Targeting Acetyl-CoA Carboxylases

17 Pages·2012·1.16 MB·English

168 Recent Patents on Anti-Cancer Drug Discovery, 2012, 7, 168-184
Targeting Acetyl-CoA Carboxylases: Small Molecular Inhibitors and their
Therapeutic Potential
Di-Xian Luo1,2, Di-Jun Tong3, Sandeep Rajput2,Chun Wang4,5, Duan-Fang Liao4,5, Deliang Cao2

and Edmund Maser6,*
1Institute of Translational Medicine & Department of Laboratory Medicine, The First People's Hospital of Chenzhou,
102 Luojiajing Road, Chenzhou 423000, Hunan, P.R. China; 2Department of Microbiology, Immunology and Cell Biol-
ogy, Simmons Cancer Institute, Southern Illinois University School of Medicine. 913 N. Rutledge Street, Springfield, IL
62794, USA; 3Department of Cardiovascular Medicine, Central Hospital of Yiyang, Yiyang 41300, P.R. China;
4Institute of Pharmacy and Pharmacology, College of Pharmaceutics and Life Science, University of South China, Hen-
gyang 421001, P.R. China; 5Department of Traditional Chinese Diagnotics, School of Pharmacy, Hunan University of
Chinese Medicine, Changsha 420108, P.R. China; 6Institute of Toxicology and Pharmacology for Natural Scientists,
University Medical School Schleswig-Holstein, Campus Kiel. Brunswiker Str. 10 24105, Kiel, Germany
Received: November 1, 2011; Accepted: January 12, 2012; Revised: February 12, 2012
Abstract: Acetyl-CoA carboxylases (ACCs) play a rate-limiting role in fatty acid biosynthesis in plants, microbes, mam-
mals and humans. ACCs have the activity of both biotin carboxylase (BC) and carboxyltransferase (CT), catalyzing car-
boxylation of Acetyl-CoA to malonyl-CoA. In the past years, ACCs have been used as targets for herbicides in agriculture
and for drug discovery and development of human diseases, such as microbial infections, diabetes, obesity and cancer. A
great number of small molecule ACC inhibitors have been developed, including natural and non-natural (artificial) prod-
ucts. These chemicals target BC reaction, CT reaction or ACC phosphorylation. This article provides a comprehensive re-
view and updates of ACC inhibitors, with a focus on their therapeutic application in metabolic syndromes and malignant
diseases. The patent status of common ACC inhibitors is discussed.
Keywords: Acetyl-CoA carboxylases, cancer, fatty acid synthesis, inhibitors, metabolic syndromes, obesity.
1. INTRODUCTION distribution and function although they both catalyze the
production of malonyl-CoA Fig. (1) [10]. ACC1 is expressed
Obesity, a worldwide epidemic, not only impacts life
mostly in lipogenic tissues (the liver, adipose and lactating
quality, but also leads to a variety of co-morbidities, such as
mammary gland) and catalyzes the rate-limiting reaction in
diabetes, hypertension, dyslipidemia, coronary heart disease,
the biosynthesis of long-chain fatty acids in cytosol. The
stroke, atherosclerosis, and cancer, accelerating obesity-
product malonyl-CoA is used for the elongation of acyl
related morbidity and mortality [1-6]. It is needed to develop
chains by fatty acid synthase (FAS) [12-15]. In contrast,
effective therapeutics of obesity and the ensuring co-
ACC2 is expressed mainly in the liver, skeletal muscle and
morbidities. Acetyl-CoA carboxylases (ACCs) are rate-
heart with high energy metabolic activity, where its product
limiting enzymes in fatty acid de novo biosynthesis, catalyz-
malonyl-CoA participates in the regulation of fatty acid (cid:2)-
ing ATP-dependent carboxylation of acetyl-CoA to malonyl-
oxidation by inhibiting carnitine palmitoyltransferase I
CoA [7-9]. This reaction continuously proceeds in two steps
(CPT-I) that catalyzes the transition of long-chain acyl-CoA
in participation of biotin prosthetic group, i.e., an ATP-
across mitochondrial membranes [16]. Therefore, malonyl-
dependent biotin carboxylation and an ATP-independent
CoA is a dual functional metabolite involved in both fatty
transfer of the carboxyl group Fig. (1) [10].
acid synthesis and oxidation, and ACC1/2 isozyme-non-
In humans and other mammals, there are two ACCs: selective inhibitors may selectively reduce fatty acid synthe-
ACC1 (also called ACC-(cid:1)) with 265kDa and ACC2 (also sis in lipogenic tissues and increase fatty acid oxidation in
known as ACC-(cid:2)) with 280kDa. ACC1 and ACC2 are en- energy production organs [17, 18].
coded by different genes, but share 75% amino acid se-
In view of the importance of ACCs in fatty acid synthesis
quence similarity except for extra 114 amino acids in the N-
and oxidation, the investigation of ACC inhibitors have been
terminus of ACC2, in which the first 20 amino acid residues
attracting the interest of researchers and many promising
constitute a signal peptide targeting mitochondrial membrane
inhibitors have been developed and used in preclinical and
[11]. Thereby, these two ACCs have distinct subcellular
clinical studies for the treatment of obesity and metabolic

syndromes or in the management of malignancies [19]. This
*Address correspondence to this author at the Institute of Toxicology and article reviews the recent updates of ACC inhibitor exploita-
Pharmacology for Natural Scientists, University Medical School Schleswig- tion and their patent situations.
Holstein, Campus Kiel. Brunswiker Str. 10 24105, Kiel, Germany;
Tel: [phone]; Fax: [phone]; E-mail: [email protected]
(cid:21)(cid:21)(cid:20)(cid:21)-(cid:22)9(cid:26)(cid:19)/12 $100.00+.00 © 2012 Bentham Science Publishers
Acetyl-CoA Carboxylase Inhibitors Recent Patents on Anti-Cancer Drug Discovery, 2012, Vol. 7, No. 2 169
(cid:2)
(cid:2)
(cid:2)
(cid:3) (cid:2) (cid:3) (cid:2)
(cid:5)(cid:4) (cid:4)
(cid:4) (cid:25) (cid:25)
(cid:3)(cid:11)(cid:2) (cid:5)(cid:4) (cid:6) (cid:13)(cid:20)(cid:23)(cid:8)(cid:20) (cid:25)(cid:20)(cid:8)(cid:23)(cid:20)(cid:13) (cid:3)(cid:11)(cid:26)(cid:29) (cid:6) (cid:13)(cid:20)(cid:23)(cid:8)(cid:20)
(cid:26)(cid:29)(cid:8)(cid:30)(cid:14)(cid:23)(cid:26)(cid:11)(cid:13)(cid:27) (cid:22)(cid:26)(cid:11)(cid:2)(cid:25)(cid:20)(cid:8)(cid:23)(cid:4)(cid:20)(cid:13)(cid:5)(cid:28)(cid:3)(cid:11)(cid:26)(cid:29)(cid:8)(cid:30)(cid:14)(cid:12) (cid:22)(cid:27)(cid:11)(cid:12)(cid:14)(cid:30)(cid:8)(cid:29)(cid:26)(cid:11)(cid:3)(cid:28) (cid:23)(cid:26)(cid:11)(cid:13)(cid:27)(cid:12)(cid:8)(cid:21)(cid:11)(cid:23)(cid:20)(cid:8)(cid:13) (cid:8)(cid:30)(cid:14)(cid:23)(cid:26)(cid:11)(cid:13)(cid:27) (cid:22)(cid:26)(cid:11)(cid:27)(cid:25)(cid:20)(cid:8)(cid:23)(cid:20)(cid:2)(cid:13)(cid:28)(cid:3)(cid:11)(cid:4)(cid:26)(cid:29)(cid:5)(cid:8)(cid:30)(cid:14)(cid:12) (cid:22)(cid:27)(cid:11)(cid:12)(cid:14)(cid:30)(cid:8)(cid:29)(cid:26)(cid:11)(cid:3)(cid:28)
(cid:27)(cid:3)(cid:11)(cid:26)(cid:26)(cid:20)(cid:22)(cid:26)(cid:28)(cid:31)(cid:26)(cid:8)(cid:23)(cid:22)(cid:20)(cid:13) (cid:22)(cid:3)(cid:11)(cid:26)(cid:26)(cid:20)(cid:22)(cid:26)(cid:28)(cid:31)(cid:26)(cid:8)(cid:23)(cid:22)(cid:20)(cid:13)
(cid:22)
(cid:2)
(cid:2) (cid:2) (cid:2) (cid:9)(cid:18)(cid:17)(cid:19)(cid:17)(cid:20)
(cid:3) (cid:4) (cid:3)
(cid:3) (cid:6) (cid:3)(cid:8)(cid:9)
(cid:5)(cid:9)(cid:24)(cid:21)(cid:22)(cid:23)(cid:14)(cid:12)(cid:15)(cid:3)(cid:8)(cid:9) (cid:5)(cid:4) (cid:25) (cid:5)(cid:2)
(cid:3) (cid:6) (cid:8)(cid:20)
(cid:2) (cid:2) (cid:11)(cid:26)(cid:29) (cid:13)(cid:20)(cid:23) (cid:9)(cid:16)(cid:17)
(cid:3) (cid:3) (cid:8) (cid:3)(cid:28)
(cid:2) (cid:10)(cid:11)(cid:12)(cid:3)(cid:5)(cid:8)(cid:13)(cid:7)(cid:14)(cid:12)(cid:15)(cid:3)(cid:8)(cid:6)(cid:9) (cid:3)(cid:8)(cid:9) (cid:30)(cid:14)(cid:23)(cid:26)(cid:11) (cid:2) (cid:4)(cid:5) (cid:8)(cid:29)(cid:26)(cid:11)
(cid:13) (cid:30)
(cid:27) (cid:14)
(cid:22) (cid:11)(cid:12)
(cid:26) (cid:27)
(cid:11)(cid:27) (cid:25)(cid:20)(cid:8)(cid:23)(cid:20)(cid:13)(cid:28)(cid:3)(cid:11)(cid:26)(cid:29)(cid:8)(cid:30)(cid:14)(cid:12) (cid:22)
(cid:22) (cid:3)(cid:11)(cid:26)(cid:26)(cid:20)(cid:22)(cid:26)(cid:28)(cid:31)(cid:26)(cid:8)(cid:23)(cid:22)(cid:20)(cid:13)

Fig. (1). ACC work mode. ACC has three functional domains and its catalyzation reaction occurs in two steps. The initial reaction is an
ATP-dependent transfer of CO from HCO - to a nitrogen atom of the biotin prosthetic group of ACCs, and the 2nd step is an transfer of the
2 3
activated CO from biotin to acetyl-CoA, forming malonyl-CoA [10].
2
nent is much lower [25]. An exception appears in plants
2. STRUCTURE OF ACETYL-COA CARBOXYLASES
where ACCs exist as a multi-functional single protein (MF-
ACCs are conserved in their amino acid sequence and ACC) and a multi-subunit heteromeric complex (MS-ACC)
function in most living organisms, such as archaea (~34% Fig. (2B) [26, 27].
similarity in amino acid sequence), bacteria (~34% similar-
ity), yeast (~56% similarity), plants (~54% similarity), ro- 2.1. BC Domain of acetyl-CoA Carboxylases
dents (~98% similarity), and mammals (~98% similarity),
Crystal structure shows that yeast BC domain consists of
compared to humans. However, genes encoding ACCs are
20 (cid:2)-strands ((cid:2)1-(cid:2)20) and 21 (cid:1)-helices ((cid:1)A–(cid:1)U), forming
varied Fig. (2A). In mammals and most eukaryotic organ-
three sub-domains (A, B, and C) and an ATP-grasp fold [28-
isms, ACCs are a multiple domain polypeptide composed of
31] Fig. (3A). The A-domain (residues 1-175) consists of
biotin carboxylase (BC), biotin carboxyl carrier (BCCP), and
helices (cid:1)A-(cid:1)G and strands (cid:2)1-(cid:2)5; B-domain (residues 234-
carboxyltransferase (CT) domains that are encoded by a sin-
293) holds helices (cid:1)K and (cid:1)L and strands (cid:2)9-(cid:2)11; and C-
gle gene. ACCs from Streptomyces coelicolor (S. coelicolor)
domain (residues 294-566) is composed of anti-parallel (cid:2)
comprise (cid:1) subunit containing BC and BCCP domains and (cid:2)
sheet ((cid:2)12-(cid:2)20) flanked with helices (cid:1)M-(cid:1)U. Residues 176-
subunit (CT domain), encoded by an accA1(A2) and pccB
233) comprise an AB linker (helices (cid:1)H-(cid:1)J and (cid:2)6-(cid:2)8). A-,
gene, respectively [20-22]. ACC in Archaeal Acidianus bri-
C-domains and AB-linker form a cylindrical structure with
erleyi consists of 3 subunits encoded by accC, accB, and
ATP located at one end and B-domain acts as a lid at another
pccB gene, respectively [23]. In Escherichia coli (E. coli),
end Fig. (3B). ATP binding site, i.e., the active site of en-
carboxyltransferase of ACCs consists of (cid:1) subunit and (cid:2)
zyme is located at the interface of the B-domain and cylinder
subunit encoded by accA and accD, respectively [24]. There-
[30]. The B-domain keeps open conformation to the entry of
fore, in many low grade organisms, ACC is an unstable
substrate or the release of product, but is closed during the
multi-submit enzyme comprised of BC, BCCP and CT
catalytic process.
subunits. BC domain/subunit catalyzes carboxylation of N1
atom in ureido ring of biotin covalently linked to a lysine
2.2. CT Domain of Acetyl-CoA Carboxylases
residue in BCCP with bicarbonate as a donor of carboxyl
group and ATP as an energy source. CT domain/subunit Crystal structures of human ACC CT domain in complex
catalyzes the transfer of the carboxyl group from the N1 with CP-640186 and bovine CT domain in complex with
atom to the methyl group of acetyl-CoA [17]. Significant novel inhibitors have been identified [32, 33]. Yeast CT do-
sequence homology exist between the BC subunit and eu- main dimer was also identified as a free enzyme or in com-
karyotic BC domain, but the conservation of the CT compo- plexes with CoA [25], herbicides haloxyfop/diclofop [34], or
170 Recent Patents on Anti-Cancer Drug Discovery, 2012, Vol. 7, No. 2 Luo et al.
(cid:2)
(cid:2)(cid:3)(cid:4)(cid:4)(cid:3)(cid:5)(cid:6)(cid:3)(cid:7)(cid:8)(cid:9)(cid:10)(cid:11)(cid:3)(cid:12)(cid:8)(cid:13)(cid:11)(cid:3)(cid:14)(cid:12) (cid:27)(cid:28) (cid:27)(cid:28)(cid:28)(cid:29) (cid:28)(cid:30) (cid:2)!"(cid:21)(cid:28)(cid:28)

(cid:2)(cid:14)(cid:23)(cid:24)(cid:23)(cid:7)(cid:6)(cid:12) (cid:3)(cid:14)(cid:23)(cid:24)(cid:23)(cid:7)(cid:6)(cid:12)

(cid:15)(cid:16)(cid:17)(cid:18)(cid:19)(cid:11)(cid:5)(cid:6)(cid:18)(cid:19)(cid:5)(cid:19)(cid:20) (cid:27)(cid:28) (cid:27)(cid:28)(cid:28)(cid:29) (cid:28)(cid:30) (cid:2)!(cid:8)(cid:2)(cid:15)"(cid:21)(cid:28)(cid:28)

(cid:2)(cid:3)(cid:4)(cid:5)(cid:6)(cid:7)(cid:3)(cid:8)(cid:9)(cid:8)(cid:10)(cid:3)(cid:10)(cid:11) (cid:12)(cid:4)(cid:4)(cid:13)(cid:14) (cid:31)(cid:13)(cid:15) (cid:16)(cid:4)(cid:4)(cid:17)

(cid:21)(cid:18)(cid:6)(cid:22)(cid:6)(cid:3)(cid:7)(cid:23)(cid:14)(cid:17)(cid:24)(cid:20)(cid:6)(cid:11)(cid:20)(cid:5)(cid:11)(cid:25)(cid:6) (cid:27)(cid:28) (cid:27)(cid:28)(cid:28)(cid:29) (cid:28)(cid:30) (cid:2)(cid:15)"(cid:21)(cid:28)(cid:28)

(cid:2)(cid:3)(cid:4)(cid:5)(cid:6)(cid:7)(cid:3)(cid:8)(cid:9)(cid:8)(cid:10)(cid:3)(cid:10)(cid:11) (cid:12)(cid:4)(cid:4)(cid:18) (cid:12)(cid:4)(cid:4)(cid:17) (cid:16)(cid:4)(cid:4)(cid:17)
(cid:28)(cid:30)
(cid:26)(cid:16)(cid:17)(cid:18)(cid:19)(cid:5)(cid:6) (cid:27)(cid:28) (cid:27)(cid:28)(cid:28)(cid:29) (cid:2)(cid:15)"(cid:21)(cid:28)(cid:28)
(cid:2)(cid:3)(cid:4)(cid:5)(cid:6)(cid:7)(cid:3)(cid:8)(cid:9)(cid:8)(cid:10)(cid:3)(cid:10)(cid:11) (cid:12)(cid:4)(cid:4)(cid:18) (cid:12)(cid:4)(cid:4)(cid:17) (cid:12)(cid:4)(cid:4)(cid:13) (cid:12)(cid:4)(cid:4)(cid:19)

(cid:3)
#(cid:20)(cid:3)(cid:4)(cid:6)(cid:7)(cid:11)(cid:3)(cid:11) $(cid:6)(cid:18)(cid:19)(cid:12)

(cid:2)!"(cid:21)(cid:28)(cid:28) (cid:2)!"(cid:21)(cid:28)(cid:28)

(cid:29)(cid:5)(cid:3)(cid:14)(cid:12)(cid:6)(cid:22) (cid:29)(cid:5)(cid:3)(cid:14)(cid:12)(cid:6)(cid:22)

(cid:2)!"(cid:21)(cid:28)(cid:28) (cid:2)(cid:15)"(cid:21)(cid:28)(cid:28)

Fig. (2). ACC function domain. (A) ACC protein domains and encoding genes. ACCs of mammalian, wheat and yeast are composed of BC,
BCCP, and CT domains encoded by a single gene. ACC from S. coelicolor consists of (cid:1) subunit consisting of BC and BCCP domains and (cid:2)
subunit, encoded by an accA1 (A2) and pccB gene, respectively. ACC form Acidianus brierleyi consists of 3 subunits encoded by an accC,
accB, and pccB gene, respectively. In E. coli, carboxyltransferase of ACCs consists of (cid:1) subunit and (cid:2) subunit encoded by accA and accD
gene. (B) ACC forms in plant, a multi-functional single protein (MF-ACC) and a multi-subunit heteromeric complex (MS-ACC).
an inhibitor CP-640186 [35]. This yeast CT domain dimer is
3. REGULATION OF ACETYL-COA CARBOXYLASE
formed by a side-to-side reverse arrangement of two mono-
ACTIVITY
mers [36]. A yeast CT domain monomer comprises 24 (cid:1)-
helices and 29 (cid:2)-strands, constructing two sub-domains (N- Due to the importance in energy and lipid metabolism,
and C-domains) intimately associated with each other Fig. ACCs activity is regulated at multiple levels, including tran-
(3C). The N-domain consists of residues 1484-1824 (strands scriptional, posttranslational, and metabolite-allosteric regu-
(cid:2)1-(cid:2)13 and helices (cid:1)1-(cid:1)8), and the C-domain is composed of lations. Transcription of ACC1/2 genes is controlled by
residues 1825-2202 ((cid:2)1-(cid:2)12 and helices (cid:1)1-(cid:1)8). The N- and sterol-regulatory-element binding protein 1 (SREBP-1), liver
C-domains share similar polypeptide backbone folds with a X receptor, retinoid X receptor, peroxisome-proliferation-
central (cid:2)-(cid:2)-(cid:1) superhelix (strands (cid:2)5, (cid:2)7, (cid:2)9, and (cid:2)11 and activated receptors (PPARs), forkhead box O (FOXO),
helix (cid:1)6). Catalytic pocket/cavity is formed by small (cid:2)- C/EBP and PPAR(cid:3) co-activator (PGC) [40-44]. By stimulat-
sheets and (cid:1)6 helix of (cid:2)-(cid:2)-(cid:1) superhelix of two domains, fea- ing these signalings, a variety of factors and hormones, such
tured with additional binding surface for CoA Fig. (3C and as glucose, insulin, and thyroid hormones regulate ACC ex-
3D). The active site is located at the middle site of the inter- pression. Please refer to the recent review articles for more
face of N- and C-domains in the dimer. Conserved residues details [45-52].
in the active site, Arg 1954 and Arg 1731 in particular, are
Posttranslational regulation of ACC activity includes
important for carboxyl group recognition of malonyl-CoA,
phosphorylation and stabilization [53]. ACCs are phosphory-
and the N1 atom of biotin itself functions as a general base
lated as inactive monomers. On the contrary, dephosphoryla-
[25].
tion activates ACCs that self-associates for a functional mul-
timeric filamentous complex. Induced polymerization of
2.3. BCCP Subunit/Domain of Acetyl-CoA Carboxylases
mammalian acetyl-CoA carboxylase by MIG12 provides a
BCCP subunit in E. coli contains the essential biotin co- tertiary level of regulation of fatty acid synthesis [54]. AMP-
valently bound to lys 35 from the C-terminus, and the inte- activated kinase (AMPK), regulated by a variety of stress
gral BCCP has strong tendency to aggregate [37, 38]. The signals and adipokines, (e.g. leptin and adiponectin), medi-
molar ratio of BC to BCCP subunits in E. coli is 1:2 [39]. ates the phosphorylation of ACC at Ser 79, Ser 1200, and
The N-terminus (residues 1-30) of BCCP is responsible for Ser 1215 [45, 55-57], and protein kinase A (PKA) activated
the interaction with BC, and the BC·BCCP complex could be by low blood glucose phosphorylates ACCs at Ser 77, and
biotinylated in vitro. Ser 1200 [42, 58]. Additionally, breast cancer protein 1
Acetyl-CoA Carboxylase Inhibitors Recent Patents on Anti-Cancer Drug Discovery, 2012, Vol. 7, No. 2 171
(cid:2)
(cid:3)

(cid:2)(cid:3)(cid:4)(cid:5)(cid:6)(cid:7)(cid:8)(cid:9) (cid:2)(cid:3)(cid:4)(cid:5)(cid:6)(cid:7)(cid:8)(cid:9)

(cid:2)% (cid:2)(cid:3)(cid:4)(cid:5)(cid:6)(cid:7)(cid:8)(cid:9)
(cid:10) (cid:3)"#
(cid:10)(cid:3)(cid:4)(cid:5)(cid:6)(cid:7)(cid:8)(cid:9) (cid:2)! (cid:2)&
(cid:3)$
(cid:2)(cid:6) (cid:2)(cid:16)
(cid:3)"" (cid:3)’
(cid:2)2 (cid:9)(cid:16)(cid:17) (cid:3)"((cid:3)"’ (cid:9)(cid:16)(cid:17) (cid:10)
(cid:3)(cid:7)# (cid:3)", (cid:3)"/ (cid:3)"(cid:7) (cid:2)*
(cid:2)) (cid:11)(cid:2)
(cid:3)"$ (cid:3)"(cid:24)
(cid:3)"+ (cid:17)(cid:5)(cid:15) (cid:2)(cid:4) (cid:2)(cid:10) (cid:12)(cid:8)(cid:9)(cid:13)(cid:14)(cid:15)
(cid:2)(cid:18) (cid:2)(cid:5) (cid:3)+ (cid:3),(cid:11)(cid:2)
(cid:2)(cid:3) (cid:12)(cid:8)(cid:9)(cid:13)(cid:14)(cid:15)
(cid:2)1
(cid:3)(cid:24)(cid:3)(cid:7) (cid:3)(cid:2)"0(cid:3)/ (cid:2).(cid:2)(cid:17)
(cid:2)- (cid:10)(cid:3)(cid:4)(cid:5)(cid:6)(cid:7)(cid:8)(cid:9)
(cid:3)(
(cid:2)(cid:2) (cid:17)(cid:5)(cid:15)

(cid:11)(cid:3)(cid:4)(cid:5)(cid:6)(cid:7)(cid:8)(cid:9) (cid:2)(cid:9)
(cid:11)(cid:3)(cid:4)(cid:5)(cid:6)(cid:7)(cid:8)(cid:9)
(cid:2)(cid:25)
(cid:16) (cid:16)

(cid:4) (cid:5)
(cid:10)(cid:8)(cid:12)"

(cid:3),(cid:3)
(cid:10)(cid:8)(cid:12)(cid:7) (cid:16)(cid:18)(cid:4)(cid:5)(cid:6)(cid:7)(cid:8)(cid:9)
(cid:13)(cid:6)(cid:7)(cid:8)(cid:9)(cid:10)(cid:11)(cid:12) (cid:3),(cid:9) (cid:4)(cid:6)(cid:7)(cid:8)(cid:9)(cid:10)(cid:11)(cid:12)
(cid:3),(cid:25) (cid:2)(cid:24)(cid:9) (cid:10)(cid:18)(cid:4)(cid:5)(cid:6)(cid:7)(cid:8)(cid:9) (cid:10)(cid:5)(cid:11) (cid:16)
(cid:3),(cid:18)

(cid:2)’(cid:3)

(cid:2)’(cid:25)
(cid:10)(cid:5)(cid:11)(cid:2)/
(cid:2)’ (cid:2)’(cid:9) (cid:2)’(cid:18) (cid:2)’(cid:2)( (cid:2)/ (cid:3)(cid:3)//(cid:25)(cid:9)
(cid:2)( (cid:2)(cid:24) (cid:3)(cid:24) (cid:3)$ (cid:2)(cid:24)
(cid:3)""(cid:3)$ (cid:2)" (cid:3)(cid:7) (cid:2), (cid:3)"" (cid:3)/(cid:3)(cid:24)
(cid:2), (cid:3)"#(cid:3)+(cid:3)’ (cid:3)/ (cid:3)" (cid:3)(cid:3)""(cid:7)# (cid:3)+(cid:3)’ (cid:2)(cid:7) (cid:3)"
(cid:3)"(cid:7) (cid:2)+ (cid:2)+(cid:9) (cid:2)+ (cid:16) (cid:11) (cid:10)(cid:3)(cid:4)(cid:5)(cid:6)(cid:7)(cid:8)(cid:9)
(cid:16) (cid:2)+(cid:25) (cid:16)
(cid:2)(cid:7) (cid:16)(cid:18)(cid:4)(cid:5)(cid:6)(cid:7)(cid:8)(cid:9)
(cid:3)"(cid:24) (cid:10)(cid:2)+(cid:3)
(cid:10)

Fig. (3). 3D structure of ACC domains. A and B: Crystal structure of BC domain of yeast ACC1. C and D: Crystal structure of CT domain
of ACC2. The crystal structure figures were produced with permission as indicated in footnote.
(BRCA1) prevents ACCs from dephosphorylation at Ser 79 epithelial cells. Through direct association with ACC1,
and Ser 1263 [59, 60]. AKR1B10 blocks its ubiquitin-dependent degradation, medi-
ating fatty acid synthesis and lipid metabolism [64, 65].
Recent studies from our laboratory have revealed a novel
regulatory mechanism on ACC activity. Aldo-keto reductase ACC activity is also regulated in molecular conformation
family 1 member B10 (AKR1B10), a NADPH-dependent by local metabolites. Citrate, a precursor of acetyl-CoA, al-
xenobiotic reductase primarily expressed in the colon and losterically activates ACCs, stimulating conversion of exces-
small intestine [61-63], upregulated simultaneously with sive acetyl-CoA to malony-CoA [66]. In contrast, palmitoyl-
ACC1 in tumorigenic transformation of human mammary CoA, an end-product of fatty acid synthesis, promotes the
inactive conformation of ACCs, diminishing malonyl-CoA
(cid:1)(cid:1)(cid:1)(cid:1)(cid:1)(cid:1)(cid:1)(cid:1)(cid:1)(cid:1)(cid:1)(cid:1)(cid:1)(cid:1)(cid:1)(cid:1)(cid:1)(cid:1)(cid:1)(cid:1)(cid:1)(cid:1)(cid:1)(cid:1)(cid:1)(cid:1)(cid:1)(cid:1)(cid:1)(cid:1)(cid:1)(cid:1)(cid:1)(cid:1)(cid:1)(cid:1)(cid:1)(cid:1)(cid:1)(cid:1)(cid:1)(cid:1)(cid:1)(cid:1)(cid:1)(cid:1)(cid:1)(cid:1)(cid:1)(cid:1)(cid:1)(cid:1)(cid:1)(cid:1)(cid:1)(cid:1)(cid:1)(cid:1)(cid:1)(cid:1)(cid:1) production [67].
1 Reprinted from Molecular Cell, Vol. 16, Shen Y, Volrath SL, Weatherly SC, Elich
TD, Tong L, A mechanism for the potent inhibition of eukaryotic acetyl-coenzyme A 4. ACETYL-COA CARBOXYLASE INHIBITORS
carboxylase by soraphen A, a macrocyclic polyketide natural product, 881-91., Copy-
right (2004) , with permission from Elsevier. As critical enzymes in fatty acid synthesis and energy
2, From Zhang H, Yang Z, Shen Y, Tong L, Crystal structure of the carboxyltransferase metabolism, ACCs are pathogenically implicated in several
domain of acetyl-coenzyme A carboxylase, 2003; 299: 2064-2067. Reprinted with
human diseases, including metabolic syndromes and deadly
permission from AAAS.
172 Recent Patents on Anti-Cancer Drug Discovery, 2012, Vol. 7, No. 2 Luo et al.
malignancies, and thus may be potent therapeutic targets. In domain [110]. These inhibitors include sulfonamide-contain-
the past decades, ACC inhibitors have been extensively ex- ing spirochromane derivatives (JP119987, US2011007726-
plored in preclinical and clinical trials. Discussed below are 2A1 and US7935712) [113, 114], non-spirocyclic matter
updates on the investigation and development of ACC in- (JP119987), spiro [chromene-2,4(cid:2)-piperidin]-4(3H)-ones
hibitors. (WO07011809 and WO07011811), and pyrazolospiroketone
(US 20110028390) [115].
4.1. Categories of Acetyl-CoA Carboxylase Inhibitors
4.2. Popular Acetyl-CoA Carboxylase Inhibitors
ACC inhibitors include two main classes: natural and
non-natural (artificial) compounds. As summarized in Table Although thousands of ACC inhibitors have been devel-
1 [17, 68-72], natural ACC inhibitors are isolated from natu- oped thus far, most published reports are based on studies
ral products, such as Soraphen A (WO03011867) from Spo- with these compounds Table 3, which are actively ap-
rangium cellulosum [73-75], avenaciolide (WO03094912 plied/investigated in agriculture for weeding and in labora-
and JP035998) from Aspergillus avenaceus, chloroacetylated tory animals for the treatment of obesity, type 2 diabetes
biotin (US6242610 and US6485941) from beans, egg yolks, mellitus, or cancer.
and cauliflower [72, 76, 77], pseudopeptide pyrrolidine di-
4.2.1. Soraphen A
one antibiotics (Moiramide and Andrimid, US7544709 and
US20050080129) from bacteria [78, 79], curcumin Soraphen A (1S,2S,3E,5R,6S,11S,14S,15R,16R,17S,
(WO05113069 and US20050267221) from turmeric [80]. 18S)-15,17-dihydroxy-5,6,16-trimethoxy-2,14,18-trimethyl-
The natural products inhibit ACC activity by three modes. 11-phenyl-12,19-dioxabicyclo[13.3.1] nonadec-3-en-13-one)
Curcumin phosphorylates and inactivates ACC via activating (WO03011867) was isolated from the culture broth of
AMPK [81-83], Moiramide B and Andrimid act as a CT Sorangium cellulosum, a soil-dwelling myxobacterium [73,
inhibitor, and other natural products inhibit the BC activity 74]. This polyketide natural product contains an unsaturated
by interacting with the allosteric site [78, 79]. 18-membered lactone ring, an extracyclic phenyl ring, two
hydroxyl groups, three methyl groups, and three methoxy
Chemically synthesized inhibitors are composed of three
groups [74, 116, 117]. Soraphen A is an allosteric inhibitor
subclasses based on their chemical structures Table 2 [18,
of the BC domain, binding to the interface between the A-
33, 84-111]. The first subclass possess commonly extended
domain and C-domain, 25Å away from the putative ATP
linear aliphatic region. Inhibitory activity of these com-
binding site. ATP and Soraphen A molecules are located at
pounds depends on their intracellular conversion to CoA
opposite ends of the cylindrical structure of the BC domain.
thioesters, inhibiting ACC activity by competing with acetyl-
Soraphen A interacts with residues from helices (cid:1)N and (cid:1)O
CoA in the CT catalyst. This subclass of ACC inhibitors
and strands (cid:3)17-(cid:3)20 in the C-domain, as well as several resi-
includes anthranilic acid derivatives (2-amino-(cid:1),(cid:1),(cid:1)-
dues of helix (cid:1)C in the A-domain. Soraphen A is a non-
trifluoro-p-toluic acids; US4307113 and JP11171848), sul-
competitive eukaryotic ACC inhibitor with sensitivity at a
fonamide derivatives (N-(1-[4-[2-(4-isopropoxyphenoxy)-
nanomolar level; soraphen A has no inhibitory activity to-
1,3-thiazol-5-yl]phenyl]ethyl)ethyl) acetamide; US0191323
wards the bacterial BC subunits [74, 118-120]. This species
and WO0202101), benzodioxepine derivatives (A1, 3,3-
selectivity of soraphen A is explained by the amino acid se-
Dimethyl-7-(4-methylsulfanyl-phenylethynyl)-3,4-dihydro-
quence and structural difference of the binding sites, e.g. the
2H-benzo[b][1,4] dioxepine; US0113374), alkynyl-subs-
absence of (cid:3)18 in E. coli BC) [117].
tituted thiazole derivatives (A1, N-[4-(2-furyl)-5-(4-pyridyl)
thiazol-2-yl]pyridine-4-carboxamide; US0105919), hetero- 4.2.2. Haloxyfop
aryl-substituted thiazole derivatives (A1, 4-(6-((dime-
Haloxyfop (2-[4-[3-chloro-5-(trifluoromethyl)pyridin-2-
thylamino)methyl)pyridin-3-yl)-N-(4-(pentyloxy)-3-
yl] oxyphenoxy]propanoic acid) contains pyridine moiety,
(trifluoromethyl) phenyl) thiazol-2-amine; US0041720), (cid:1),
and two forms of Haloxyfop are synthesized i.e. haloxyfop-
(cid:4)-dicarboxylic acid derivatives (MEDICA 16 and ESP-
methyl and haloxyfop-ethoxyethyl (US0184980). Haloxy-
55016; US4711896), benzoic acid derivative (S-2E;
fops are commercially used as pre- and post-emergence se-
US5145865), furan-2,5-dicarboxylic acid diamides (TOFA;
lective herbicides in broad leaf crops. They are absorbed by
US3546255), aryloxyphenoxypropionate derivatives (Ha-
the foliage and roots and hydrolyzed to haloxyfop, inhibiting
loxyfop; US0014643), and cyclohexanedione derivatives
growth of meristematic tissues. The (R)-isomer, not (S)-
(sethoxydim, US4640706).
isomer, of haloxyfop is herbicidally active [34]. Another
The second subclass of ACC inhibitors is bipiperidinyl- derivative, diclofop (2-(4-(2,4-dichlorophenoxy) phe-
carboxamide pharmacophores or cyclohexyl. They are po- noxy)propionate) (US0184980) inhibits fatty acid synthesis
tent, reversible, isozyme-nonselective inhibitors targeting the in Zea mays. Haloxyfop or diclofop binds to the active site at
CT domain of ACC [112], and however, the cyclohexyl de- the interface of CT dimer and leads to large conformational
rivatives exhibit potent inhibition of human ACC2, 10-fold changes of several residues, creating a highly conserved hy-
selectivity over inhibition of human ACC1 [33]. These com- drophobic pocket extended into the core of the dimer [34].
pounds include bipiperidinylcarboxamide analogs Two residues Leu 1705 and Val 1967 that affect herbicide
(CP640186), (4-piperidinyl)-piperazine, pseudopeptide pyr- sensitivity are located in this binding site, and their mutation
rolidine dione antibiotics, benzthiazolylamide analogs, and disrupts the structure of the domain and affect the response
cyclohexyl derivative. to this inhibitor.
The third subclass of ACC inhibitors is spirochromanone
pharmacophores and they may inhibit ACC by targeting CT
Acetyl-CoA Carboxylase Inhibitors Recent Patents on Anti-Cancer Drug Discovery, 2012, Vol. 7, No. 2 173
Table 1. Natural ACC Inhibitors.
ACC Inhibitors Chemical Formula Action Mecha- Sources Active Spe- Selectivity Ref.
nism cies
Soraphen OMe Inhibit BC reaction Myxobacteria Fungal ACC1 [17, 68]
(e.g. Soraphen A) Sorangium Eukaryote ACC2
OMe Cellulosum
O O
O OH
OH
OMe

Avenaciolide O Inhibit glutamate Aspergillus Bacteria ACC2? [69-71]
transport in avenaceus
Fungal
O mitochondria ?
Eukaryote
H H
O O C8H17
Chloroacetylated Cl O Inhibit BC reaction Beans, egg Bacteria ACC1 [72]
biotin yolks, and
N NH Eukaryote ACC2
O O cauliflower
H H
O
S
Pseudopeptide Inhibit CT reaction Bacteria Bacteria -- [131,
O
pyrrolidine dione R2 R3 133, 138]
O
(e.g. Andrimid, NH
Moiramide B) R1 N N
H H O O
Curcumin deriva- O O Activate AMPK Turmeric Mammalian ACC2 [82]
tive
HO OH
OCH3 OCH3

Table 2. Non-natural ACC Inhibitors.
ACC Inhibitors Chemical Formula Action Mechanism Active Species Selectivity Ref.
Inhibitors with Linear Aliphatic Region
Anthranilic acid deriva- Inhibit carboxylase Bacteria ACC1, ACC2 [84-85]
tives reaction?
O Eukaryote
NH
OR
1
Sulfonamide derivatives H Suppress Eukaryote ACC1, ACC2 [86]
O N R
1 ACC activation?

H O
S N
O2 R2
Benzodioxepine deriva- R O ? Mammalian ACC2 [87]
tives
O
174 Recent Patents on Anti-Cancer Drug Discovery, 2012, Vol. 7, No. 2 Luo et al.
(Table 2) Contd….

ACC Inhibitors Chemical Formula Action Mechanism Active Species Selectivity Ref.
Alkynyl-substituted thia- O S ? Eukaryote? ACC2 [88-91]
zole derivatives
NH
R
1 O

Heteroaryl-substituted O R3 N ? Eukaryote? ACC1, ACC2 [92]
thiazole derivatives
R N R2
1
O

Alkanedicarboxylic de- O O OH Inhibit CT reaction Eukaryote ACC1, ACC2 [93-94]
rivatives
HO
(e.g. MEDICA 16,
ESP-55016)
Benzoic acid derivative R2 Noncompetitively Eukaryote ACC1, ACC2 [95-97]
(e.g.S-2E) inhibit ACC by S-2E-
O CoA
O
R
1
Furan-2,5-dicarboxylic R2 Inhibit CT reaction Bacteria ACC1, ACC2 [111]
acid diamides R Eukaryote
1
(e.g. TOFA)
O
Aryloxyphenoxy- R1 R2 O COOH Inhibit CT reaction Grass -- [98-100]
propionates

Me
(e.g. Haloxyfop) N O
Cyclohexanediones R1 O Inhibit CT reaction Grass -- [98-101]
(e.g. Sethoxydim)
N O R
3
O R
2
Inhibitors with Bipiperidinylcarboxamide Pharmacophore or Cyclohexyl
Bipiperidinyl- O Inhibit CT reaction Eukaryote ACC1, ACC2 [18, 102-
carboxamide analog (e.g. 103]
N N
CP640186)
O N O

(4-Piperidinyl)-piperazine O Inhibit CT reaction Eukaryote ACC1, ACC2 [104]
N N
N O
N
O N

(cid:1)
Acetyl-CoA Carboxylase Inhibitors Recent Patents on Anti-Cancer Drug Discovery, 2012, Vol. 7, No. 2 175
(Table 2) Contd….

ACC Inhibitors Chemical Formula Action Mechanism Active Species Selectivity Ref.
Benzthiazolylamide ana- Inhibit CT reaction Eukaryote ACC1, ACC2 [18, 105-
O R2
logs N 106]
NH
S NHR
1
O
Cyclohexyl derivatives O Inhibit CT reaction Mammalian ACC1, ACC2 [33]
(10-fold selec-
O NH
tivity over inhi-
bition of human
ACC1)
HN
O
R

Inhibitors with Spirochromaone Pharmacophore
Sulfonamide-containing O Inhibit CT reaction Mammalian ACC1, ACC2 [107]
Spirochromane Deriva- R1
tives
R2 O H
A N
R R
3 4
O
Non-spirocyclic matter R3 Inhibit CT reaction Mammalian ACC1, ACC2 [108]
R
1
R
4
R2 H
R N
5
R
6
O
Spiro[chromene-2,4(cid:1)- O Inhibit CT reaction Mammalian ACC1, ACC2 [109]
piperidin]-4(3H)-ones R
1

O
N R
2
O
Azaspirochromanones O Inhibit CT reaction Mammalian ACC1, ACC2 [110]
R
1
N
O
N R
2
O
176 Recent Patents on Anti-Cancer Drug Discovery, 2012, Vol. 7, No. 2 Luo et al.
Table 3. Popular ACC Inhibitors.
Inhibitors Chemical Chemical Name Molecular Molecular
(Abbr.) Formula Weight Formula
Soraphen A (1S,2S,3E,5R,6S,11S,14S,15R,16R,17S,18S 520.65 C H O
O 29 44 8
)-15,17-Dihydroxy-5,6,16-trimethoxy-
O
2,14,18-trimethyl-11-phenyl-12,19-
dioxabicyclo [13.3.1]nonadec-3-en-13-one
OH
O
O
O
HO
O

Andrimid O HN (2E,4E,6E)-N-[(1S)-3-[[(2S)-3-Methyl-1- 479.57 C27H33N3O5
[(3R,4S)-4-methyl-2,5-dioxopyrrolidin-3-
O
yl]-1-oxobutan-2-yl]amino]-3-oxo-1-
H O
N H phenylpropyl]octa-2,4,6-trienamide
N
O
O

Moiramide O HN (2E,4E)-N-[(1S)-3-[[(2S)-3-Methyl-1- 453.53 C25H31N3O5
B [(3R,4S)-4-methyl-2,5-dioxopyrrolidin-3-
O
yl]-1-oxobutan-2-yl]amino]-3-oxo-1-
H O
N H phenylpropyl]hexa-2,4-dienamide
N
O
O

Haloxyfop Cl 2-[4-[3-Chloro-5-(trifluoromethyl)pyridin- 361.70 C H ClFNO
HO O 15 11 3 4
2-yl]oxyphenoxy]propanoic acid
O
N
F
F F
Sethoxydim O 2-[1-(Ethoxyamino)butylidene]-5-(2- 327.48 C H NOS
17 29 3
S HN O ethylsulfanylpropyl)cyclohexane-1,3-dione
O
ToFA 5-Tetradecoxyfuran-2-carboxylic acid 324.45 C H O
19 32 4
OH
O O
O
(cid:1)
Acetyl-CoA Carboxylase Inhibitors Recent Patents on Anti-Cancer Drug Discovery, 2012, Vol. 7, No. 2 177
(Table 3) Contd….

Inhibitors Chemical Chemical Name Molecular Molecular
(Abbr.) Formula Weight Formula
S-2E O (+)-(S)- p -[1-( p-Tert- 519.61 C H NO
28 42 6
butylphenyl)-2-oxo-4-pyrrolidinyl]-
N methoxybenzoic acid
O
OH
O
MEDICA O OH 3,3,14,14- 342.51 C20H38O4
16 Tetramethylhexadecanedioic acid
HO O

ESP- O 8-Hydroxy-2,2,14,14-Tetramethyl- 344.49 C H O
19 36 5
55016 OH pentadecanedioic acid
HO
O
OH

CP- [(3R)-1-[1-(Anthracene-9- 485.62 C H NO
O 30 35 3 3
640186 carbonyl)piperidin-4-yl]piperidin-
N N
3-yl]-morpholin-4-ylmethanone
O N O

4.2.3. Sethoxydim fatty acids, cells, and nutritional state. In isolated rat adipo-
cytes, TOFA inhibits fatty acid synthesis and leads to accu-
Sethoxydim (2-[1-(ethoxyamino)butylidene]-5-(2-ethyl-
mulation of lactate and pyruvate, and release of CO by
sulfanylpropyl)cyclohexane-1,3-dione) (US4602935 and 2
blocking synthesis of malonyl-CoA [122]. Ketogenesis from
US0033897) inhibits lipid synthesis in two dicot species,
palmitate was slightly inhibited (~ 20%) by TOFA at a con-
Nicotiana sylvestris (wild tobacco) and Glycine max (soy-
centration less than CoA, but the inhibition was almost com-
bean) [121]. It is a selective post-emergence herbicide used
plete (up to 90%) at a concentration equal to or greater than
to control annual and perennial grass weeds in broad-leaved
the CoA [15]. In some conditions, TOFA may inhibit fatty
vegetables, fruits, fields, and ornamental crops. Sethoxydim
acid synthesis, but not affect fatty acid oxidation [122-124].
is rapidly absorbed through the leaf surfaces, transported in
TOFA can also inhibit glycolysis as a secondary effect of
the xylem and phloem, and accumulated in the meristematic
fatty acid synthesis inhibition and resultant citrate accumula-
tissues. Non-susceptible broadleaf species have a different
tion, a metabolite inhibitor of phosphofructokinase [125].
acetyl-CoA carboxylase binding site resistant to sethoxydim.
TOFA inhibition of ACCs in human cancer cells is contro-
Sethoxydim is water-soluble and does not bind readily with
versial. It has been reported that TOFA induces the apoptosis
soils, thus being mobile.
of lung cancer cells NCI-H460 and colon carcinoma cells
4.2.4. TOFA HCT-8 and HCT-15, but not of some breast and ovary cancer
cells, such as MCF-7 [15, 126-129].
Five-tetradecyloxy-2-furoic acid (TOFA) (US3546255)
itself has no activity. In adipocytes and hepatocytes, TOFA 4.2.5. Andrimid
is converted to 5-tetradecyloxy-2-furoyl-CoA (TOFyl-CoA)
Andrimid ((2E,4E,6E)-N-[(1S)-3-[[(2S)-3-methyl-1-
that binds to CT domain and exerts an allosteric inhibition on
[(3R,4S)-4-methyl-2,5-dioxopyrrolidin-3-yl]-1-oxobutan-2-
ACCs. TOFA is a mammalian ACC inhibitor. The inhibitory
yl]amino]-3-oxo-1-phenylpropyl]octa-2,4,6-trienamide;
activity of TOFA depends on its concentration relative to
JP11171848) is a hybrid non-ribosomal peptide-polyketide