Deconstructing Noncovalent Kelch-like ECH-Associated Protein 1 (Keap1) Inhibitors into Fragments to Reconstruct New Potent Compounds

Pallesen, Jakob; Narayanan, D.; Tran, Kim T.; Solbak, Sara Marie Øie; Marseglia, Giuseppe; Sørensen, Louis M.E.; Høj, Lars Jakobsen; Munafò, Federico; Carmona, Rosa María; Garcia, Anthony D.; Desu, Haritha L.; Brambilla, Roberta; Johansen, Tommy N.; Popowicz, Grzegorz M.; Sattler, Michael; Gajhede, Michael; Bach, Anders

doi:10.1021/acs.jmedchem.0c02094

Cited by 32 publications

(56 citation statements)

References 102 publications

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“…Retaining the 2-propylpiperidine amide of 23, further growth from the cyclopropyl ring was assessed in the R 1 position (Table 3) with pyridazine (34) giving the best affinity for the six-membered aromatic systems explored. A larger dropoff in the cell-based potency was observed compared to simpler examples shown in Table 2, but introduction of a triazole moiety at this position (35) led to a 10-fold improvement in BEAS-2B activity compared to the pyridazine. Single enantiomers of this compound were subsequently prepared with the most active stereoisomer (37) giving a potency (EC 50 ) in the BEAS-2B assay of 43 nM.…”

Section: ■ Resultsmentioning

confidence: 89%

“…We highlight here how knowledge of key points of molecular recognition obtained from fragment screening can be used to inform additional hit identification campaigns and rapidly identify alternative lead series. Fragment screening and traditional HTS-based drug discovery campaigns are both important components of the medicinal chemist’s “tool-kit”, and can be synergistic, for example, through deconstruction of larger hits, − combined HTS/FBDD campaigns, , and exploitation of motifs identified from fragment screening to enrich or focus screening decks. In addition, recapitulating patterns of protein–ligand interactions identified through fragment screening is a powerful route to increasing affinity and, when combined with structural information, provides an effective approach to scaffold-hopping.…”

Section: Discussionmentioning

confidence: 99%

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Fragment-Guided Discovery of Pyrazole Carboxylic Acid Inhibitors of the Kelch-like ECH-Associated Protein 1: Nuclear Factor Erythroid 2 Related Factor 2 (KEAP1:NRF2) Protein−Protein Interaction

Norton¹,

Bonnette

Callahan

et al. 2021

J. Med. Chem.

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The NRF2-mediated cytoprotective response is central to cellular homoeostasis, and there is increasing interest in developing small-molecule activators of this pathway as therapeutics for diseases involving chronic oxidative stress. The protein KEAP1, which regulates NRF2, is a key point for pharmacological intervention, and we recently described the use of fragment-based drug discovery to develop a tool compound that directly disrupts the protein−protein interaction between NRF2 and KEAP1. We now present the identification of a second, chemically distinct series of KEAP1 inhibitors, which provided an alternative chemotype for lead optimization. Pharmacophoric information from our original fragment screen was used to identify new hit matter through database searching and to evolve this into a new lead with high target affinity and cell-based activity. We highlight how knowledge obtained from fragment-based approaches can be used to focus additional screening campaigns in order to de-risk projects through the rapid identification of novel chemical series.

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Section: ■ Resultsmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Fragment-Guided Discovery of Pyrazole Carboxylic Acid Inhibitors of the Kelch-like ECH-Associated Protein 1: Nuclear Factor Erythroid 2 Related Factor 2 (KEAP1:NRF2) Protein−Protein Interaction

Norton¹,

Bonnette

Callahan

et al. 2021

J. Med. Chem.

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show abstract

“…One of legitimate ways to create new, potent inhibitors is deconvolution of existing inhibitors into several fragments and re‐combination of these fragments in different ways 15,16 . The information of approximate binding sites of fragments can be extracted from co‐crystal structures of existing inhibitors with Keap1, and hybridization of fragments can be rationally performed based on this knowledge.…”

Section: Figurementioning

confidence: 99%

Structural hybridization for inhibitors of the interaction between NRF2 and Keap1

Lee

Seo

Gotina

et al. 2022

Bulletin Korean Chem Soc

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NRF2 is considered as a master regulator of cellular defense system under stressed conditions such as oxidative stress. In physiological conditions, NRF2 forms a complex with Keap1‐Cul3 in the cytoplasm and undergoes ubiquitination and subsequent degradation. Under stressed conditions, the interaction between NRF2 and Keap1 is perturbed leading to NRF2 stabilization and migration to the nucleus where NRF2 activates genes accounting for antioxidative activities. Thus, small molecules that can disturb the interaction between NRF2 and Keap1 has been considered as promising for a variety of diseases. Herein, we report development of new, potent inhibitors of the interaction between NRF2 and Keap1 by deconvoluting previous inhibitors followed by structural hybridization. The most potent inhibitor identified by our FP assay showed IC50 of 0.6 μM. We believe that our compounds will help to expand structural diversity of NRF2–Keap1 interaction inhibitors contributing to further development of promising candidates for various diseases.

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“…We choose six diverse inhibitors of different kinases as starting points and in each case generate and explore the chemical space around this inhibitor. We describe a “deconstruction-reconstruction” approach, , in which the synthetic route used to build the known inhibitor is generalized and used to create a huge chemical library that densely samples synthetically accessible chemical space. The resulting libraries can exceed billions of compounds, vastly exceeding the scales amenable to explicit docking even when the protein is held fully fixed .…”

Section: Introductionmentioning

confidence: 99%

Efficient Hit-to-Lead Searching of Kinase Inhibitor Chemical Space via Computational Fragment Merging

Andrianov

Ong

Serebriiskii

et al. 2021

J. Chem. Inf. Model.

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In early-stage drug discovery, the hit-to-lead optimization (or "hit expansion") stage entails starting from a newly identified active compound and improving its potency or other properties. Traditionally, this process relies on synthesizing and evaluating a series of analogues to build up structure−activity relationships. Here, we describe a computational strategy focused on kinase inhibitors, intended to expedite the process of identifying analogues with improved potency. Our protocol begins from an inhibitor of the target kinase and generalizes the synthetic route used to access it. By searching for commercially available replacements for the individual building blocks used to make the parent inhibitor, we compile an enumerated library of compounds that can be accessed using the same chemical transformations; these huge libraries can exceed many millionsor billionsof compounds. Because the resulting libraries are much too large for explicit virtual screening, we instead consider alternate approaches to identify the top-scoring compounds. We find that contributions from individual substituents are well described by a pairwise additivity approximation, provided that the corresponding fragments position their shared core in precisely the same way relative to the binding site. This key insight allows us to determine which fragments are suitable for merging into single new compounds and which are not. Further, the use of pairwise approximation allows interaction energies to be assigned to each compound in the library without the need for any further structure-based modeling: interaction energies instead can be reliably estimated from the energies of the component fragments, and the reduced computational requirements allow for flexible energy minimizations that allow the kinase to respond to each substitution. We demonstrate this protocol using libraries built from six representative kinase inhibitors drawn from the literature, which target five different kinases: CDK9, CHK1, CDK2, EGFR T790M , and ACK1. In each example, the enumerated library includes additional analogues reported by the original study to have activity, and these analogues are successfully prioritized within the library. We envision that the insights from this work can facilitate the rapid assembly and screening of increasingly large libraries for focused hit-to-lead optimization. To enable adoption of these methods and to encourage further analyses, we disseminate the computational tools needed to deploy this protocol.

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Deconstructing Noncovalent Kelch-like ECH-Associated Protein 1 (Keap1) Inhibitors into Fragments to Reconstruct New Potent Compounds

Cited by 32 publications

References 102 publications

Fragment-Guided Discovery of Pyrazole Carboxylic Acid Inhibitors of the Kelch-like ECH-Associated Protein 1: Nuclear Factor Erythroid 2 Related Factor 2 (KEAP1:NRF2) Protein−Protein Interaction

Fragment-Guided Discovery of Pyrazole Carboxylic Acid Inhibitors of the Kelch-like ECH-Associated Protein 1: Nuclear Factor Erythroid 2 Related Factor 2 (KEAP1:NRF2) Protein−Protein Interaction

Structural hybridization for inhibitors of the interaction between NRF2 and Keap1

Efficient Hit-to-Lead Searching of Kinase Inhibitor Chemical Space via Computational Fragment Merging

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