Inhibitors of the mitochondrial branched chain aminotransferase may have therapeutic potential in the treatment of diet-induced obesity and dyslipidemia. To explore the pharmacology of this metabolic pathway requires a potent and selective molecule that is well tolerated and has appropriate pharmacokinetic properties. The combination of fragment-based and high-throughput screening with structure-guided compound elaboration has yielded a tool compound that may serve as a chemical probe of this pathway.
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http://dx.doi.org/10.1021/acs.jmedchem.5b01244 | DOI Listing |
Curr Med Chem
January 2025
School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, China.
Branched-chain amino acids (BCAAs) are essential amino acids for humans and play an indispensable role in many physiological and pathological processes. Branched-chain amino acid aminotransferase (BCAT) is a key enzyme that catalyzes the metabolism of BCAAs. BCAT is upregulated in many cancers and implicated in the development and progress of some other diseases, such as metabolic and neurological diseases; and therefore, targeting BCAT might be a potential therapeutic approach for these diseases.
View Article and Find Full Text PDFBiochem J
May 2020
Department of Biochemistry and Nutrition, Des Moines University, 3200 Grand Avenue, Des Moines, IA 50312, U.S.A.
Osteosarcoma and chondrosarcoma are sarcomas of the bone and the cartilage that are primarily treated by surgical intervention combined with high toxicity chemotherapy. In search of alternative metabolic approaches to address the challenges in treating bone sarcomas, we assessed the growth dependence of these cancers on leucine, one of the branched-chain amino acids (BCAAs), and BCAA metabolism. Tumor biopsies from bone sarcoma patients revealed differential expression of BCAA metabolic enzymes.
View Article and Find Full Text PDFACS Med Chem Lett
April 2016
Centre de Recherche, GlaxoSmithKline , Les Ulis, 25,27 Avenue du Québec, 91140 Villebon sur Yvette, France.
To identify BCATm inhibitors suitable for in vivo study, Encoded Library Technology (ELT) was used to affinity screen a 117 million member benzimidazole based DNA encoded library, which identified an inhibitor series with both biochemical and cellular activities. Subsequent SAR studies led to the discovery of a highly potent and selective compound, 1-(3-(5-bromothiophene-2-carboxamido)cyclohexyl)-N-methyl-2-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamide (8b) with much improved PK properties. X-ray structure revealed that 8b binds to the active site of BACTm in a unique mode via multiple H-bond and van der Waals interactions.
View Article and Find Full Text PDFJ Med Chem
March 2016
Medicines Research Centre, GlaxoSmithKline R&D , Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, U.K.
Inhibitors of mitochondrial branched chain aminotransferase (BCATm), identified using fragment screening, are described. This was carried out using a combination of STD-NMR, thermal melt (Tm), and biochemical assays to identify compounds that bound to BCATm, which were subsequently progressed to X-ray crystallography, where a number of exemplars showed significant diversity in their binding modes. The hits identified were supplemented by searching and screening of additional analogues, which enabled the gathering of further X-ray data where the original hits had not produced liganded structures.
View Article and Find Full Text PDFJ Med Chem
September 2015
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
Inhibitors of the mitochondrial branched chain aminotransferase may have therapeutic potential in the treatment of diet-induced obesity and dyslipidemia. To explore the pharmacology of this metabolic pathway requires a potent and selective molecule that is well tolerated and has appropriate pharmacokinetic properties. The combination of fragment-based and high-throughput screening with structure-guided compound elaboration has yielded a tool compound that may serve as a chemical probe of this pathway.
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