Lead optimisation of small molecule sulfatase reactivators for multiple sulfatase deficiency

Abstract

Sulfatases are enzymes essential for the degradation of sulfate esters. Formylglycine (FGly) is fundamental for their catalytic activity and is generated from a cysteine precursor by the FGly-generating enzyme (FGE). The critical importance of the FGly residue for the biological function of sulfatases is illustrated by multiple sulfatase deficiency (MSD), a fatal rare autosomal recessive disorder characterised by almost complete lack of all sulfatase activities due to mutations of the SUMF1 gene, which encodes FGE. A recent in-house drug repurposing screening assay identified Tazarotene, Bexarotene and their derivatives as enhancers of sulfatases activity in MSD patient derived cell lines. Herein, we report the synthesis and biological evaluation of several Tazarotene and Bexarotene analogues as well as novel small-molecule stabilizers of FGE using fragment-based drug discovery (FBDD). Iterative design, synthesis and biological and crystallographic characterization of these compounds were used to determine the structure-activity relationship (SAR) and identify analogues with improved affinity and selectivity for biological targets, towards new therapies for MSD.

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Identifiers

ORCID for Niama Ezzaidi: orcid.org/0009-0007-0705-6911

ORCID for Matthias Baud: orcid.org/0000-0003-3714-4350

ORCID for Sam Thompson: orcid.org/0000-0001-6267-5693

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