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BCKDK: an Emerging Kinase Target for Metabolic Diseases and Cancer

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BCKDK: an Emerging Kinase Target for Metabolic Diseases and Cancer NEWS & ANALYSIS TARGET WATCH tolerated, with no signs of apparent toxicity, further supporting the therapeutic promise for BCAA- associated metabolic diseases. BCKDK: an emerging kinase target for In patients with colorectal cancer, high expression of BCKDK was associated metabolic diseases and cancer with poor prognosis. In experiments in colorectal cancer cell lines and xenograft The understudied kinase branched-chain The rate- limiting step of BCAA catabolism and models, BCKDK promoted tumorigenesis ketoacid dehydrogenase kinase (BCKDK) has clearance is the irreversible decarboxylation through activation of the MEK/ERK pathway recently been implicated in various human of BCKAs by the branched-chain α- ketoacid (EBioMedicine 20, 50–60; 2017). diseases. In addition to its established role in dehydrogenase complex (BCKDH). BCKDH regulating the catabolic flux of branched-chain activity is inhibited by phosphorylation of the Chemical tools amino acids (BCAAs), BCKDK was also E1α subunit by BCKDK. The literature landscape for BCKDK found to enhance MEK/ERK signalling, Inhibition of BCKDK with the selective, small- molecule inhibitors has focused on a key pathway driving cell growth and allosteric inhibitor BT2 (FIG. 1) was sufficient the development of allosteric inhibitors. proliferation in cancer. So, BCKDK has to enhance BCKDH activity across tissue These inhibitors bind to BCKDK, triggering become an attractive therapeutic target for types in insulin-resistant, diet- induced obese movements within the N-terminal domain BCAA- associated diseases and cancers. mice (Diabetes 68, 1730–1746; 2019). This helix that result in separation of BCKDK from correlated with lower plasma concentrations BCKDH. This separation works in tandem Biological functions of BCAAs and BCKAs. BT2 treatment with the degradation of BCKDK in vivo. BCAAs (leucine, isoleucine and valine) are improved both glucose tolerance and The most commonly used allosteric essential amino acids and play important roles insulin sensitivity. inhibitor is BT2, which was identified in nutrient sensing and cellular signalling BCAA catabolic dysfunction is a hallmark through a high-throughput screen (J. Biol. (Nat. Rev. Endocrinol. 10, 723–736; 2014). of diseased hearts. BT2 treatment of mice Chem. 289, 20583–20593; 2014). BT2 has Deficiencies in BCAA catabolism are linked with pre- existing cardiac dysfunction an IC50 of 3.2 μM compared with 3 μM for to insulin resistance, maple syrup urine preserved cardiac function and structure, (S)- α- chlorophenylpropionate, one of the earlier disease, congenital heart disease and heart and improved systolic contractility and iterations of an allosteric BCKDK inhibitor. failure. Circulating BCAAs and their catabolic ventricular mechanics (J. Am. Heart. Assoc. BT2 also has good metabolic stability, with a product branched- chain α- ketoacids (BCKAs) 8, e011625; 2019). In this study and the study T1⁄2 ≥240 minutes; however, the charged nature are also indicators of the onset of diabetes. in diet- induced obese mice, BT2 was well of the carboxylic acid means that a prodrug is a O advantageous (but not required) to increase cellular potency. The prodrug BT3 (FIG. 1) NH In vivo Cl S OH and BT2 increased residual BCKDH activity N Cl S HN in cultured cells, primary hepatocytes and in O N O O a mouse model of maple syrup urine disease. O NH Cl In conclusion, the current literature, albeit Cl N limited, reports viable tool compounds to BT3 H2N BT2 O investigate the roles of BCKDK in disease. Pro-drug of BT2 N BCKDK IC50 = 3.2 μM Optimization of these inhibitors could lead b BH2 A102 I72 to drug candidates for the treatment of Y99 metabolic diseases caused by elevated BCAA BH1 concentrations as well as cancers. Michael P. East1, Tuomo Laitinen2 and L128 Christopher R. M. Asquith1 ✉ 1Department of Pharmacology, School of Medicine, H132 University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. V135 2 L68 School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland. ✉e- mail: [email protected] https://doi.org/10.1038/d41573-021-00107-6 Acknowledgements V125 This article is part of a series from the NIH Common Fund Illuminating the Druggable Genome (IDG) program. The BH3 L129 goal of IDG is to catalyse research on understudied proteins from drug ga ble gene families by providing reagents, phe- notypes and a mineable database; focusing on GPCRs, kinases and ion channels. For more information, see https:// R167 druggablegenome.net/ I170 Competing interests The authors declare no competing interests. BH4 R171 RELATED LINKS Dark Kinase Knowledgebase (BCKDK): https://darkkinome.org/ Fig. 1 | BCKDK protein structure and inhibitor docking. a | Reaction of the prodrug BT3 to kinase/BCKDK Pharos (BCKDK): https://pharos.nih.gov/targets/BCKDK afford BT2. b | Co- crystal structure of BT2 in the BCKDK allosteric pocket (PDB: 4E00). 498 | JULY 2021 | VOLUME 20 www.nature.com/nrd 0123456789();: .
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