Discovery of a Novel Class of ERRα Agonists

Article abstract of DOI:10.1021/acsmedchemlett.1c00100

A novel class of estrogen-related receptor α (ERRα) agonists has been discovered. A structure-activity relationship study of high-throughput screening hits 1 and 2 led to the discovery of benzimidazole 3d (DS20362725) and acetophenone analogue 5c (DS45500853). The X-ray crystal structure of the ERRα ligand-binding domain in complex with 5c and PGC-1α coactivator peptide revealed conformational changes in the ligand-binding pocket to accommodate 5c and the key interaction between the protein and ligand. Since both analogues avoided PPARγtranscriptional activity, they can be useful tool compounds for investigating biological ERRα functions.

Full text of DOI:10.1021/acsmedchemlett.1c00100

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Letter
Discovery of a Novel Class of ERRα Agonists
Tsuyoshi Shinozuka,* Shuichiro Ito, Takako Kimura, Masanori Izumi, and Kenji Wakabayashi
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ABSTRACT: A novel class of estrogen-related receptor α (ERRα) agonists has
been discovered. A structure−activity relationship study of high-throughput
screening hits 1 and 2 led to the discovery of benzimidazole 3d (DS20362725)
and acetophenone analogue 5c (DS45500853). The X-ray crystal structure of the
ERRα ligand-binding domain in complex with 5c and PGC-1α coactivator peptide
revealed conformational changes in the ligand-binding pocket to accommodate 5c
and the key interaction between the protein and ligand. Since both analogues
avoided PPARγ transcriptional activity, they can be useful tool compounds for
investigating biological ERRα functions.
KEYWORDS: ERRα, PPARγ, TZD, crystal structure
ERRα upregulation or downregulation is beneficial for
metabolic disorders, including type 2 diabetes mellitus
(T2DM), a novel class of ERRα ligands is highly
demanded.7−9 It has also been reported that the development
of ERRα agonists is challenging because small molecules might
not induce the conformational changes needed to activate
ERRα.10 In this Letter, the identification of a novel class of
ERRα agonists with structural biological properties is
described.
Our high-throughput screening (HTS) strategy was to
evaluate the suppression of binding between FITC-RIP140
peptide and the GST-hERRα ligand-binding domain (LBD) in
a fluorescence polarization (FP) assay, which led to the
discovery of HTS hits 1 and 2. Compound 1 inhibited binding
of RIP140 corepressor peptide with IC50 = 0.67 μM, while 2
showed IC50 = 0.78 μM. Accordingly, derivatization of these
HTS hits was commenced to acquire potent ERRα agonists.
Our initial efforts were focused on the modification of 1 as
presented in Table 1. Since compound 1 is a potent PPARγ
agonist,11,12 the avoidance of PPARγ activity was desired. This
led us to synthesize non-thiazolidinedione (non-TZD)
derivatives because the TZD moiety is known to enhance
PPARγ activity.13 As presented in Table 1, the potent PPARγ
strogen-related receptors (ERRs) are orphan nuclear
Ereceptors with three subtypes: ERRα, ERRβ, and ERRγ.
Among them, ERRα is expressed mainly in metabolically active
tissues such as muscle and adipose tissue and is known as a
transcriptional regulator of energy metabolism.1,2 It is also
known that transcription factor peroxisome proliferator-
activated receptor γ (PPARγ) coactivator 1α (PGC-1α) is
the endogenous coactivator protein for ERRα2 and corepressor
receptor-interacting protein 140 (RIP140) is the endogenous
corepressor protein for ERRα.3 ERRα knockout mice
displayed suppressed weight gain, adipose synthesis, and β-
oxidation under high-fat-diet feeding.4 In addition, ERRα
agonist I (Figure 1) has been reported to improve glucose and
fatty acid uptake in C2C12 mouse muscle cells,5 whereas
ERRα inverse agonist II normalized serum triglyceride and
insulin levels in vivo.6 As it remains controversial whether
agonist activity of 1 was confirmed (EC50 = 0.41 nM, Emax
=
119%). To our delight, non-TZD derivative 3a maintained its
inhibitory potency. Compounds with potent binding activity
were evaluated in a full-length ERRα luciferase reporter assay
to assess the ERRα agonist activity. HTS hit 1 exhibited
Received: February 14, 2021
Accepted: April 19, 2021
Published: April 21, 2021
Figure 1. Chemical structures of ERRα agonist I from the Chinese
Academy of Sciences,5 ERRα inverse agonist II from Johnson &
Johnson Pharmaceutical,6 and HTS hits 1 and 2 with binding-
inhibitory and reporter activities.
https://doi.org/10.1021/acsmedchemlett.1c00100
© 2021 American Chemical Society
ACS Med. Chem. Lett. 2021, 12, 817−821
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ACS Medicinal Chemistry Letters
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Letter
Table 1. Binding and Transcriptional Activities of Compounds 3
a
Inhibition of the binding between 10 nM F-RIP140 and 1.2 μM GST-ERRα LBD in 10 mM HEPES, 0.10 mM EDTA, 5% bovine gamma
globulin, 2.0 mM DTT, and buffer (pH 6.8). Each value represents the mean of at least two independent experiments run in quadruplicate, unless
b
otherwise noted. Transcriptional activity of full-length ERRα in MG63 cells. Mean values of at least two independent experiments run in
sextuplicate are shown, unless otherwise noted. Transcriptional activity of full-length PPARγ. Values from single experiments run in quadruplicate
are shown. Value from a single experiment. NT = not tested. ND = not determined.
c
d
e
f
Table 2. Binding and Transcriptional Activities of Compounds 4 and 5
a
b
c
ERRα binding
Imax (%)
ERRα reporter
PPARγ reporter
compd
X
Y
Z
IC50 (μM)
Hill slope
EC50 (μM)
Emax (%)
slope
0.90
EC50 (μM)
Emax (%)
slope
e
d
d
d
d
d
d
e
2
Cl
Cl
Cl
Cl
Cl
Cl
Cl
H
Cl
Cl
Cl
H
NHAc
NHCOEt
NHCOn-Pr
NHAc
NHAc
NHAc
Ac
0.78
0.34
48
53
49
58
45
1.7
1.6
2.1
1.4
1.1
1.0
1.5
1.4
ND
149
99
97
101
102
115
278
>10
>10
>10
>10
>10
ND
>10
>10
−5
ND
d
d
e
d
e
4a
4b
4c
4d
5a
5b
5c
>10
ND
ND
ND
ND
12
ND
d
d
d
d
e
d
e
0.35
>10
18
ND
d
d
d
d
e
d
e
0.42
>10
10
ND
d
d
d
d
e
d
e
H
3.8
>10
19
ND
d
d
e
e
d
e
OH
OH
OH
1.0
0.12
38
51
>10
ND
62
ND
d
d
d
d
d
d
e
5.9
5.4
1.9
1.3
6
ND
d
d
e
Ac
0.80
40
354
15
ND
a
Inhibition of the binding between 10 nM F-RIP140 and 1.2 μM GST-ERRα LBD in 10 mM HEPES, 0.10 mM EDTA, 5% bovine gamma
globulin, 2.0 mM DTT, and buffer (pH 6.8). Each value represents the mean of at least two independent experiments run in quadruplicate, unless
b
otherwise noted. Transcriptional activity of full-length ERRα in MG63 cells. Mean values of at least two independent experiments run in
c
sextuplicate are shown, unless otherwise noted. Transcriptional activity of full-length PPARγ. Values from single experiments run in quadruplicate
d
e
are shown. Value from a single experiment. ND = not determined.
micromolar potency in the reporter assay, whereas non-TZD
derivative 3a lost the activity. The poor correlation between
the activities in the reporter assay and those observed in the
coactivator binding assay was previously reported.6 With
regard to the subtype selectivity, compound 1 did not
modulate ERRβ or ERRγ transcriptional activity up to 7.9
μM (less than 10% modulation; see the Supporting
Information). The phenolic hydroxyl group is essential for
the binding activity, as removal of the hydroxyl group led to
the loss of binding potency (compound 3b). These results led
us further to modify the 2-substituent of the benzimidazole
ring. Phenyl derivative 3c retained binding activity, whereas 3c
lost transcriptional activity. The phenyl ring on the right-hand
side of the molecule was not required for binding activity
because methyl analogue 3d retained binding activity. Methyl
analogue 3d displayed the same range of potency as HTS hit 1
in the reporter assay (EC50 = 1.1 μM). By the removal of the
aromatic ring of the 2-benzimidazole, compound 3d
successfully avoided PPARγ agonist activity.
We then focused on the modification of HTS hit 2 (Table
2). Although 2 exhibited the same level of binding potency as
1, it displayed poor transcriptional activity in the reporter
assay. Since it appeared that the diphenyl ether moiety was
essential for the activity, our derivatization strategy involved
minor modifications of the X, Y, and Z moieties as indicated in
Table 2. Elongation of the acetyl group effectively enhanced
binding activity, as compounds 4a and 4b had 2-fold higher
activity than 2. However, neither compound displayed
transcriptional activity. In a similar manner, although removal
of the chloro group from the right-hand side of the molecule
maintained the binding activity, compound 4c exerted no
transcriptional activity. The chloro group on the naphthyl ring
plays a pivotal role in the binding activity, as compound 4d
exhibited 5-fold lower activity. The structural similarity
818
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Figure 2. Crystal structure of the ERRα LBD in complex with 5c and PGC-1α coactivator peptide. (A) σA-weighted 2Fo − Fc electron density map
around 5c contoured at 1.0σ. The protein (dark blue) and 5c (cyan) are shown as a stick model and a ball-and-stick model, respectively. (B)
Schematic representation of the ERRα LBD (dark blue) with 5c (cyan) and PGC1α peptide (yellow). Helix 12 is colored in green. The N-
terminus, C-terminus, and secondary structure assignment are labeled. (C) Details of the interaction of 5c with ERRα. Residues of ERRα involved
in the binding of 5c are depicted as stick models. Hydrogen bonds are marked as dotted lines. (D) Superposition of the 5c-bound (dark blue) and
apo (pink) ERRα LBDs. Significant conformational changes are induced to accommodate the binding of 5c.
between HTS hits 1 and 2 led us to replace the naphthyl ring
with a tert-butylphenol group, giving 5a. Modification of 5a
was required because the compound showed modest binding
activity and almost no transcriptional activity in the reporter
assay. Replacement of the acetamide moiety with an acetyl
group enhanced both binding and transcriptional activity
(compound 5b). A close analogue of 5b also retained binding
and transcriptional activity (compound 5c). A reporter assay
indicated that 5b and 5c did not possess PPARγ transcriptional
activity.
To obtain structural information on the interaction of the
protein with the ligand responsible for activity, the X-ray
crystal structure of the ERRα LBD complexed with compound
5c and PGC-1α coactivator peptide was determined at 2.7 Å
resolution, as shown in Figure 2. Two ERRα LBD monomers
in an asymmetric unit form a dimer and display the canonical
fold of nuclear receptor LBDs. The nomenclature of the
secondary structure elements is based on the RXR LBD crystal
structure14 (Figure 2B). The ERRα LBD adopts an agonist
conformation with the bound coactivator peptide, as judged by
the position of H12.15 The crystal structure revealed that 5c
binds in the same ligand-binding pocket (LBP) of the ERRα
LBD as inverse agonist II.6,16 Inside the LBP, 5c forms
extensive hydrophobic interactions with the protein, including
50 van der Waals contacts (Figure 2C). In addition, the
phenolic hydroxyl group of 5c has a hydrogen-bonding
interaction mediated through a water molecule with the side-
chain nitrogen atom of Arg-372 and the main-chain oxygen
atom of Phe-382, which are the only hydrophilic interactions
between the protein and 5c. This explains why the phenolic
hydroxyl group is essential for activity, as described in Table 1
(compound 3b). Because this pocket is lipophilic, only
lipophilic substituents were tolerated except for the sub-
stituents involved in this hydrogen-bonding network.
To better understand the structural rearrangement required
for the binding of 5c to the ERRα LBD, the LBD structure in
complex with 5c was compared with that of the apo ERRα
LBD (PDB accession code 1XB7)17 (Figure 2D). The overall
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structures of the 5c-bound LBD and the apo LBD were similar;
however, there were significant differences in the LBPs.
Although residues from Val-321 to Leu-324 form helix H3 in
apo ERRα, the same residues are unwound in the 5c-bound
LBD. The N-terminal part of H3 moves away from the LBP to
create the necessary space for 5c. In particular, the Cα atoms
of Leu-324, Cys-325, and Phe-328 in H3 move by 5.4, 3.6, and
1.7 Å, respectively, to create the binding site for 5c.
Furthermore, 5c induces multiple conformational changes
within the LBP, including the side-chain atoms of Phe-328,
Leu-365, Phe-382, and Phe-495.
In summary, a novel class of ERRα agonists has been
discovered. From HTS hit 1, a slight enhancement of RIP140
corepressor peptide binding inhibitory potency and agonistic
activity was achieved to give methylbenzimidazole 3d. Since a
strong requirement was the elimination of PPARγ activity, the
derivatization strategy involved the removal of the TZD
moiety. From HTS hit 2, a structure−activity relationship
study identified acetyl derivative 5c. The X-ray crystal structure
of the ERRα LBD complexed with 5c revealed that the LBD
adopts an agonist conformation and 5c induces multiple
conformational changes in the LBP. This crystal structure also
explains the importance of the phenolic hydroxyl group for
binding potency. As compounds 3d (DS20362725) and 5c
(DS45500853) did not activate PPARγ, both compounds can
be useful tool compounds to investigate the biological roles of
ERRα agonists. Pharmacological evaluations of these com-
pounds are underway, and the findings will be reported when
available.
ACKNOWLEDGMENTS
■
We thank the researchers of the Biologics Technology
Research Laboratories, Daiichi Sankyo Co., Ltd., especially
Toshihiro Suzuki (current affiliation: Daiichi Sankyo Chemical
Pharma Co., Ltd.) and Yoshiyuki Kanari (current affiliation:
Daiichi Sankyo RD Novare Co., Ltd.) for large-scale expression
experiments. We also thank the staff of the Photon Factory
(Tsukuba, Japan) for support with diffraction data collection.
ABBREVIATIONS
■
ERR, estrogen-related receptor; PGC-1α, PPARγ coactivator
1α; PPAR, peroxisome proliferator-activated receptor; RIP140,
receptor-interacting protein 140; HTS, high-throughput
screening; TZD, thiazolidinedione; LBD, ligand-binding
domain; LBP, ligand-binding pocket
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■
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acsmedchemlett.1c00100.
■
sı
Experimental procedures, characterization data for all
synthesized compounds, procedures for pharmacological
activities, and X-ray crystallography (PDF)
AUTHOR INFORMATION
Corresponding Author
Tsuyoshi Shinozuka − R&D Division, Daiichi Sankyo Co.,
Ltd., Shinagawa-ku, Tokyo 140-8710, Japan; orcid.org/
0000-0002-7785-6080; Phone: +81-70-1440-2862;
Email: sinozu.xf6@gmail.com, shinozuka.tsuyoshi.s5@
daiichisankyo.co.jp; Fax: +81-3-5436-8561
■
Authors
Shuichiro Ito − Daiichi Sankyo RD Novare Co., Ltd.,
Edogawa-ku, Tokyo 134-8630, Japan
Takako Kimura − Daiichi Sankyo RD Novare Co., Ltd.,
Edogawa-ku, Tokyo 134-8630, Japan
Masanori Izumi − R&D Division, Daiichi Sankyo Co., Ltd.,
Shinagawa-ku, Tokyo 140-8710, Japan
Kenji Wakabayashi − Daiichi Sankyo RD Novare Co., Ltd.,
Edogawa-ku, Tokyo 134-8630, Japan
Complete contact information is available at:
https://pubs.acs.org/10.1021/acsmedchemlett.1c00100
Notes
The authors declare no competing financial interest.
The atomic coordinates have been deposited in the Protein
Data Bank (www.rcsb.org) with the accession code 7E2E.
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