91818-29-0Relevant articles and documents
Identification of Novel Fused Heteroaromatics-Based MALT1 Inhibitors by High-Throughput Screening to Treat B Cell Lymphoma
Liang, Xuewu,Sun, Chenxia,Li, Chunpu,Yu, Haolan,Wei, Xiaohui,Liu, Xuyi,Bao, Wei,Shi, Yuqiang,Sun, Xiaochen,Khamrakulov, Mirzadavlat,Yang, Chenghua,Liu, Hong
, p. 9217 - 9237 (2021/07/20)
Development of mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) inhibitors is of great value and significance in the treatment of neoplastic disorders and inflammatory and autoimmune diseases. However, there is a lack of effective MALT1 inhibitors in clinic. Herein, a novel class of potent 5-oxo-1-thioxo-4,5-dihydro-1H-thiazolo[3,4-a]quinazoline-based MALT1 inhibitors and their covalent derivatives were first identified and designed through high-throughput screening. We demonstrated that compounds 15c, 15e, and 20c effectively inhibited the MALT1 protease and displayed selective cytotoxicity to activated B cell-like diffuse large B cell lymphoma with low single-digit micromolar potency. Furthermore, compound 20c specifically repressed NF-κB signaling and induced cell apoptosis in MALT1-dependent TMD8 cells in a dose-dependent manner. More importantly, 20c showed good pharmacokinetic properties and antitumor efficacy with no significant toxicity in the TMD8 xenograft tumor model. Collectively, this study provides valuable lead compounds of MALT1 inhibitors for further structural optimization and antitumor mechanism study.
Discovery and Optimization of 5-Amino-1,2,3-triazole-4-carboxamide Series against Trypanosoma cruzi
Brand, Stephen,Ko, Eun Jung,Viayna, Elisabet,Thompson, Stephen,Spinks, Daniel,Thomas, Michael,Sandberg, Lars,Francisco, Amanda F.,Jayawardhana, Shiromani,Smith, Victoria C.,Jansen, Chimed,De Rycker, Manu,Thomas, John,Maclean, Lorna,Osuna-Cabello, Maria,Riley, Jennifer,Scullion, Paul,Stojanovski, Laste,Simeons, Frederick R. C.,Epemolu, Ola,Shishikura, Yoko,Crouch, Sabrinia D.,Bakshi, Tania S.,Nixon, Christopher J.,Reid, Iain H.,Hill, Alan P.,Underwood, Tim Z.,Hindley, Sean J.,Robinson, Sharon A.,Kelly, John M.,Fiandor, Jose M.,Wyatt, Paul G.,Marco, Maria,Miles, Timothy J.,Read, Kevin D.,Gilbert, Ian H.
, p. 7284 - 7299 (2017/09/22)
Chagas' disease, caused by the protozoan parasite Trypanosoma cruzi, is the most common cause of cardiac-related deaths in endemic regions of Latin America. There is an urgent need for new safer treatments because current standard therapeutic options, benznidazole and nifurtimox, have significant side effects and are only effective in the acute phase of the infection with limited efficacy in the chronic phase. Phenotypic high content screening against the intracellular parasite in infected VERO cells was used to identify a novel hit series of 5-amino-1,2,3-triazole-4-carboxamides (ATC). Optimization of the ATC series gave improvements in potency, aqueous solubility, and metabolic stability, which combined to give significant improvements in oral exposure. Mitigation of a potential Ames and hERG liability ultimately led to two promising compounds, one of which demonstrated significant suppression of parasite burden in a mouse model of Chagas' disease.
