI interaction

Alcock, Lisa J; Mills, Joshua; Bythell-Douglas, Rohan; Sudhakar, Haritha Krishna; Deshpande, Chandrika; Passioura, Toby; Deans, Andrew J; Lau, Yu Heng

DOI:

Abstract

The FANCM-RMI protein-protein interaction plays an essential role in cancers that extend their telomeres through the Alternative Lengthening of Telomeres (ALT) pathway. Here, we report the first cell-active peptide inhibitors of FANCM-RMI. Screening of mRNA-displayed peptide libraries treated with trans-1,4-dibromo-2-butene led to the discovery of both linear and cyclic peptide hits that bind RMI at the FANCM interaction site. The most potent peptides engage RMI with nanomolar affinity (KD = 4-37 nM) and outcompete the native peptide mimic of FANCM (IC50 = 24-155 nM). A bound X-ray crystal structure of the optimal peptide hit revealed novel interactions at the RMI binding site that are not found in the native interaction. Conjugation to a cell-penetrating peptide resulted in inhibitors that induced an antiproliferative effect in ALT-positive osteosarcoma cell lines. These inhibitors represent the first bioactive RMI binders that can be used as chemical tools for studying the involvement of FANCM-RMI in ALT-driven cancers.

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Fmoc-Asp(OtBu)-OH

A13152271989-14-598%

Fmoc-Asp(OtBu)-OH

10.0/250mg

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Fmoc-Ser(tBu)-OH

A25221671989-33-898%

Fmoc-Ser(tBu)-OH

12.0/5g

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Fmoc-Thr(tBu)-OH

A41574471989-35-097%

Fmoc-Thr(tBu)-OH

10.0/5g

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