Covalent fragment libraries in drug discovery—Design, synthesis, and screening methods

Hocking, Brad; Armstrong, Alan; Mann, David J.

doi:10.1016/bs.pmch.2023.10.003

“…Due to the reactive nature of the compounds in the covalent screening library, there were concerns about their long-term stability . To understand whether these concerns were valid, a purity assessment was conducted using LC-UV/MS on initial solubilization ( T 0 ) and subsequently at a further time point that was >5 days (this varied depending on when a specific compounds was added to the collection) .…”

Section: Resultsmentioning

confidence: 99%

“…They should contain functionality capable of making molecular interactions with target proteins and display the CRG along diverse vectors from the reversible scaffold. Most libraries reported in the literature contain fragment-sized molecules and typically consist of <2 k compounds, which should enable broad coverage of fragment chemical space. , Despite reported successes of hit finding from these fragment-based approaches, we were conscious that reported hits for targets such as KRAS G12C were typically in lead-like space . For such intractable targets lacking obvious drug-like pockets, the potential to bind to allosteric binding sites and then covalently modify the target is viewed to be more likely with lead-like ligands than with covalent fragments, for which binding tends to be more reactivity driven.…”

Section: Introductionmentioning

confidence: 99%

Design of a Lead-Like Cysteine-Targeting Covalent Library and the Identification of Hits to Cys55 of Bfl-1

Lucas,

Milbradt,

Blackwell

et al. 2024

J. Med. Chem.

1

0

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Covalent hit identification is a viable approach to identify chemical starting points against difficult-to-drug targets. While most researchers screen libraries of <2k electrophilic fragments, focusing on lead-like compounds can be advantageous in terms of finding hits with improved affinity and with a better chance of identifying cryptic pockets. However, due to the increased molecular complexity, larger numbers of compounds (>10k) are desirable to ensure adequate coverage of chemical space. Herein, the approach taken to build a library of 12k covalent lead-like compounds is reported, utilizing legacy compounds, robust library chemistry, and acquisitions. The lead-like covalent library was screened against the antiapoptotic protein Bfl-1, and six promising hits that displaced the BIM peptide from the PPI interface were identified. Intriguingly, X-ray crystallography of lead-like compound 8 showed that it binds to a previously unobserved conformation of the Bfl-1 protein and is an ideal starting point for the optimization of Bfl-1 inhibitors.

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Synthesis and Functionalization of Sulfoximine‐Bicyclo[1.1.0]butanes: Functionalizable, Tuneable and Cysteine‐Selective Chiral Warheads

Zhong,

Hocking,

Brown

et al. 2024

Angewandte Chemie

0

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Electrophilic covalent warheads with appropriate reactivity and selectivity are crucial to the investigation of protein function and the discovery of therapeutics. Here we report the synthesis of sulfoximine bicyclo[1.1.0]butanes (BCBs) as novel thiol reactive chiral warheads, achieved in one‐pot from methylsulfoximines. Unusually the warhead can then be derivatized, keeping the BCB intact, over 3 vectors: i) sulfoximine N‐modification instills a broad range of strain‐release reactivity; ii) sp2‐cross‐coupling reactions on aryl‐BCB‐sulfoximines allows direct diversification, and iii) functionalization of the BCB motif itself is achieved by metalation and trapping with electrophiles. The BCB sulfoximines are shown to react selectively with cysteine including in a protein model (CDK2) under biocompatible conditions. Preliminary data indicate suitability for chemoproteomic applications, and enantioselective cysteine‐labelling. The reactivity of sulfoximine BCBs with electron withdrawing groups on nitrogen is comparable to acrylamides with low to moderate reactivity.

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Synthesis and Functionalization of Sulfoximine‐Bicyclo[1.1.0]butanes: Functionalizable, Tuneable and Cysteine‐Selective Chiral Warheads

Zhong,

Hocking,

Brown

et al. 2024

Angew Chem Int Ed

0

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Electrophilic covalent warheads with appropriate reactivity and selectivity are crucial to the investigation of protein function and the discovery of therapeutics. Here we report the synthesis of sulfoximine bicyclo[1.1.0]butanes (BCBs) as novel thiol reactive chiral warheads, achieved in one‐pot from methylsulfoximines. Unusually the warhead can then be derivatized, keeping the BCB intact, over 3 vectors: i) sulfoximine N‐modification instills a broad range of strain‐release reactivity; ii) sp2‐cross‐coupling reactions on aryl‐BCB‐sulfoximines allows direct diversification, and iii) functionalization of the BCB motif itself is achieved by metalation and trapping with electrophiles. The BCB sulfoximines are shown to react selectively with cysteine including in a protein model (CDK2) under biocompatible conditions. Preliminary data indicate suitability for chemoproteomic applications, and enantioselective cysteine‐labelling. The reactivity of sulfoximine BCBs with electron withdrawing groups on nitrogen is comparable to acrylamides with low to moderate reactivity.

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Covalent fragment libraries in drug discovery—Design, synthesis, and screening methods

Cited by 4 publications

References 109 publications

Design of a Lead-Like Cysteine-Targeting Covalent Library and the Identification of Hits to Cys55 of Bfl-1

Design of a Lead-Like Cysteine-Targeting Covalent Library and the Identification of Hits to Cys55 of Bfl-1

Synthesis and Functionalization of Sulfoximine‐Bicyclo[1.1.0]butanes: Functionalizable, Tuneable and Cysteine‐Selective Chiral Warheads

Synthesis and Functionalization of Sulfoximine‐Bicyclo[1.1.0]butanes: Functionalizable, Tuneable and Cysteine‐Selective Chiral Warheads

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