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Discovery and optimization of cyclohexane-1,4-diamines as allosteric MALT1 inhibitors
Ist Teil von
European journal of medicinal chemistry, 2022-01, Vol.227, p.113925-113925, Article 113925
Ort / Verlag
France: Elsevier Masson SAS
Erscheinungsjahr
2022
Link zum Volltext
Quelle
Elsevier ScienceDirect Journals Complete
Beschreibungen/Notizen
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.
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•Cis substituted cyclohexane-1,4-diamines were identified as novel MALT1 inhibitors.•X-ray analyses confirm binding to an induced allosteric pocket.•Compound 8 shows single digit micromolar cell activity.•Compound 8 is very selective in secondary pharmacology panel (including 16 proteases).•In vivo rat PK of compound 8 shows low clearance and high bioavailability.