An oral androgen receptor PROTAC degrader for prostate cancer
Taavi K Neklesa, Lawrence B Snyder, Martha Altieri, Mark Bookbinder, Xin Chen, Andrew P Crew, Craig M Crews1, Hanqing Dong, Deborah A Gordon, Jennifer Macaluso, Kanak
Raina, AnnMarie K Rossi, Ian Taylor, Nicholas Vitale, Gan Wang, Jing Wang, Ryan R Willard, Kurt Zimmermann
2017 GU ASCO
Abstract #273
Board D13
Arvinas LLC, New Haven, CT, USA; 1Yale University, New Haven, CT, USA; contact: [email protected]
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Summary
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ARCC-34 retains potency in high
androgen environment
Enzalutamide loses potency in
high androgen environment
1 nM R 1881
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• Antitumor activity observed with daily oral dosing of ARCC-34 in castrated VCaP
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VCaP cells harbor TMPRSS2-Erg
fusion, putting Erg under
transcriptional control of AR:
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• AR point mutations are amenable to AR PROTAC mediated degradation
E2
Orally bioavailable AR PROTACs demonstrate pM AR degradation potency and consistent
functional activity in various in vitro and in vivo systems thought to represent the shortcomings
of current prostate cancer treatment regimens.
Complete degradation of AR provides a novel mechanism to address mCRPC:
Ubiquitin tagged target is
recognized and degraded
by the proteasome
Selected publications on PROTAC technology:
1. PNAS. 2016 Jun 28;113(26):7124-9
2. Nature Chem Biology. 2015 Aug;11(8):611-7
3. Nature Reviews Drug Discov. 2017 Feb;16(2):101-114
+
Ubiquitin and
PROTAC are
recycled
• Degradation is ideally suited for AR-amplified mCRPC
100
AR
mutation
• ARCC-34 has no antiproliferative effect on AR-negative PC-3
prostate cancer cells:
agonist
F876L
Enzalutamide, ARN-509
T877A
Glucocorticoids, progesterone
H874Y
Glucocorticoids, progesterone
M896V
Bicalutamide
L702H
Glucocorticoids
% A R r e m a in in g
Target
E3
Protein,
Ligase
e.g. AR
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60
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E3 Ligase is recruited to the
target protein by the PROTAC
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• There is a good correlation between AR
degradation potency and the
corresponding antiproliferative potency in
VCaP cells:
Ubiquitin
Target
Protein,
e.g. AR
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• ARCC-34 causes poly-ubiquitination of AR:
E3 ligase
recognition
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Ligase,
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MCF7:
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Inhibition of LNCaP cell proliferation
stimulated with 0.3 nM R1881
ARCC-44; qdx3; PO
10mpk
1mpk
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• ARCC-34 degrades AR across common prostate cancer cell lines, yet it does not degrade
Glucocorticoid Receptor (GR)
VCaP:
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400
300
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• Dose dependent in vivo AR degradation observed in VCAP xenografts upon oral
dosing of ARCC-44, concomitant with inhibition of AR signaling5 0 0
Vehicle
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• ARCC-34 retains potency in high androgen milieu
Technology developed by Prof. Craig Crews, Yale University
Platform licensed to Arvinas in 2013
Ligand for
target
protein
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2.2
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1 0 -5
H o u rs
PROTAC: PROteolysis TArgeting Chimera
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e n z a lu ta m id e
ARCC-34
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AUC/Dose
(μM*hr)/(mg/kg)
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Mouse %F
R
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P r o lif e r a tio n , R L U
80
R e la tiv e P S A le v e l
100
Inhibition of cell proliferation in VCaP
cells stimulated with 0.1 nM R1881
Inhibition of PSA synthesis in VCAP
cells stimulated with 0.1 nM R1881
Mouse Cl
(mL/min/kg)
A
Timecourse of AR degradation by 10 nM
ARCC-34 in VCaP cells:
Dose response of ARCC-34 in VCaP cells:
0
0 .0 0 1
• ARCC-34 blocks PSA synthesis, inhibits AR-dependent cell proliferation and causes
apoptosis in VCaP cells
• ARCC-34 and ARCC-44 possess robust oral bioavailability
A R r e m a in in g , % o f V e h ic le
• AR PROTAC ARCC-34 is a sub-nanomolar AR degrader and achieves Dmax by 4 hrs
A R r e m a in in g , % o f c o n t r o l
Background: The Androgen Receptor (AR) remains the principal driver of castrationresistant prostate cancer during the transition from a localized to metastatic disease.
Most patients initially respond to inhibitors of the AR pathway, but the response is
often short-lived. The majority of patients progressing on enzalutamide or
abiraterone exhibit genetic alterations in the AR locus, either in the form of
amplifications or point mutations in the AR gene. Given these mechanisms of
resistance, our goal is to eliminate the AR protein using the PROteolysis TArgeting
Chimera (PROTAC) technology. Further, we sought to make an orally bioavailable AR
PROTAC.
Methods: Medicinal chemistry efforts yielded a small molecule AR PROTAC that
simultaneously binds E3-ubiquitin ligase and AR, thus leading to ubiquitination and
degradation of AR. This molecule has been characterized in in vitro and in
vivo preclinical studies.
Results: Our lead oral AR PROTAC degrades >90% of total AR in all cell lines tested,
with a 50% degradation concentration (DC50) < 1 nM. AR degradation suppresses the
expression of AR-target gene PSA, inhibits cell proliferation, and induces potent
apoptosis in VCaP cells. No activity is observed in AR-null cell lines, such as PC-3.
While enzalutamide loses its activity in the presence of elevated androgens, the AR
PROTAC maintains its antiproliferative activity. Further, the AR PROTAC is able to
degrade all clinically relevant mutant AR proteins. Overall ADME properties are
sufficient to enable robust oral bioavailablity, resulting in 95% AR degradation in ARamplified VCaP xenografts at doses as low as 3 mg/kg. Congruent with AR
degradation, a dose responsive tumor growth inhibition is observed in AR-dependent
xenograft studies.
Conclusions: In summary, we report the first orally bioavailable AR PROTAC that
robustly degrades AR in vitro and in vivo.
A R r e m a in in g ( % )
Abstract
Orally bioavailable AR PROTACs ARCC-34 and
ARCC-44
Functional characterization of ARCC-34
T u m o r V o lu m e (m m )
Characterization of ARCC-34 – a potent AR PROTAC
degrader
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• PROTACs target AR irrespective of its mutational status and binding partners
A R -W T
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A R -T 8 7 7 A
A R -H 8 7 4 Y
A R -M 8 9 6 V
A R -L 7 0 2 H
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• Since PROTACs only need to make a transient interaction with their targets, AR PROTACs
retain efficacy in a high androgen environment
1
[P R O T A C ] u M
Acknowledgements
s ta u r o s p o r in e
This work was partly funded by NIH SBIR grant 1R44CA203199-01
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