- Demonstrating Ligandability of the LC3A and LC3B Adapter Interface
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Autophagy is the common name for a number of lysosome-based degradation pathways of cytosolic cargos. The key components of autophagy are members of Atg8 family proteins involved in almost all steps of the process, from autophagosome formation to their selective fusion with lysosomes. In this study, we show that the homologous members of the human Atg8 family proteins, LC3A and LC3B, are druggable by a small molecule inhibitor novobiocin. Structure-activity relationship (SAR) studies of the 4-hydroxy coumarin core scaffold were performed, supported by a crystal structure of the LC3A dihydronovobiocin complex. The study reports the first nonpeptide inhibitors for these protein interaction targets and will lay the foundation for the development of more potent chemical probes for the Atg8 protein family which may also find applications for the development of autophagy-mediated degraders (AUTACs).
- Hartmann, Markus,Huber, Jessica,Kramer, Jan S.,Heering, Jan,Pietsch, Larissa,Stark, Holger,Odadzic, Dalibor,Bischoff, Iris,Fürst, Robert,Schr?der, Martin,Akutsu, Masato,Chaikuad, Apirat,D?tsch, Volker,Knapp, Stefan,Biondi, Ricardo M.,Rogov, Vladimir V.,Proschak, Ewgenij
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p. 3720 - 3746
(2021/05/04)
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- A Developability-Focused Optimization Approach Allows Identification of in Vivo Fast-Acting Antimalarials: N -[3-[(Benzimidazol-2-yl)amino]propyl]amides
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Malaria continues to be a major global health problem, being particularly devastating in the African population under the age of five. Artemisinin-based combination therapies (ACTs) are the first-line treatment recommended by the WHO to treat Plasmodium falciparum malaria, but clinical resistance against them has already been reported. As a consequence, novel chemotypes are urgently needed. Herein we report a novel, in vivo active, fast-acting antimalarial chemotype based on a benzimidazole core. This discovery is the result of a medicinal chemistry plan focused on improving the developability profile of an antichlamydial chemical class previously reported by our group. (Graph Presented).
- Keurulainen, Leena,Vahermo, Mikko,Puente-Felipe, Margarita,Sandoval-Izquierdo, Elena,Crespo-Fernández, Benigno,Guijarro-López, Laura,Huertas-Valentín, Leticia,De Las Heras-Due?a, Laura,Leino, Teppo O.,Siiskonen, Antti,Ballell-Pages, Lluís,Sanz, Laura M.,Casta?eda-Casado, Pablo,Jiménez-Díaz, M. Belén,Martínez-Martínez, María S.,Viera, Sara,Kiuru, Paula,Calderón, Félix,Yli-Kauhaluoma, Jari
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supporting information
p. 4573 - 4580
(2015/06/25)
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- Design, synthesis, and pharmacological evaluation of highly potent and selective dipeptidyl peptidase-4 inhibitors
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The optimization of a series of fused β-homophenylalanine inhibitors of dipeptidyl peptidase-4 (DPP-4) is described. Modification on the P2-binding moiety of 6 (IC50 = 10 nM) led to the discovery of β-homophenylalanine derivatives containing pyrrolidin-2-ylmethyl amides. The introduction of a sulfamine in the meta position of the phenyl ring improved the potency against DPP-4 (6-12-fold increase). Compound 14k showed DPP-4 inhibitory activity with an IC50 value of 0.87 nM. Meanwhile, in vivo experiments exhibited that 14h had an efficiency comparable to sitagliptin at the dose of 10 mg/kg.
- Jiang, Tao,Zhou, Yuren,Zhu, Jianming,Chen, Zhuxi,Sun, Peng,Zhang, Qiang,Wang, Zhen,Shao, Qiang,Jiang, Xiangrui,Li, Bo,Wang, Heyao,Zhu, Weiliang,Shen, Jingshan
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p. 399 - 407
(2015/06/08)
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- NOVEL COMPOUNDS USEFUL FOR THE TREATMENT OF DEGENERATIVE and INFLAMMATORY DISEASES
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The present invention relates to compounds of formula (I) that are inhibitors of PDElA, a phosphodiesterase that is involved in the modulation of the degradation of cartilage, joint degeneration and diseases involving such degradation and/or inflammation.
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Page/Page column 69
(2008/12/05)
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- 4-(3,4-dihydroxyphenyl)-1,2,3,4-tetrahydroisoquinoline derivatives. II. Their renal vasodilation activity and structure-activity relationship
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A series of 4-(3,4-dihydroxyphenyl)-1,2,3,4-tetrahydroisoquinoline derivatives showed potent DA1 agonistic activities. We investigated the structure-activity relationship of the racemic compounds of this series. 4- (3,4-Dihydroxyphenyl)-7-metha
- Anan, Hideki,Tanaka, Akihiro,Tsuzuki, Ryuji,Yokota, Masaki,Yatsu, Takeyuki,Fujikura, Takashi
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p. 1865 - 1870
(2007/10/03)
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