Discovery of a C-8 hydroxychromene as a potent degrader of estrogen receptor alpha with improved rat oral exposure over GDC-0927

Article abstract of DOI:10.1016/j.bmcl.2019.07.013

Phenolic groups are responsible for the high clearance and low oral bioavailability of the estrogen receptor alpha (ERα) clinical candidate GDC-0927. An exhaustive search for a backup molecule with improved pharmacokinetic (PK) properties identified several metabolically stable analogs, although in general at the expense of the desired potency and degradation efficiency. C-8 hydroxychromene 30 is the first example of a phenol-containing chromene that not only maintained excellent potency but also exhibited 10-fold higher oral exposure in rats. The improved in vivo clearance in rat was hypothesized to be the result of C-8 hydroxy group being sterically protected from glucuronide conjugation. The excellent potency underscores the possibility of replacing the presumed indispensable phenolic group at C-6 or C-7 of the chromene core. Co-crystal structures were obtained to highlight the change in key interactions and rationalize the retained potency.

Full text of DOI:10.1016/j.bmcl.2019.07.013

Accepted Manuscript
Discovery of a C-8 Hydroxychromene as a Potent Degrader of Estrogen Re-
ceptor alpha with Improved Rat Oral Exposure over GDC-0927
Sharada S. Labadie, Jun Li, Robert A. Blake, Jae H. Chang, Simon Goodacre,
Steven J. Hartman, Weiling Liang, James R. Kiefer, Tracy Kleinheinz, Tommy
Lai, Jiangpeng Liao, Daniel F. Ortwine, Vidhi Mody, Nicholas C. Ray, Fabien
Roussel, Maia Vinogradova, Siew Kuen Yeap, Birong Zhang, Xiaoping Zheng,
Jason R. Zbieg, Jun Liang, Xiaojing Wang
PII:
S0960-894X(19)30457-3
https://doi.org/10.1016/j.bmcl.2019.07.013
BMCL 26554
DOI:
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
20 March 2019
2 July 2019
5 July 2019
Please cite this article as: Labadie, S.S., Li, J., Blake, R.A., Chang, J.H., Goodacre, S., Hartman, S.J., Liang, W.,
Kiefer, J.R., Kleinheinz, T., Lai, T., Liao, J., Ortwine, D.F., Mody, V., Ray, N.C., Roussel, F., Vinogradova, M.,
Kuen Yeap, S., Zhang, B., Zheng, X., Zbieg, J.R., Liang, J., Wang, X., Discovery of a C-8 Hydroxychromene as a
Potent Degrader of Estrogen Receptor alpha with Improved Rat Oral Exposure over GDC-0927, Bioorganic &
Medicinal Chemistry Letters (2019), doi: https://doi.org/10.1016/j.bmcl.2019.07.013
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Graphical Abstract
Discovery of a C-8 Hydroxychromene as a
Potent Degrader of Estrogen Receptor alpha
with Improved Rat Oral Exposure over
GDC-0927
Leave this area blank for abstract info.
Sharada S. Labadie, Jun Li, Robert A. Blake, Jae H. Chang, Simon Goodacre, Steven J. Hartman, Weiling
Liang, James R. Kiefer, Tracy Kleinheinz, Tommy Lai, Jiangpeng Liao, Daniel F. Ortwine, Vidhi Mody,
Nicholas C. Ray, Fabien Roussel, Maia Vinogradova, Siew Kuen Yeap, Birong Zhang, Xiaoping Zheng, Jason
R. Zbieg, Jun Liang, Xiaojing Wang
OH
O
8
F
OH
N
O
30

Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com
Discovery of a C-8 Hydroxychromene as a Potent Degrader of Estrogen
Receptor alpha with Improved Rat Oral Exposure over GDC-0927
Sharada S. Labadiea,*, Jun Lia, Robert A. Blakea, Jae H. Changa, Simon Goodacreb, Steven J. Hartmana,
Weiling Lianga, James R. Kiefera, Tracy Kleinheinza, Tommy Laic, Jiangpeng Liaoc, Daniel F. Ortwinea,
Vidhi Modya, Nicholas C. Rayb, Fabien Rousselb, Maia Vinogradovaa, Siew Kuen Yeapb, Birong Zhanga,
Xiaoping Zhengc, Jason R. Zbiega, Jun Lianga, and Xiaojing Wanga,*
a Genentech Inc., South San Francisco, California, 94080, USA
b Charles River Laboratories 7-9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, United Kingdom
c WuXi AppTec Co., Ltd., Shanghai, 200131, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Accepted
Available online
Phenolic groups are responsible for the high clearance and low oral bioavailability of the
estrogen receptor alpha (ER) clinical candidate GDC-0927. An exhaustive search for a backup
molecule with improved pharmacokinetic (PK) properties identified several metabolically stable
analogs, although in general at the expense of the desired potency and degradation efficiency.
C-8 hydroxychromene 30 is the first example of a phenol-containing chromene that not only
maintained excellent potency but also exhibited 10-fold higher oral exposure in rats. The
improved in vivo clearance in rat was hypothesized to be the result of C-8 hydroxy group being
sterically protected from glucuronide conjugation. The excellent potency underscores the
possibility of replacing the presumed indispensable phenolic group at C-6 or C-7 of the
chromene core. Co-crystal structures were obtained to highlight the change in key interactions
and rationalize the retained potency.
Keywords:
Estrogen receptor
GDC-0927
Chromene
Oral bioavailability
Degradation
2018 Elsevier Ltd. All rights reserved.
Breast cancer (BC) is the second largest cause of death in women.1 Estrogen receptor (ER) positive breast cancer (ER+ BC) constitutes
70% of all diagnosed breast cancers. Selective ER modulators (SERMs), such as tamoxifen, and aromatase inhibitors (AIs), such as
letrozole, have been effectively used to treat early stage ER+ BC.2 However, 20-30% of tumors are refractory to these therapies, either
due to mutations in ER alpha (ERα), activations of other pathways, or through other resistance mechanisms.3 Fulvestrant (1, Figure 1), a
selective ER degrader (SERD), has emerged as a second line treatment option for patients with metastatic diseases.4 Fulvestrant is not
orally bioavailable and consequently dosed intramuscularly.5,6 Fulvestrant was shown to only partially occupy ER which may lead to
compromised efficacy and disease progression.7 Limited systemic exposure through intramuscular injection and poor physiochemical
properties were hypothesized for its partial occupancy. Recent efforts towards the identification of orally bioavailable SERDs have led to
the discovery of several clinical candidates (2-5, Figure 1).8-13 Among them, GDC-0927 (3) is a full ERα antagonist in breast and uterine
tissues and is highly efficacious in tamoxifen-sensitive and resistant xenograft models.13 However, GDC-0927 suffered from low oral
exposure as a result of high clearance and low oral bioavailability in all species tested. The resulting high pill burden in human limited its
dose escalation and likelihood of reaching maximum efficacy.
OH
F
F
F
F
Cl
F
H
F
H
H
HO
N
S
OH
O
N
H
O
1
2 (
(Fulvestrant)
D
GDC-0810)
N
H
N
HO
O
F

Figure 1. SERDs approved by FDA or tested in clinical trials
The high clearance and low oral bioavailability of GDC-0927 are likely due to the presence of two electron-rich phenols in the
molecule. In addition to Cytochrome P450 (CYP) mediated oxidative metabolism, extensive glucuronide conjugation was observed.
Previous attempts at replacing the 3′-OH with a fluorine atom to improve the absorption, distribution, metabolism and excretion (ADME)
properties resulted in improved microsomal stability but at a ten-fold loss of degradation potency and only a modest improvement in oral
exposure.14 In addition to reducing the number of phenolic hydroxy moieties, other common approaches to mitigate the metabolic
liabilities of phenol-containing molecules have been reported.15-18 In this report, we describe our extensive efforts to improve the PK
profile of GDC-0927 by replacing the phenol group with bioisosteres, introducing structural changes with higher fraction sp3 distal to the
phenol group, and shielding the phenol hydroxys with adjacent substituents. Ultimately by replacing a key pharmacophore which exists
in the majority of known ER ligands, C-8 hydroxychromene 30 was identified, maintaining excellent potency and also improving rat oral
exposure compared to GDC-0927.
Table 1. Evaluation of D-ring replacements
MCF-7
Degrad.b
IC50 (nM)
Sinf (%)
MCF-7
Prolif.b
EC50
H/R
LM
CLc
H/R
Hep
CLc
IDa
R
(nM)
3
6
0.03; 97
0.5; 89
0.3
2
12/46
19/46
10/19
16/45
ND
OH
N
O
7d
>100; n/a
>196
ND
NH
NH2
8
0.3; 97
2
14/46
ND
N
NH
9
0.08; 99
0.2; 101
0.07; 98
0.8
5
16/46
13/35
17/37
13/41
18/42
ND
N
O
10
11
0.7
F
F
12
0.17; 100
0.3
17/34
15/37
OH
13e
14d
0.28; 99
72; 50
2.4
ND
ND
ND
NH
>196
9/12
O
15d
>100; n/a
ND
14/25
ND
N
F
16
0.3; 93
0.6
10/28
14/31
aAll are single stereoisomers unless otherwise indicated. bAverage of at least two runs. See Supplementary Material for experimental details. n/a: not applicable. c
Projected hepatic clearance using human/rat liver microsomes or hepatocytes (mL/min/kg). ND: not determined. dMixture of enantiomers. eMixture of
diastereomers.
To reduce the number of phenols, the D-ring phenol group of 3 was replaced with heterocycles, alkyl, or cycloalkyl moieties (Table
1). Compounds 68 with heterocycles at the C-3 position were, in general, less potent (> 10-fold) than 3 in the degradation and MCF-7
proliferation assays. Analog 9 only lost 3-fold potency in both cellular assays compared to 3, however, it suffered extensive CYP
(Cytochrome P450) mediated oxidative metabolism in human and rat liver microsomes. Although most analogs with cycloalkyl D-rings
represented by 10 and 1315 displayed significant erosion of cellular potency, it was encouraging that 11 and 12 maintained proliferation
potency (within 2-fold) and excellent degradation efficiency (Sinf > 97%) compared to 3. Unfortunately, both 11 and 12 exhibited high

clearance while incubated with either human liver microsomes or hepatocytes. Compound 16 improved the metabolic stability in both rat
liver microsomes and hepatocytes at an expense of the degradation potency (IC50 differs by 10-fold) and efficiency (Sinf decreases by
4%).14 Efforts were also made to replace the 4-methyl group of the B-ring by other functionalities such as a chloro group exemplified by
compound S1 (Table S2). However, either erosion in potency or high in vivo clearance was observed. Collectively, these data
demonstrated that changes to the B- and D-ring failed to improve the metabolic stability while maintaining potency. We therefore set out
to work
on A-ring modifications to replace the problematic phenol.
A-
ring phenol replacements and bioisosteres were carefully investigated (Table 2).
eliminate potentially confounding metabolism on the D-ring phenol, a 4′-F-phenyl
fixed as the D-ring substituent (16, Table 2). Unfortunately, erosion of degradation
proliferation potencies were drastic in almost all representative compounds 1725.
data seemed to reinforce the long-standing belief that the C-6 phenol in GDC-0927
To
was
and
These
was crucial for optimal binding affinity to ER.
Table 2. SAR of A-ring phenol bioisosteres
MCF-7b
Degrad.
IC50 (nM) Sinf (%)
MCF-7
Prolif.b
EC50 (nM)
0.6
IDa
R1
R2
16
17
18c
HO
H2N
H
H
0.3; 93
2.5; 95
21
AcNH
H
>100; n/a
>200
19d
20c,d
21
MeSO2NH
H
MeO
H
H
H
>100; n/a
1.1; 98
15, 72
>200
16
ND
22
F
H
H
3; 95
30
23d
100; 81
ND
24
5.7; 82
20
25
27; 81
83
aAll are single stereoisomers unless otherwise indicated. bAverage of at least two runs. See the Supplementary Material for experimental details. n/a: not
applicable. cMixture of enantiomers. dH on D-ring C-4′ instead of F.
We next attempted to modulate the acidity of the phenol and consequently reactivity towards glucuronidation with analogs 2629
(Table 3). Compared to 16, fluoro- or chloro- substituents at C-5 (26 and 28) were better tolerated than those at C-7 (27 and 29).
Encouragingly, both 26 and 28, with a C-5 halogen substitution, showed improved liver microsomal stability indicating lower phase I
metabolism. However, clearance in hepatocytes was high similar as 16, indicating phase II metabolism such as glucuronidation
potentially. Ultimately, it was extremely challenging to reduce the phase II metabolism of C-6 hydroxychromenes.
Table 3. SAR of chromene A-ring hydroxy variations
MCF-7
Degrad.b
IC50(nM)
Sinf (%)
MCF-7
Prolif.b
EC50
H/R
LM
CLc
H/R
Hep
CLc
IDa
R
R′
(nM)

3
6-OH
6-OH
3′-OH
4′-F
0.03; 97
0.3; 93
0.3
0.6
0.9
4
12/45
10/28
4/16
8/20
4/18
6/14
9/43
9/27
16/46
14/31
17/36
15/28
ND
16
26
27
28
29
30
31
5-F,
6-OH
4′-F
0.2; 99
6-OH,
7-F
4′-F
0.58; 96
0.03; 92
1.0; 97
5-Cl,
6-OH
4′-F
1
6-OH,
7-Cl
4′-F
20
0.3
14
16/28
13/44
ND
8-OH
3′-OH
0.05; 97
8-OH
4′-F
0.42; 92
aAll are single isomers unless otherwise indicated. bAverage of at least two runs. See Supplementary Material for experimental details. c Projected hepatic
clearance using human/rat liver microsomes or hepatocytes (mL/min/kg). ND: not determined.
A co-crystal structure of 3 bound in the ER ligand binding pocket (Figure 2) was obtained to aid the structure based drug design. In
the structure, the C-6 hydroxy forms three hydrogen bonds, one each to the sidechains of Glu353 and Arg394 and one to the backbone
carbonyl of Leu387, the latter two interactions likely weak due to their interatomic distances being at the long range for hydrogen bonds.
Additional hydrogen bonds are made between the azetidine nitrogen and Asp351 and the D-ring phenol and His524.
While the ligand binding pocket is otherwise lined with hydrophobic sidechains, we noted that the distance between the C-8 carbon of
the chromene core and the backbone carbonyl oxygen of Leu346 was 3.7Å. We speculated that the incorporation of a hydroxy group at
the C-8 position might provide a hydrogen bond interaction with this carbonyl oxygen. We also hypothesized that a C-8 hydroxy group
might be more sterically shielded from glucuronidation by the adjacent chromene oxygen atom. Gratifyingly, the degradation potency
and efficiency of compound 30 was equivalent to that of 3. Excellent potency in the MCF-7 cell proliferation assay was also maintained.
There was a slight improvement in human hepatocyte stability from 3 to 30 but not in rat. Compound 31 with a 4′-F group was then made
to balance the potency and PK properties. Unfortunately, the degradation potency and efficiency of 31 were significantly compromised
compared to 30, even though liver microsomal metabolic stability in rat was improved.
Figure 2: Co-crystal structure of ER bound to GDC-0927 (PDB: 6PFM). Van der Waals interactions between GDC-0927 (3) and ER position the
chromene core within the ligand binding pocket, and the compound forms five hydrogen bonds (black dashed lines) to the protein.
Given that 30 had excellent cellular potency, degradation efficiency, and also moderate human in vitro stability, it was dosed IV and
PO in rats to evaluate the PK. To our surprise, 30 displayed moderate in vivo clearance (CL: 18 mL/min/kg, repeated twice), lower than
predicted from in vitro (CL: 43 or 44 mL/min/kg in liver microsomes or hepatocytes, Table 4). In addition to the improvement in clearance,
rat oral bioavailability of 30 also increased compared to 3 (F%: 30% vs. 10%). These improvements resulted in a 10-fold increase in oral
exposure from 3 to 30.
Table 4. Comparison of pharmacokinetics of compounds 3 and 30
In vitro
Rat in vivo
H/R
LM
H/R
Hep
ID
Papp
AUCoral/De
(uM*hr)
CLc
F%d
A-Ba
CLb
12/45
9/43
CLb
3
30
4.6
2.4
16/46
13/44
100
18
10%
30%
0.04
0.43
aPapp: measured permeability using Madin-Darby Canine Kidney (MDCK) epithelial cell lines, A to B (10-06 cm/s). bProjected hepatic clearance using human/rat
liver microsomes or hepatocytes (mL/min/kg). cTotal clearance in rat in vivo (mL/min/kg); compound was dosed at 1 mg/kg in a solution of PEG400/water

(35/65)
for 3 and DMSO/PEG400/water (10/60/30) for 30. dRat bioavailability calculated using
(AUCoral÷AUCiv) x (Doseiv÷Doseoral) x 100; compound was dosed at 5 mg/kg in a solution of
for 3 and at 1 mg/kg in a suspension of MCT for 30. dArea under curve was normalized by 1
oral dose.
MCT
mg/kg
To
the
confirm the interaction with Leu346, an X-ray co-crystal structure of 30 bound to
ER ligand binding site was obtained (Figure 3). The orientation of 30 in the
binding pocket was similar to that of 3, retaining hydrogen bonds to Asp351 and
His524. This was different from our other findings where the core adopted a
binding mode with the 3′-OH group pointing to Glu353 and Arg394. Consistent
our initial design idea, a new hydrogen bond (2.7 Å) was indeed observed between
hydroxy moiety and the backbone carbonyl of Leu346.
flipped
with
the C-8
Figure 3. Co-crystal structure of ER bound to 30 (PDB: 6PET). In contrast to GDC-0927, 30 forms only three hydrogen bonds to the protein (black dashed
lines), one each to the sidechains of His254 and Asp351 and the other to the mainchain carbonyl oxygen of Leu346.
Independently, a similar hydrogen bond between the indole NH of AZD-9496 and the same Leu346 carbonyl was reported.9 In that
molecule, the indole NH to carbonyl oxygen interaction appears to compensate for the loss of a hydrogen bond to the acid of Glu353,
since AZD-9496 lacks a phenolic hydroxy at a position equivalent to that of the C-6 hydroxy of GDC-0927 (Figure 4) and yet has high
affinity for the receptor. While 30 no longer possessed a hydroxy capable of hydrogen bonding with Glu353, an -oxygen of the sidechain
was 3.0 Å from C-7 carbon of the A-ring. Normally, this close approach of a charged atom to a phenyl ring would be energetically
unfavorable; however, the proximity of Arg394 to this Glu (Figure 3) appears to dissipate the charge such that the compound retains high
affinity for the binding site. In the complex with 30, the fluoromethyl tail is not well ordered, nor is the adjacent loop in the protein
connecting helices 11 and 12.
Figure 4. Mainchain hydrogen bonds anchor diverse chemical series.
Superposition of the crystal structures of 30 (blue protein and purple ligand
carbons) and AZD-9496 5a (PDB: 5ACC, gray carbons). Both chemical series
form hydrogen bonds to the mainchain carbonyl of Leu346 (dashed lines, image
center), but the positions of the ligand and protein atoms differ. [Some protein
sidechains omitted for clarity.]
In summary, extensive efforts were made to optimize the ADME
properties of 3 (GDC-0927). Attempts to replace the C-6 phenol with
bioisosteres, flank the C-6 phenol OH with halogens, or modify the
B and D-rings distal to C-6 phenol all failed to yield analogs with
improved metabolic stability that also retained desired level of
potency. These efforts served to confirm the need for two phenolic

groups for optimal potency of these chromenes as SERDs and SERMs. A crystal structure of the GDC-0927:ER complex revealed
space adjacent to the C-8 position, which was exploited to generate a C-8 hydroxy analog (30) that maintained significant potency and
displayed improved in vivo clearance and oral bioavailability over GDC-0927. This is the first known example of a chromene ER
modulator with a hydroxy group interacting with the mainchain carbonyl of Leu346, and represents a novel approach to engineer a key
hydrogen bond into SERM/SERD molecules. We envision such an approach may be applied to other ER ligands and may open up avenues
in identifying the next generation SERDs with a superior overall profile.
Acknowledgments
We thank the purification, analytical, and compound management groups at Genentech for their support. Crystal diffraction data were
collected at Southeast Regional Collaborative Access Team (SER-CAT) 22-ID (or 22-BM) beamline at the Advanced Photon Source,
Argonne National Laboratory. SER-CAT is supported by its member institutions (see www.ser-cat.org/members.html), and equipment
grants (S10_RR25528 and S10_RR028976) from the National Institutes of Health. Additional diffraction data were collected at beamline
12-2 of SSRL. Use of the Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, is supported by the U.S.
Department of Energy, Office of Science, Office of Basic Energy Sciences under Contract No. DE-AC02-76SF00515. The SSRL
Structural Molecular Biology Program is supported by the DOE Office of Biological and Environmental Research, and by the National
Institutes of Health, National Institute of General Medical Sciences (including P41GM103393) . The contents of this publication are
solely the responsibility of the authors and do not necessarily represent the official views of NIGMS or NIH. Coordinates and structure
factors for the crystal structures have been deposited at the RCSB with accession codes 6PFM and 6PET for GDC-0927 and 30,
respectively.
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Graphical Abstract
Discovery of a C-8 Hydroxychromene as a
Potent Degrader of Estrogen Receptor alpha
with Improved Rat Oral Exposure over
GDC-0927
Leave this area blank for abstract info.
Sharada S. Labadie, Jun Li, Robert A. Blake, Jae H. Chang, Simon Goodacre, Steven J. Hartman, Weiling
Liang, James R. Kiefer, Tracy Kleinheinz, Tommy Lai, Jiangpeng Liao, Daniel F. Ortwine, Vidhi Mody,
Nicholas C. Ray, Fabien Roussel, Maia Vinogradova, Siew Kuen Yeap, Birong Zhang, Xiaoping Zheng, Jason
R. Zbieg, Jun Liang, Xiaojing Wang
OH
O
8
F
OH
N
O
30