Unexpected equivalent potency of a constrained chromene enantiomeric pair rationalized by co-crystal structures in complex with estrogen receptor alpha

Article abstract of DOI:10.1016/j.bmcl.2019.01.036

Despite tremendous progress made in the understanding of the ERα signaling pathway and the approval of many therapeutic agents, ER+ breast cancer continues to be a leading cause of cancer death in women. We set out to discover compounds with a dual mechan

Full text of DOI:10.1016/j.bmcl.2019.01.036

Accepted Manuscript
Unexpected Equivalent Potency of a Constrained Chromene Enantiomeric Pair
Rationalized by co-Crystal Structures in Complex with Estrogen Receptor Al-
pha
Birong Zhang, James R. Kiefer, Robert A. Blake, Jae H. Chang, Steven Hartman,
Ellen Rei Ingalla, Tracy Kleinheinz, Vidhi Mody, Michelle Nannini, Daniel F.
Ortwine, Yingqing Ran, Amy Sambrone, Deepak Sampath, Maia Vinogradova,
Yu Zhong, Jerome C. Nwachukwu, Kendall W. Nettles, Tommy Lai, Jiangpeng
Liao, Xiaoping Zheng, Hai Chen, Xiaojing Wang, Jun Liang
PII:
S0960-894X(19)30057-5
https://doi.org/10.1016/j.bmcl.2019.01.036
BMCL 26273
DOI:
Reference:
To appear in:
Bioorganic & Medicinal Chemistry Letters
Received Date:
Revised Date:
Accepted Date:
13 December 2018
24 January 2019
30 January 2019
Please cite this article as: Zhang, B., Kiefer, J.R., Blake, R.A., Chang, J.H., Hartman, S., Ingalla, E.R., Kleinheinz,
T., Mody, V., Nannini, M., Ortwine, D.F., Ran, Y., Sambrone, A., Sampath, D., Vinogradova, M., Zhong, Y.,
Nwachukwu, J.C., Nettles, K.W., Lai, T., Liao, J., Zheng, X., Chen, H., Wang, X., Liang, J., Unexpected Equivalent
Potency of a Constrained Chromene Enantiomeric Pair Rationalized by co-Crystal Structures in Complex with
Estrogen Receptor Alpha, Bioorganic & Medicinal Chemistry Letters (2019), doi: https://doi.org/10.1016/j.bmcl.
2
019.01.036
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Unexpected Equivalent Potency of a
Constrained Chromene Enantiomeric Pair
Rationalized by co-Crystal Structures in
Complex with Estrogen Receptor Alpha
a*
a
a
a
a
Birong Zhang , James R. Kiefer , Robert A. Blake , Jae H. Chang , Steven Hartman , Ellen Rei
a
a
a
a
a
a
Ingalla , Tracy Kleinheinz , Vidhi Mody , Michelle Nannini , Daniel F. Ortwine , Yingqing Ran ,
a
a
a
a
b
Amy Sambrone , Deepak Sampath , Maia Vinogradova , Yu Zhong , Jerome C. Nwachukwu ,
b
c
c
c
c
Kendall W. Nettles , Tommy Lai , Jiangpeng Liao , Xiaoping Zheng , Hai Chen , Xiaojing
a
a*
Wang , Jun Liang
a. Genentech Inc., 1 DNA Way, South San Francisco, California, 94080, USA
b. Department of Integrated Structural and Computational Biology, The Scripps Research
Institute, 130 Scripps Way, Jupiter, FL 33458, USA
c. WuXi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai, 200131,
China
1

Graphic Abstract
ABSTRACT
Despite tremendous progress made in the understanding of the ER signaling pathway and the
approval of many therapeutic agents, ER+ breast cancer continues to be a leading cause of cancer
death in women. We set out to discover compounds with a dual mechanism of action in which
they not only compete with estradiol for binding with ER, but also can induce the degradation
of the ER protein itself. We were attracted to the constrained chromenes containing a
tetracyclic benzopyranobenzoxepine scaffold, which were reported as potent selective estrogen
receptor modulators (SERMs). Incorporation of a fluoromethyl azetidine side chain yielded
highly potent and efficacious selective estrogen receptor degraders (SERDs), such as 16aa and
surprisingly, also its enantiomeric pair 16ab. Co-crystal structures of the enantiomeric pair 16aa
and 16ab in complex with ER revealed default (mimics the A-D rings of endogenous ligand
estradiol) and core-flipped binding modes, rationalizing the equivalent potency observed for
these enantiomers in the ER degradation and MCF-7 anti-proliferation assays.
2

Keywords:
ER
Estrogen receptor degrader
SERD
Constrained chromene
1
Estrogen receptor alpha (ERα), an estrogen-dependent nuclear transcription factor, is a
well validated therapeutic target for the treatment of estrogen receptor positive (ER+) breast
2
cancer (BC). The FDA-approved drug tamoxifen (1) and its active metabolite 4-
3
hydroxytamoxifen (2) are SERMs. SERMs compete with the endogenous ligand 17-estradiol
(
E
2
) and function as antagonists in breast and uterus tissues while acting as agonists in bone cells
4
and lipid metabolism. Despite many BC patients initially responding to tamoxifen, resistance to
5
treatment often occurs. Consequently, ERα degradation has emerged as a new mechanism for
6
inhibiting growth of ERα-dependent tumors. Fulvestrant (3), originally designed as a full
antagonist, was approved to treat ER+ advanced or metastatic BC, and was later determined to
7
be a SERD. However, clinical efficiency of fulvestrant is limited by its poor pharmacokinetic
8
and pharmaceutical properties. We thus aimed to identify an orally bioavailable SERD for
which ERα degradation efficiency was optimized. Due to the remarkable conformational
flexibility of the ERα, many structurally diverse SERMs can be accommodated in the ligand
binding domain (LBD). We envisioned a rational approach would be to design novel SERDs
based on known SERM templates. An example of this approach was the discovery of a potent
9
SERD (4, GDC-0927, Figure 1) by researchers at Seragon. Compound 4 demonstrated robust
tumor growth inhibition in a mouse xenograft breast cancer tumor model which is resistant to
3

tamoxifen treatment. Other researchers have developed a series of tetracyclic chromene-derived
1
0
benzopyranobenzoxepines, such as 5 (Figure 1), to maintain the conformation of the D-ring.
Compound 5 was found to be a potent SERM that behaved as a full antagonist in uterus and an
1
0
agonist in bone cells, plasma lipid metabolism and vagina. The degree of ER degradation by
fulvestrant, 4, and 5 is depicted in Figure 2 by the maximum percentage change in ER protein
(
(
S
inf) at high drug concentrations in an ER high-content fluorescence imaging assay
Supplementary Method 1). Compound 4 achieved almost the same level of ER degradation
efficiency as fulvestrant (97% of fulvestrant control), while 5 displayed much less degradation
efficiency (64%). Herein, we describe our effort in optimizing the degradation efficiency of 5
and the interesting binding modes of a pair of enantiomers based on co-crystal structures.
4

Figure 1. Known ER ligands
5

a
Figure 2. Immunofluorescent ER degradation assay in MCF-7 breast cancer cell lines
a
:
MCF-7 breast cancer cells in phenol-red free RPMI medium containing 10% charcoal stripped FBS; readings taken after 4 hours of compound
incubation using an ER-binding antibody (ESR1mAb F10) and quantitated with fluorescence imaging. The “Robust Fit” method was used to
define the inflection point of curve (IC50), the plateau of the maximal effect (Sinf) with DMSO and 5 nM fulvestrant treated samples being used to
define 0% and 100% changes in ER (see Supplementary Method 1 for assay details).
10
Tetracyclic compounds 16-19 were prepared according to a reported method (Scheme 1).
A modified Perkins reaction of a mixture of hydroxyacetophenones 6a-b and substituted
phenylacetic acids 7a-b in the presence of trimethylamine in refluxing acetic anhydride afforded
6

coumarines 8a-d. Homologation was achieved by reaction of the lithium homoenolate of 8a-d
with MOMCl. Global de-methylation using BBr followed by cyclization under Mitsunobu
3
conditions gave 11a-d. The phenolic hydroxyl groups in 11a-d were protected as tert-
butyldimethylsilyl (TBDMS) derivatives 12a-d. Reduction of 12a-d with DIBAL-H cleanly
afforded lactols 13a-d. Addition of an organolithium derivative of the aminoalkoxybenzene 14 to
lactols 13a-d opened up the pyran B ring to afford a diol intermediate, which was subsequently
cyclized to chromenes 15a-d by treatment with concentrated HCl. Removal of the silyl
protecting groups with tetrabutylammonium fluoride (TBAF) furnished target compounds 16-19
as racemic mixtures, which were separated by chiral supercritical fluid chromatography (SFC)
into pure enantiomers.
7

Scheme 1.
Reagents and conditions: (a) Ac
9%; (c) BBr , DCM, 0 °C to rt, 82-90%; (d) diethylazidodicarboxylate, PPh
DCM, rt, 58-88%; (f) DIBAL-H, DCM, -78 °C, 90-97%; (g) nBuLi, THF, -78 °C; (h) conc. HCl, DCM, 0 °C, 58-
2
O, Et
3
N, reflux, 36 h, 42-52%; (b) LiHMDS, MOMCl, THF -78 °C to 0 °C, 70-
9
3
3
, THF, rt, 20-60%; (e) TBDMSCl,
7
0% over 2 steps; (i) TBAF, THF, rt, 26-37%.
Previous results showed that fluoromethyl substituents on either the azetidine or
pyrrolidine rings at the terminus of an ethoxy linker were optimal for maximizing ERα
9
degradation for the chromene scaffold found in 4. Incorporation of a fluoromethyl substituted
azetidine or pyrrolidine into a tetracyclic scaffold led to compounds 16a-c (Table 1), resulting in
8

a significant improvement in ERαdegradation potency and efficiency compared to 5 (IC50: 0.045
0.076 nM, Sinf: 96-98% vs IC50: 0.28 nM, Sinf: 64%). In fact, the degradation efficiency of 16a-c
–
was comparable to 4 (Sinf: 97%). It was also noteworthy that the anti-proliferative potency against
MCF-7 breast cancer cell lines trends with ERαdegradation potency, with 16a-c (IC50 < 0.7 nM)
displaying increased potency over 5 (IC50 = 1.2 nM). The fluoromethyl azetidine side chain in
1
6a was selected over the fluoromethyl pyrrolidine in 16b-c for further SAR investigation and
profiling due to the reduced number of stereocenters and ease of synthesis (fluoromethyl
azetidine commercially available).
9

Table 1. Evaluation of basic amine sidechains
MCF-7
a
ER Degradation
Proliferationc
Compound
4
R
IC50 (nM)
S
inf (%)b
IC50 (nM)
N/A
0.03
97
0.2
5
-(±)
0.28
64
1.2
1
6a-(±)
0.045
0.076
96
98
0.7
0.3
d
1
6b
d
6c
1
0.051
97
0.2
a
:
MCF-7 breast cancer cells in phenol-red free RPMI medium containing 10% charcoal stripped FBS; readings taken after 4 hours of
compound incubation using an ER-binding antibody (ESR1mAb F10) and quantitated with fluorescence imaging. The “Robust Fit” method was
used to define the inflection point of curve (IC50) and the plateau of the maximal effect (Sinf) with DMSO and 5 nM fulvestrant treated samples
b
being used to define 0% and 100% changes in ER (see Supplemental Method 1 for assay details). : Recorded as a percentage of the curve
c
plateau of fulvestrant at 5 nM as a control. : MCF-7 proliferation assay in RPMI medium containing 10% FBS; 3-day incubation (see
d
Supplementary Method 2 for assay details). : mixture of diastereomers
In the constrained chromene structure and activity relationship (SAR) reported earlier,
only a small number of enantiomeric pairs exhibited equivalent potencies in antagonist assays
1
0
(
ER binding and MCF-7 proliferation), without structural rational being provided. However,
in the chromene core SAR, all enantiomeric pairs showed significant difference in degradation
9
potency, while with similar Sinf value. We separated racemic compound 16a by chiral SFC into
two enantiomers, 16aa and 16ab. To our surprise, enantiomers 16aa (IC50: 0.055 nM) and 16ab
1
0

(
IC50: 0.059 nM) were nearly equipotent in the ERαdegradation assay with 16aa being a slightly
better degrader (Table 2: Sinf: 96% vs 93% for 16aa and 16ab, respectively). The anti-
proliferative potencies of enantiomers 16aa (IC50: 0.4 nM) and 16ab (IC50: 0.9 nM) were also
nearly identical considering the assay variability (2-3 fold).
1
1

Table 2. Potencies of single enantiomers of 16a
MCF-7
a
ER Degradation
Proliferationc
Compound
6aa (S)
6ab (R)
IC50 (nM)
S
inf (%)b
IC50 (nM)
1
0.055
96
0.4
1
0.059
93
0.9
a
:
MCF-7 breast cancer cells in phenol-red free RPMI medium containing 10% charcoal stripped FBS; readings taken after 4 hours of compound
incubation using an ER-binding antibody (ESR1mAb F10) and quantitated with fluorescence imaging. The “Robust Fit” method was used to
define the inflection point of curve (IC50), the plateau of the maximal effect (Sinf) with DMSO and 5 nM fulvestrant treated samples being used to
b
define 0% and 100% changes in ER (Supplementary Method 1). : Recorded as a percentage of the curve plateau of fulvestrant at 5 nM as a
c
control. : MCF-7 proliferation assay in RPMI medium containing 10% FBS; 3-day incubation (see Supplementary Method 2 for assay details).
To gain insight into this interesting observation, we obtained X-ray crystal structures of the
enantiomers in complex with the ERαLBD. The structures of the complexes were determined at
2
.2 Å and 2.6 Å resolution for 16aa and 16ab, respectively (Figure 3). The co-crystal structures
revealed that the more active enantiomer 16aa possesses the (S)-absolute configuration and binds
to ERαin the expected orientation. The phenolic hydroxyl 7-OH on the A-ring hydrogen bonds
with Glu353 and Arg394, while the 3ʹ-phenol on the D-ring forms a hydrogen bond with His524
(
Figure 3a). On the other hand, the enantiomer 16ab, which possesses the (R)-absolute
configuration, binds to ERαin a “flipped” mode, with the 3ʹ-phenol on the D-ring forming
hydrogen bonds with Glu353 and Arg394, while the chromene 7-phenol on the A-ring forms a
hydrogen bond with His524 (Figure 3b). In both cases, the basic side-chains of 16aa and 16ab
adopt similar positions (Figure 3d); however, local disorder of the 16aa tail and the adjacent
protein sequence between helices 11 and 12 were poorly ordered. By contrast, this region is
better defined in the 16ab complex, and a hydrogen bond between the azetidine nitrogen and the
sidechain of Glu353 is observed. To the best of our knowledge, this flipped A- and D-ring
binding mode of a chromene with ERαhas not been reported and in our case readily explains the
1
2

equivalent potency of the enantiomers in the ER degradation and MCF-7 anti-proliferation
assays. This unexpected result shows that pseudo-symmetry of this template can bind in different
modes within the ERαLBD.
Figure 3. Structures of 16aa (a) (PDB code 6DFN) and 16ab (b) (PDB code 6DF6) bound at the
ERα LBD site. Dotted lines denote hydrogen bonds between ligand and protein. Amino acids
within van der Waals distance of the ligand are shown, with key amino acids and structural
elements labeled. The loop connecting Helix 11 and Helix 12 is disordered and/or destabilized
by the ligand tail. Some portions of the protein, including regions interacting with Helix 12, were
removed for visual clarity. (c) Interior binding site molecular surface of the crystal structures of
1
6aa (yellow) and 16ab (magenta) reveal that binding of the two different compound cores
required no substantive conformational changes of the protein (only three fiducial protein
sidechains shown). (d) Overlay of 16aa (yellow) and 16ab (magenta) based on protein
coordinates. Their superposition reveals that their cores sweep out different space, yet their
sidechains align well. Differences in position of the termini of the basic amine sidechains occur
in areas of weak electron density and are consistently observed across crystal structures of
similar compounds (data not shown).
1
3

More recently, reports on related chromene systems have shown that the position of the
1
1
hydroxy on the core can have an unexpected yet dramatic effect on potency and PK properties.
Therefore, we systematically examined the effect of the hydroxy’s position by preparing three
additional pairs of enantiomers 17a-19a and 17b-19b (Table 3). The 17a / 17b pair containing 6-
OH and 3ʹ-OH groups again demonstrated high and equivalent potency and efficiency in the ERα
1
4

degradation assay, similar to the 16aa / 16ab pair. Interestingly, for the other two pairs of
enantiomers with a 4ʹ-OH group on the D-ring, one enantiomer (18a and 19a) was about 10-fold
more potent than the matching enantiomers (18b and 19b) in the ERα degradation and MCF-7
proliferation assays. The more potent enantiomers with a 4ʹ-OH on the D-ring showed 10-fold
reductions in ER degradation potencies compared to their 3ʹ-OH counterparts (18a vs 16aa,
1
9a vs 17a). In summary, 3ʹ-OH substitution on the D-ring seems to be optimal for high
potencies for either binding mode. Once again, the anti-proliferation potencies tracked well with
the ER degradation potencies for all compounds listed.
1
5

Table 3. Evaluation of hydroxyl positions on the A- and D-rings
ER Degradationa
MCF-7 Proliferationc
Compound
6aa (S)
6ab (R)
7a (enant 1)
7b (enant 2)
8a (enant 1)
8b (enant 2)
9a (enant 1)
9b (enant 2)
A-ring
7-OH
7-OH
6-OH
6-OH
7-OH
7-OH
6-OH
6-OH
D-ring
3ʹ-OH
3ʹ-OH
3ʹ-OH
3ʹ-OH
4ʹ-OH
4ʹ-OH
4ʹ-OH
4ʹ-OH
inf (%)b
S
IC50 (nM)
IC50 (nM)
1
0.055
96
0.4
1
0.059
0.021
0.024
0.61
9.6
93
0.9
0.3
0.6
5
1
98
1
100
90
1
1
85
20
0.8
10
1
0.24
3.2
93
1
100
a
:
MCF-7 breast cancer cells in phenol-red free RPMI medium containing 10% charcoal stripped FBS; readings taken after 4 hours of compound
incubation using an ER-binding antibody (ESR1mAb F10) and quantitated with fluorescence imaging. The “Robust Fit” method was used to
define the inflection point of curve (IC50), the plateau of the maximal effect (Sinf) with DMSO and 5 nM Fulvestrant treated samples being used to
b
define 0% and 100% changes in ER (Supplementary Method 1). : Recorded as a percentage of the curve plateau of fulvestrant at 5 nM as a
c
control. : MCF-7 proliferation assay in RPMI medium containing 10% FBS; 3-day incubation (see Supplementary Method 2 for assay details).
We then proceeded to examine the metabolic stability of a few selected ligands in vitro
(
Table 4). All compounds were found to be labile upon incubation with rat hepatocytes, possibly
due to a couple of reasons: 1) the measured lipophilicities of all compounds were high (LogD
.7–3.2), suggesting that the compounds might be prone to oxidative metabolism; 2) the phenol
hydroxy had extensive sulfation and glucuronidation. Indeed, when tested in vivo, compounds 4,
2
1
6

1
6aa, 17a-b all showed high clearance in rat, consistent with in vitro hepatocyte stability
prediction. Additionally, 16aa had poor oral bioavailability.
Table 4. Physicochemical properties, rat in vitro and in vivo PK for selected analogs
Rat Hep CLhep Rat In Vivo CL
(
%Fb
LogDc
Compound
4
mL/min/kg)a
(mL/min/kg)b
46
85
16
2.9
3.0
3.2
2.7
2.7
1
6aa
6ab
36
27
31
57
3.2
ND
ND
ND
1
ND
140
237
1
7a
1
7b
31
a
b
:
Hepatic clearance predicted from hepatocytes. : Female Sprague Dawley rats were given an intravenous dose of 1 mg/kg in 10/60/30
c
DMSO/PEG400/H
2
O as a solution and an oral dose of 1 mg/kg in MCT as a suspension. : Measured log of distribution coefficient between
octanol and aqueous pH 7.4 buffer
We assessed the pharmacology of 16aa in an ER responsive tissue utilizing a 4-day
1
2
immature rat uterine wet weight (UWW) assay. The assay was run in an antagonist mode in
which the ligand competes against ethynyl estradiol, an agonist of ERα. Tamoxifen (a SERM)
and 4 (a SERD) were included as positive controls in this assay. Tamoxifen had 36% reduction
of uterine wet weight at a dose of 60 mg/kg, while 4 achieved 105.7% reduction at a dose of 10
mg/kg. Reduction of uterine wet weight was observed in a dose-responsive fashion for 16aa
(
17% for 0.1 mg/kg vs 87% for 10 mg/kg, Figure 4). The plasma concentration of 16aa at 4-hour
time point was lower than that of 4, which may help explain the smaller reduction in uterine wet
weight (87% vs 105.7%).
1
7

a
Figure 4. Immature rat uterine wet weight assayin an antagonist mode
1
0
Plasma 4hr
BLQ
6
5
4
3
2
1
0
5
0
0
0
.2
.1
.0
e
E
6
E
1
E
E
1
E
l
c
E
E
E
E
E
i
+
+
+
+
+
h
e
e
f
/kg
/kg
/kg
/kg
l
V
c
i
g
m
g
m
g
m
g
m
h
e
V
0
0
1
0
.
0
,
,
,
,
n
4
a
a
e
a
a
i
6
6
1
x
1
o
m
a
t
a
:
Compounds administered orally for 3 days (tamoxifen at 60 mg/kg, 4 at 10 mg/kg, 16aa at 0.1, 10 mg/kg). On the fourth day, 24
hours after dose, the animals were euthanized. The uteri were collected, trimmed to 1 cm above uterine horn and weighed (see
Supplementary Method 3 for assay details).
In summary, we investigated a SAR of tetracyclic benzopyranobenzoxepine analogs.
Incorporating a fluoromethyl azetidine or fluoromethyl pyrrolidine side-chain led to highly
potent and efficacious SERDs. The default and flipped binding mode of enantiomers 16aa and
1
6ab with ERαhelped us rationalize the equivalent potency of 16aa and 16ab in the ER
degradation and MCF-7 anti-proliferation assays. Despite the excellent potency of 16aa, further
development was halted due to the poor pharmacokinetic profile of this class of molecules.
Discovery of such a flipped binding mode may help design additional potent ER ligands with
unique structures.
1
8

ACKNOWLEDGEMENT
We thank the purification and analytical group, and the compound management group at
Genentech for their support. We thank Joachim Rudolph for reviewing the manuscript. Research
described in this paper was performed using beamline 08ID-1 at the Canadian Light Source,
which is supported by the Canada Foundation for Innovation, Natural Sciences and Engineering
Research Council of Canada, the University of Saskatchewan, the Government of Saskatchewan,
Western Economic Diversification Canada, the National Research Council Canada, and the
Canadian Institutes of Health Research. This research used data collected at beamline 5.0.2 of
the Advanced Light Source, which is a DOE Office of Science User Facility under contract no.
DE-AC02-05CH11231.
The crystal structures of 16aa and 16ab have accession codes 6DFN and 6DF6,
respectively at the RCSB.
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