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

Preview

PDF - Accepted Post-Print Version Available under License Creative Commons Attribution Non-commercial No Derivatives. Download (922kB) | Preview

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:	07 Nov 2023 05:47
URI:	https://orca.cardiff.ac.uk/id/eprint/146131

Actions (repository staff only)

Edit Item