Discovery and optimization of antibacterial AccC inhibitors

Cheng, Cliff C.; Shipps, Gerald W.; Yang, Zhiwei; Sun, Bo; Kawahata, Noriyuki; Soucy, Kyle A.; Soriano, Aileen; Orth, Peter; Li, Xiao; Mann, P. R.; Black, Todd A.

doi:10.1016/j.bmcl.2009.10.057

Cited by 44 publications

(25 citation statements)

References 15 publications

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“…9(a)]. 52 These types of compounds bind in the ATP pocket using the same amino acid residues as the pyridopyrimidines and aminooxazoles [ Fig. 9(b)].…”

Section: Biotin Carboxylase Domains Bound To Inhibitorsmentioning

confidence: 99%

The enzymes of biotin dependent CO₂ metabolism: What structures reveal about their reaction mechanisms

2012

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Biotin is the major cofactor involved in carbon dioxide metabolism. Indeed, biotindependent enzymes are ubiquitous in nature and are involved in a myriad of metabolic processes including fatty acid synthesis and gluconeogenesis. The cofactor, itself, is composed of a ureido ring, a tetrahydrothiophene ring, and a valeric acid side chain. It is the ureido ring that functions as the CO 2 carrier. A complete understanding of biotin-dependent enzymes is critically important for translational research in light of the fact that some of these enzymes serve as targets for antiobesity agents, antibiotics, and herbicides. Prior to 1990, however, there was a dearth of information regarding the molecular architectures of biotin-dependent enzymes. In recent years there has been an explosion in the number of three-dimensional structures reported for these proteins. Here we review our current understanding of the structures and functions of biotindependent enzymes. In addition, we provide a critical analysis of what these structures have and have not revealed about biotin-dependent catalysis.

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“…9(a)]. 52 These types of compounds bind in the ATP pocket using the same amino acid residues as the pyridopyrimidines and aminooxazoles [ Fig. 9(b)].…”

Section: Biotin Carboxylase Domains Bound To Inhibitorsmentioning

confidence: 99%

The enzymes of biotin dependent CO₂ metabolism: What structures reveal about their reaction mechanisms

2012

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“…The other group of bacterial ACCase inhibitors was isolated with screening mixture-based combinatorial library against bacterial biotin carboxylase with Automated Ligand Identification System (Cheng et al, 2009). The selected compounds, namely bezimidazoles of affinity to biotin carboxylase, were confirmed as low micromolar enzyme inhibitors, and, subsequently, optimized with computer-aided drug design combined with a synthetic approach.…”

Section: Accase As a Target In Infectious Diseasesmentioning

confidence: 99%

OPINIONS Acetyl-coenzyme A carboxylase – an attractive enzyme for biotechnology

Podkowiński¹,

Tworak²

2011

bta

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Acetyl-CoA carboxylase catalyzes the carboxylation of acetyl-CoA to malonyl-CoA. This reaction constitutes the first committed step of fatty acid synthesis in most organisms, while its product also serves as a universal precursor for various other high-value compounds. The important regulatory and rate-limiting role of acetyl-CoA carboxylase makes this enzyme a powerful tool in a variety of biotechnological and medical projects. This review presents the current knowledge on structural and functional features of the enzyme and focuses on its divergent applications. Different metabolic engineering attempts that lead to the production of various compounds, such as fatty acids, polyketides or flavonoids, are presented and their advantages and limitations discussed. The importance of studies on acetyl-CoA carboxylase activity for design and development of new herbicides and antibiotics as well as for medical intervention is also highlighted. Acetyl-coenzyme A carboxylase -enzyme architecture, biochemistry and its role in cell physiologyA variety of biotechnological projects targeted to modulate acetyl-coenzyme A carboxylase activity in bacteria, plants and humans have been proposed and experimentally tested. Here, we would like to present a comprehensive review of these strategies together with a survey of the potential of acetyl-CoA carboxylase for biotechnology.Acetyl-coenzyme A carboxylase (ACC, E.C.6.4.1.2), recognized as an essential enzyme for all Eukaryotes and the majority of Bacteria, is responsible for carboxylation of acetyl-CoA that results in malonyl-coenzyme A formation (Fig. 1). Malonyl-CoA is a major building block for compounds such as fatty acids, polyketides and flavonoids -important components for cell growth, as well as for food, pharmaceuticals and energy production.The malonyl-CoA synthesis consists of two half-reactions (Nikolau et al., 2003). The first one, adenosine triphosphate-dependent carboxylation of biotin prosthetic group covalently bound to a module named biotin carboxyl carrier protein (BCCP), is catalyzed by ACCase segment of biotin carboxylase activity (BC) (Fig. 2). This reaction is immediately followed by the second half-re action: the transfer of a carboxyl group from carboxylated biotin to acetyl-CoA, resulting in malonyl-CoA formation. Carboxyl transferase (CT) is a module that catalyzes the second reaction and provides the required specificity in recognition of the carboxyl acceptor (acetyl-CoA). The ACCase model usually presents BCCP, a module with covalently attached biotin, as a beam responsible for biotin dislocation between two active centers -one with BT and the other with CT activity. The three (Fig. 3). The prokaryotic and eukaryotic types of ACCases are evolutionary related and the phylogeny of the modules provides some hints about their cenancestor, a split between Archaea and Bacteria, and arising of Eukaryota (Lombard and Moreira, 2011).Phylogeny is out of scope of this manuscript, but acetyl-coenzyme A carboxylases from various organisms representing v...

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“…Modifications to probe the interaction between the C−H of the thiazole and the carbonyl of Glu85 in the hinge region were attempted (Table 2), such as substitution with a methyl group (13), different connectivity at the thiazole (14), and replacement with isoxazole (15). All of these changes resulted in a significant loss of potency and reinforced the value of the C−H/Glu85 to the overall binding affinity.…”

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confidence: 99%

Discovery of a Novel Series of CHK1 Kinase Inhibitors with a Distinctive Hinge Binding Mode

Huang

Cheng

Fischmann

et al. 2012

ACS Med. Chem. Lett.

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A novel series of CHK1 inhibitors with a distinctive hinge binding mode, exemplified by 2-aryl-N-(2-(piperazin-1-yl)phenyl)thiazole-4-carboxamide, was discovered through high-throughput screening using the affinity selection−mass spectrometry (AS-MS)-based Automated Ligand Identification System (ALIS) platform. Structure-based ligand design and optimization led to significant improvements in potency to the single digit nanomolar range and hundred-fold selectivity against CDK2.KEYWORDS: affinity selection−mass spectrometry (AS-MS), Automated Ligand Identification System (ALIS), CHK1 protein kinase, structure-based drug design, thiazole-4-carboxamide C ancer is the leading cause of death globally. 1 Among the treatments used in cancer clinics, DNA-damaging chemotherapies have received widespread use despite their severe side effects on highly proliferative tissues and vulnerability to drug resistance. 2 There is an urgent need in cancer therapy for improved tolerability and longer lasting efficacy. When cells are exposed to agents that induce DNA damage, DNA repair pathways are activated by arresting at various cell cycle check points, G1, S, and G2/M. 3 While normal cells could arrest in the G1 phase through the tumor suppressor protein p53, most cancer cells lack this option because of p53 mutations and will have to rely on the S or G2/M checkpoint for DNA repair and survival. Such reliance in p53 mutant cancer cells would offer a significant opportunity for targeted cancer therapy. 4 CHK1 (checkpoint kinase 1) is a serine/threonine kinase and the key mediator in S and G2/M checkpoints. 5 The abrogation of CHK1 and the remaining checkpoints consequentially will cause cancer cells with DNA damage premature entry into mitosis and result in cell death. 6 Therefore, an enlarged therapeutic window would be expected in anticancer therapies utilizing a combination of a DNA-damaging agent with a CHK1 inhibitor.Over the past years, extensive research efforts in CHK1 inhibition have been undertaken in oncology. Several small molecule CHK1 inhibitors have been discovered and entered into clinical trials. 7−11 In our efforts to discover novel small molecule CHK1 inhibitors, the AS-MS ALIS (affinity selection−mass spectrometry-based Automated Ligand Identification System) platform was used to identify hits from mixture-based combinatorial libraries. 12 ALIS has demonstrated its unique capability in screening label-free mixture-based libraries and finding hits that were subsequently developed into lead compounds in various classes of protein targets, including the anti-infective target Escherichia coli dihydrofolate reductase, 13 antibacterial AccC (acetyl coenzyme-A carboxylase), 14 HCV NS5B (hepatitis C virus nonstructural protein 5B) polymerase, 15−17 protein kinase CDK2 (cyclin-dependent kinase 2), 18 KSP (kinesin spindle protein) in oncology, 19 FABP4 (fatty acid binding protein-4) 20 and the lipid phosphatase SHIP2 (SH2 domain-containing inositol 5-phosphatase 2) 21 in diabetes, MK2 (mitogen-activated protein ...

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Discovery and optimization of antibacterial AccC inhibitors

Cited by 44 publications

References 15 publications

The enzymes of biotin dependent CO₂ metabolism: What structures reveal about their reaction mechanisms

The enzymes of biotin dependent CO₂ metabolism: What structures reveal about their reaction mechanisms

OPINIONS Acetyl-coenzyme A carboxylase – an attractive enzyme for biotechnology

Discovery of a Novel Series of CHK1 Kinase Inhibitors with a Distinctive Hinge Binding Mode

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Discovery and optimization of antibacterial AccC inhibitors

Cited by 44 publications

References 15 publications

The enzymes of biotin dependent CO2 metabolism: What structures reveal about their reaction mechanisms

The enzymes of biotin dependent CO2 metabolism: What structures reveal about their reaction mechanisms

OPINIONS Acetyl-coenzyme A carboxylase – an attractive enzyme for biotechnology

Discovery of a Novel Series of CHK1 Kinase Inhibitors with a Distinctive Hinge Binding Mode

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The enzymes of biotin dependent CO₂ metabolism: What structures reveal about their reaction mechanisms

The enzymes of biotin dependent CO₂ metabolism: What structures reveal about their reaction mechanisms