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 |
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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: | 26 Nov 2024 16:15 |
URI: | https://orca.cardiff.ac.uk/id/eprint/146131 |
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