A fragment-based approach towards the discovery of N-substituted tropinones as inhibitors of Mycobacterium tuberculosis transcriptional regulator EthR2

Prevet, Hugues; Moune, Martin; Tanina, Abdalkarim; Kemmer, Christian; Herlédan, Adrien; Frita, Rosangela; Wohlkonig, A.; Bourotte, Marilyne; Villemagne, Baptiste; Leroux, Florence; Gitzinger, Marc; Baulard, Alain R.; Déprez, Benoît; Wintjens, René; Willand, Nicolas; Flipo, Marion

doi:10.1016/j.ejmech.2019.02.023

Cited by 14 publications

(9 citation statements)

References 32 publications

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“…It is inevitable and unfortunate that the necessity to define strict criteria for inclusion in the table leads to a number of "near-misses". These can still be interesting, inspiring, and pioneering FBDD stories, and 2019 examples include inhibitors of protein−protein interactions, 9 protein−DNA interactions, 10,11 bacterial targets 12 including bacterial quorum sensing, 13 sepiapterin reductase, 14 Glyoxalase 1, 15 Bruton's tyrosine kinase, 16 and the CXCR4 chemokine receptor. 17 Candidate articles for inclusion in Table 1 were identified as described in detail in previous perspectives.…”

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confidence: 99%

Fragment-to-Lead Medicinal Chemistry Publications in 2019

Jahnke

Erlanson²,

Esch

et al. 2020

J. Med. Chem.

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Fragment-based drug discovery (FBDD) has grown and matured to a point where it is valuable to keep track of its extent and details of application. This Perspective summarizes successful fragment-to-lead stories published in 2019. It is the fifth in a series that started with literature published in 2015. The analysis of screening methods, optimization strategies, and molecular properties of hits and leads are presented in the hope of informing best practices for FBDD. Moreover, FBDD is constantly evolving, and the latest technologies and emerging trends are summarized. These include covalent FBDD, FBDD for the stabilization of proteins or protein–protein interactions, FBDD for enzyme activators, new screening technologies, and advances in library design and chemical synthesis.

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confidence: 99%

Fragment-to-Lead Medicinal Chemistry Publications in 2019

Jahnke

Erlanson²,

Esch

et al. 2020

J. Med. Chem.

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“…The EthR2 protein has three tryptophan residues ( Fig. 6 ), one of which is near to the binding site of several known inhibitors of EthR2 ( Prevet et al, 2019 ). However, there is insufficient evidence from the intrinsic tryptophan fluorescence binding assays to predict whether BM212 also binds to this site as it is unclear which tryptophan residue(s) is affected by ligand binding.…”

Section: Discussionmentioning

confidence: 99%

“…6 Amino acid sequence of EthR2 (Rv0078) with tryptophan residues (W) highlighted in yellow. The tryptophan residue near to the binding site of several known EthR2 inhibitors is in bold and underlined ( Prevet et al, 2019 ). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)…”

Section: Discussionmentioning

confidence: 99%

The multi-target aspect of an MmpL3 inhibitor: The BM212 series of compounds bind EthR2, a transcriptional regulator of ethionamide activation

et al. 2021

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The emergence of drug-resistant strains of Mycobacterium tuberculosis ( Mtb ) ensures that drug discovery efforts remain at the forefront of TB research. There are multiple different experimental approaches that can be employed in the discovery of anti-TB agents. Notably, inhibitors of MmpL3 are numerous and structurally diverse in Mtb and have been discovered through the generation of spontaneous resistant mutants and subsequent whole genome sequencing studies. However, this approach is not always reliable and can lead to incorrect target assignment and requires orthogonal confirmatory approaches. In fact, many of these inhibitors have also been shown to act as multi-target agents, with secondary targets in Mtb , as well as in other non-MmpL3-containing pathogens. Herein, we have investigated further the cellular targets of the MmpL3-inhibitor BM212 and a number of BM212 analogues . To determine the alternative targets of BM212, which may have been masked by MmpL3 mutations, we have applied a combination of chemo-proteomic profiling using bead-immobilised BM212 derivatives and protein extracts, along with whole-cell and biochemical assays. The study identified EthR2 (Rv0078) as a protein that binds BM212 analogues. We further demonstrated binding of BM212 to EthR2 through an in vitro tryptophan fluorescence assay, which showed significant quenching of tryptophan fluorescence upon addition of BM212. Our studies have demonstrated the value of revisiting drugs with ambiguous targets, such as MmpL3, in an attempt to find alternative targets and the study of off-target effects to understand more precisely target engagement of new hits emerging from drug screening campaigns.

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“…The success encountered with the fragment-based approach for the identification of EthR inhibitors encouraged us to start from fragments to identify new chemotypes of EthR 2 ligands. The screening of EthR 2 with our fragment library using thermal shift assay led to the identification of five new chemical series [ 41 ]. Structure-based optimisation of the tropinone-based scaffold led to BDM76150 ( Figure 5 B), a sub-micromolar EthR 2 inhibitor.…”

Section: Chemical Biology Strategies To Identify New Hitsmentioning

confidence: 99%

Molecular Design in Practice: A Review of Selected Projects in a French Research Institute That Illustrates the Link between Chemical Biology and Medicinal Chemistry

et al. 2021

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Chemical biology and drug discovery are two scientific activities that pursue different goals but complement each other. The former is an interventional science that aims at understanding living systems through the modulation of its molecular components with compounds designed for this purpose. The latter is the art of designing drug candidates, i.e., molecules that act on selected molecular components of human beings and display, as a candidate treatment, the best reachable risk benefit ratio. In chemical biology, the compound is the means to understand biology, whereas in drug discovery, the compound is the goal. The toolbox they share includes biological and chemical analytic technologies, cell and whole-body imaging, and exploring the chemical space through state-of-the-art design and synthesis tools. In this article, we examine several tools shared by drug discovery and chemical biology through selected examples taken from research projects conducted in our institute in the last decade. These examples illustrate the design of chemical probes and tools to identify and validate new targets, to quantify target engagement in vitro and in vivo, to discover hits and to optimize pharmacokinetic properties with the control of compound concentration both spatially and temporally in the various biophases of a biological system.

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A fragment-based approach towards the discovery of N-substituted tropinones as inhibitors of Mycobacterium tuberculosis transcriptional regulator EthR2

Cited by 14 publications

References 32 publications

Fragment-to-Lead Medicinal Chemistry Publications in 2019

Fragment-to-Lead Medicinal Chemistry Publications in 2019

The multi-target aspect of an MmpL3 inhibitor: The BM212 series of compounds bind EthR2, a transcriptional regulator of ethionamide activation

Molecular Design in Practice: A Review of Selected Projects in a French Research Institute That Illustrates the Link between Chemical Biology and Medicinal Chemistry

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