Repurposing of the RIPK1-Selective Benzo[1,4]oxazepin-4-one Scaffold for the Development of a Type III LIMK1/2 Inhibitor

Benzoxazepinones have been extensively studied as exclusively selective RIP kinase 1 inhibitors. This scaffold binds to an allosteric pocket created by an αC-out/DFG-out conformation. This inactive conformation results in a large expansion of the kinase back pocket, a conformation that has also been reported for LIM kinases. Scaffold hopping is common in the design of orthosteric kinase inhibitors but has not been explored in the design of allosteric inhibitors, mainly due to the typically exclusive selectivity of type III inhibitors. Here, we hypothesized that the shared structural properties of LIMKs and RIPKs could lead to novel type III LIMK inhibitors using the benzoxazepinone scaffold. We report the discovery of a novel LIMK1/2 inhibitor that relies on this scaffold-based approach. The discovered compound <b>10</b> showed low nanomolar potency on LIMK1/2 and exceptional selectivity, as confirmed by a comprehensive selectivity panel with residual RIPK activity as the only off-target. The study provides one of the few examples for scaffold hopping for allosteric inhibitors, which are usually associated with exclusive target selectivity.

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Publication Details

Journal
ACS Chemical Biology
Published
2025-04-14
DOI
https://doi.org/10.1021/acschembio.5c00097
Citations
2
Primary Topic
Cytokine Signaling Pathways and Interactions
Type
article
Field-Weighted Citation Impact
2.09

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article

Repurposing of the RIPK1-Selective Benzo[1,4]oxazepin-4-one Scaffold for the Development of a Type III LIMK1/2 Inhibitor

Daniela S. Krause, Patricia Alfonso, Stefan Knapp, Satoshi Yamamoto et al.
2 citations
ACS Chemical Biology
Cytokine Signaling Pathways and Interactions
2.09
article

Repurposing of the RIPK1-Selective Benzo[1,4]oxazepin-4-one Scaffold for the Development of a Type III LIMK1/2 Inhibitor

Daniela S. Krause, Patricia Alfonso, Stefan Knapp, Satoshi Yamamoto, M. I. Baena, Benedict‐Tilman Berger, Ana Corrionero, Raquel Pereira, Sebastian Mathea, Sandra Röhm, Terufumi Takagi, Martin P. Schwalm, Susanne Müller, Lewis Elson, Thomas Hanke, Michiko Tawada, Sebastian Mandel, Mahmood Ahmed, Deep Chatterjee, Andreas Krämer, Amelie Menge, Hayuningbudi Saraswati
article en
2 citations

Abstract

Benzoxazepinones have been extensively studied as exclusively selective RIP kinase 1 inhibitors. This scaffold binds to an allosteric pocket created by an αC-out/DFG-out conformation. This inactive conformation results in a large expansion of the kinase back pocket, a conformation that has also been reported for LIM kinases. Scaffold hopping is common in the design of orthosteric kinase inhibitors but has not been explored in the design of allosteric inhibitors, mainly due to the typically exclusive selectivity of type III inhibitors. Here, we hypothesized that the shared structural properties of LIMKs and RIPKs could lead to novel type III LIMK inhibitors using the benzoxazepinone scaffold. We report the discovery of a novel LIMK1/2 inhibitor that relies on this scaffold-based approach. The discovered compound <b>10</b> showed low nanomolar potency on LIMK1/2 and exceptional selectivity, as confirmed by a comprehensive selectivity panel with residual RIPK activity as the only off-target. The study provides one of the few examples for scaffold hopping for allosteric inhibitors, which are usually associated with exclusive target selectivity.

ACS Chemical BiologyVol. 20(5)
Goethe University Frankfurt (DE), German Cancer Research Center (DE), Johannes Gutenberg University Mainz (DE), Institute for Transfusion Medicine (US), University Medical Center of the Johannes Gutenberg University Mainz (DE), Deutsches Konsortium für Translationale Krebsforschung (DE), Takeda (Japan) (JP)
Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, Bayer, Takeda Pharmaceutical Company, Genome Canada, Deutsche Forschungsgemeinschaft, Deutsche Krebshilfe, Innovative Medicines Initiative, Deutschen Konsortium für Translationale Krebsforschung, Genentech, Janssen Biotech
Openalex Percentile: Top 13%
Cytokine Signaling Pathways and Interactions
2.09
DOIOpen Access PDFOpenAlex
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