7PAW

MALT1 in complex with compound 1

Summary for 7PAW

• Entry DOI: 10.2210/pdb7paw/pdb
• Descriptor: Mucosa-associated lymphoid tissue lymphoma translocation protein 1, ~{N}1-(3-chloranyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-~{N}4-[2-(trifluoromethyl)pyrimidin-4-yl]cyclohexane-1,4-diamine (3 entities in total)
• Functional Keywords: paracaspase, inhibitor complex, cbm complex, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 88752.64

Authors

Kack, H.,Oster, L. (deposition date: 2021-07-30, release date: 2021-11-17, Last modification date: 2024-01-31)

Primary citation

Schiesser, S.,Hajek, P.,Pople, H.E.,Kack, H.,Oster, L.,Cox, R.J.
Discovery and optimization of cyclohexane-1,4-diamines as allosteric MALT1 inhibitors.
Eur.J.Med.Chem., 227:113925-113925, 2021

PubMed 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.

PubMed: 34742013
DOI: 10.1016/j.ejmech.2021.113925

Experimental method

X-RAY DIFFRACTION (2.19 Å)