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Discovery and optimization of cyclohexane-1,4-diamines as allosteric MALT1 inhibitors

Schiesser, Stefan, Hajek, Peter, Pople, Huw E., Käck, Helena, Öster, Linda and Cox, Rhona J. 2022. Discovery and optimization of cyclohexane-1,4-diamines as allosteric MALT1 inhibitors. European Journal of Medicinal Chemistry 227 , 113925. 10.1016/j.ejmech.2021.113925
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Abstract

Inhibition of mucosa-associated lymphoid tissue lymphoma translocation protein-1 (MALT1) is a promising strategy to modulate NF-κB signaling, with the potential to treat B-cell lymphoma and autoimmune diseases. We describe the discovery and optimization of (1s,4s)-N,N′-diaryl cyclohexane-1,4-diamines, a novel series of allosteric MALT1 inhibitors, resulting in compound 8 with single digit micromolar cell potency. X-ray analysis confirms that this compound binds to an induced allosteric site in MALT1. Compound 8 is highly selective and has an excellent in vivo rat PK profile with low clearance and high oral bioavailability, making it a promising lead for further optimization.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Chemistry
Publisher: Elsevier
ISSN: 0223-5234
Funders: Astra Zeneca
Date of First Compliant Deposit: 14 December 2021
Date of Acceptance: 13 October 2021
Last Modified: 16 Dec 2021 13:31
URI: https://orca.cardiff.ac.uk/id/eprint/146131

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