7paw
From Proteopedia
MALT1 in complex with compound 1
Structural highlights
DiseaseMALT1_HUMAN Note=A chromosomal aberration involving MALT1 is recurrent in low-grade mucosa-associated lymphoid tissue (MALT lymphoma). Translocation t(11;18)(q21;q21) with BIRC2. This translocation is found in approximately 50% of cytogenetically abnormal low-grade MALT lymphoma. FunctionMALT1_HUMAN Enhances BCL10-induced activation of NF-kappa-B. Involved in nuclear export of BCL10. Binds to TRAF6, inducing TRAF6 oligomerization and activation of its ligase activity. Has ubiquitin ligase activity. MALT1-dependent BCL10 cleavage plays an important role in T-cell antigen receptor-induced integrin adhesion.[1] [2] [3] Publication Abstract from PubMedInhibition of mucosa-associated lymphoid tissue lymphoma translocation protein-1 (MALT1) is a promising strategy to modulate NF-kappaB 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. Discovery and optimization of cyclohexane-1,4-diamines as allosteric MALT1 inhibitors.,Schiesser S, Hajek P, Pople HE, Kack H, Oster L, Cox RJ Eur J Med Chem. 2021 Oct 21;227:113925. doi: 10.1016/j.ejmech.2021.113925. PMID:34742013[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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