EPZ011989, A potent, orally-available EZH2 inhibitor with robust in vivo activity

Article abstract of DOI:10.1021/acsmedchemlett.5b00037

Inhibitors of the protein methyltransferase Enhancer of Zeste Homolog 2 (EZH2) may have significant therapeutic potential for the treatment of B cell lymphomas and other cancer indications. The ability of the scientific community to explore fully the spectrum of EZH2-associated pathobiology has been hampered by the lack of in vivo-active tool compounds for this enzyme. Here we report the discovery and characterization of EPZ011989, a potent, selective, orally bioavailable inhibitor of EZH2 with useful pharmacokinetic properties. EPZ011989 demonstrates significant tumor growth inhibition in a mouse xenograft model of human B cell lymphoma. Hence, this compound represents a powerful tool for the expanded exploration of EZH2 activity in biology.

Full text of DOI:10.1021/acsmedchemlett.5b00037

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Letter
pubs.acs.org/acsmedchemlett
EPZ011989, A Potent, Orally-Available EZH2 Inhibitor with Robust in
Vivo Activity
John E. Campbell,*,† Kevin W. Kuntz,† Sarah K. Knutson,† Natalie M. Warholic,† Heike Keilhack,†
Tim J. Wigle,† Alejandra Raimondi,† Christine R. Klaus,† Nathalie Rioux,† Akira Yokoi,‡ Satoshi Kawano,‡
Yukinori Minoshima,‡ Hyeong-Wook Choi,§ Margaret Porter Scott,†,∥ Nigel J. Waters,† Jesse J. Smith,†
Richard Chesworth,† Mikel P. Moyer,†,⊥ and Robert A. Copeland†
†Epizyme, Inc., 400 Technology Square, Fourth Floor, Cambridge, Massachusetts 02139, United States
‡Eisai Co., Ltd., Tokodai 5-1-3, Tsukuba, Ibarakai 300-2635, Japan
§Eisai, Inc., 4 Corporate Drive, Andover, Massachusetts 01810, United States
S
* Supporting Information
ABSTRACT: Inhibitors of the protein methyltransferase Enhancer of Zeste Homolog 2 (EZH2) may have significant
therapeutic potential for the treatment of B cell lymphomas and other cancer indications. The ability of the scientific community
to explore fully the spectrum of EZH2-associated pathobiology has been hampered by the lack of in vivo-active tool compounds
for this enzyme. Here we report the discovery and characterization of EPZ011989, a potent, selective, orally bioavailable
inhibitor of EZH2 with useful pharmacokinetic properties. EPZ011989 demonstrates significant tumor growth inhibition in a
mouse xenograft model of human B cell lymphoma. Hence, this compound represents a powerful tool for the expanded
exploration of EZH2 activity in biology.
KEYWORDS: Methyltransferase, PRC2, EZH2, B cell lymphoma, KARPAS-422, xenograft, in vivo chemical probe
coid-agonist component of the standard chemotherapy regimen
nhibitors of Enhancer of Zeste Homolog 2 (EZH2) target
Ithe catalytic center of a multiprotein complex known as CHOP; this sensitivity can be extended to EZH2 wild-type
GCB and to inhibitor-refractory, EZH2 mutant GCB cell lines.6
polycomb repressive complex 2 (PRC2). The PRC2 complex is
In stark contrast, myeloid malignancies and T cell leukemia7
bear mutations in EZH2 and other PRC2 components that lead
responsible for methylating a specific histone lysine referred to
as H3K27.1,2 In multiple human cancers, hyper-trimethylation
to a loss of function of the complex, thus exemplifying the
biological complexity of the role of H3K27 methylation in
cancers.8 As a result of this complexity and the importance of
EZH2 as a therapeutic target for specific human cancers,
research in the field has continued to expand in recent years
thereby driving the need for well-characterized chemical probes.
As we have described previously, the pyridone-benzamide
core represents a highly optimized feature for binding to EZH2
in a SAM-competitive manner. This is a common feature in
of H3K27 results in the aberrant silencing of genes that
otherwise control cell proliferation and induce differentiation.3
Moreover, genetic alterations of PRC2 components have been
documented in both hematologic and solid tumors.4 For
instance, EZH2 change-of-function mutations (affecting resi-
dues Y646, A682, and A692) are found in subsets of B cell non-
Hodgkin lymphoma (NHL) where they confer an oncogenic
dependency on EZH2. Hence, EZH2 mutant-bearing, diffuse
large B cell lymphoma (DLBCL) cell lines can be effectively
killed by EZH2 inhibitors in vitro and in vivo.5 Intriguingly, we
have also shown that sensitivity to EZH2 inhibition in EZH2
mutant DLBCL cell lines of germinal center origin (GCB) can
be enhanced by combination with prednisone, the glucocorti-
Received: January 26, 2015
Accepted: March 4, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acsmedchemlett.5b00037
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ACS Medicinal Chemistry Letters
Letter
Figure 1. Representative reported EZH2 inhibitors.
Figure 3. Effect of EPZ011989 concentration on the proliferation of
WSU-DLCL2 cells in culture over an 11-day period.
Figure 2. SAR affords a potent, stable EZH2 inhibitor.
known indazole EZH2 inhibitors (e.g., EPZ005687,9 UNC-
199910), indole EZH2 inhibitors (e.g., GSK-126,11 EI1,12 CPI-
16913) and EPZ-6438, our EZH2 inhibitor presently under-
going clinical trials.4 In pyridone-containing EZH2 inhibitors,
pyridone oxidation is a common site of metabolism. Recently,
there have been a series of published reports that propose a
pyridone-replacement chemotype, 4-amino-2,2′,6,6′-tetrameth-
yl-piperidine, as one means to avoid this issue and to expand
the breadth of EZH2 inhibitors.14,15 To date, however,
compounds with this novel substitution have not demonstrated
potency equivalent to pyridone-containing inhibitors and have
not reported in vivo activity. Because the pyridone plays such a
role in binding and therefore potency, our continued research
in this area has focused on modifications to other regions of our
chemical scaffold to further investigate the impact on in vivo
activity. What is needed today are potent, bioavailable tool
compounds that can be made widely available to the greater
research community to augment our collective understanding
of the role of EZH2 in pathobiology. Herein we describe the
discovery, characterization, and in vivo profile of such a
chemical probe, EPZ011989.
Figure 4. Single dose PK in SCID mice following oral administration
of 125, 250, 500, and 1000 mg/kg dosed as suspensions in 0.5% w/v
methyl cellulose and 0.1% Tween-80 acidified with 1 mol equiv of
HCl. LCC predicted efficacious plasma level for compound
EPZ011989 (158 ng/mL) is shown by a horizontal, dashed line.
N-((4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-
(ethyl((trans)-4-((2-methoxyethyl)(methyl)amino)cyclohexyl)-
amino)-2-methyl-5-(3-morpholinoprop-1-yn-1-yl)benzamide
(EPZ011989, Figure 2) was discovered through modification
of the pyran substituent in EPZ-6438 (Figure 1). In this
position, a trans-N,N-dimethylcyclohexylamine substituent
appears to maintain biochemical activity, but when combined
with the morpholine side-chain, the cellular activity of the
resulting dibasic compound is negatively impacted. A series of
compounds were designed to attenuate the pKa of the amine
components, and a balance of properties and potency was
achieved through the addition of a methoxyethyl group to the
cyclohexylamine (ca. pKa = 9.8)16 combined with the
replacement of the second benzene ring in EPZ-6438 with
Table 1. EPZ011989 in Vitro Data Summary
property
EZH2 activity
analysis
units
EPZ011989
biochemical Ki
ELISA H3K27me3 IC50
nM
nM
<3 (WT) <3 (Y646)
a
94 48 (n = 20)
b
c
liver microsome clearance
plasma protein binding
LCC
scaled microsomal clearance
mL/min/kg (%Eh)
human
6
0.5(29)
rat
<10(<14)
<10(<11)
mouse
human
rat
equilibrium dialysis
percent unbound
97
91
3
6
mouse
80 11
208 75 (n = 4)
11d proliferation WSU-DLCL2
nM
d
predicted efficacious plasma exposure
nM (ng/mL)
human
rat
214(130)
223(135)
260(158)
mouse
a
b
c
Enzyme-linked immunoassay measure of cellular methyl mark reduction. Scaled according to the well-stirred liver model. Percent hepatic
d
extraction. Plasma protein binding corrected LCC.
B
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Figure 5. (a) Pharmacokinetic analysis of day 7 plasma samples for EPZ011989. (b) Pharmacodynamic analysis of histone methyl mark in bone
marrow tissue at day 7 of dosing EPZ011989.
Table 2. Summary of Rat PK for EPZ011989
EPZ011989 Rat PK
dose
(mg/kg) route
t1/2
(h)
tmax
(h)
Cmax
AUCinf
time above
LCC (h)
(ng/mL) (h·ng/mL)
30
p.o.
p.o.
p.o.
4.7
3.9
3.7
2
240
970
4
100
300
2.7
2.7
1600
2900
5600
10000
8
10
Figure 8. Methyl mark reduction observed in tumor tissue over time
on day 7 of EPZ011989 administration.
Figure 6. PK after oral dosing of EPZ011989 DTAL at doses of 30,
100, and 300 mg/kg.
Figure 9. Total and free plasma exposure time courses for EPZ011989
in the KARPAS-422 xenograft study. Values measured postdose on
day 7 of 21.
>3000-fold selectivity relative to the Ki of 20 other histone
methyltransferases (HMTs) tested. As evidenced by the human
and rat liver microsomal turnover (HLM and RLM
respectively, Figure 2), EPZ011989 also exhibits metabolic
stability (Table 1). Furthermore, EPZ011989 reduces cellular
H3K27 methylation in the Y641F, mutant-bearing human
lymphoma cell line, WSU-DLCL2, with an IC50 below 100 nM.
This functional response translates to activity in a long-term
proliferation assay where EPZ011989 demonstrates an average
lowest cytotoxic concentration (LCC) in WSU-DLCL2 cells of
208 nM (Figure 3).
Figure 7. Robust tumor growth inhibition seen at 250 and 500 mg/kg
BID EPZ011989.
an acetylene linker to modify the adjacent morpholine (ca. pKa
= 5.7).
These adjustments led to a compound, EPZ011989, that
equipotently inhibits mutant and wild-type EZH2 with an
inhibition constant (Ki) of <3 nM. EPZ011989 is also a specific
EZH2 inhibitor with a >15-fold selectivity over EZH1 and
The LCC parameter, when corrected for plasma protein-
binding, predicts an efficacious plasma level in mouse for
EPZ011989 of 158 ng/mL. The LCC-predicted exposure was
used as a benchmark to enable the selection of doses bracketing
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ACS Medicinal Chemistry Letters
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this value for in vivo studies. The pharmacokinetics in SCID
mice following oral administration of 125, 250, 500, and 1000
mg/kg indicated that the 1000 mg/kg dose provided coverage
over the LCC for 24 h, while the 250 and 500 mg/kg doses
provided coverage over this value for approximately 8 h (Figure
4). This confirmed that, with appropriate formulation,
sustained exposure above the LCC could be achieved in vivo.
On the basis of the preliminary PK results, we conducted a 7-
day PK study with pharmacodynamic (PD) measurement of
H3K27 methylation in bone marrow at 125, 250, 500, 750, and
1000 mg/kg dosed twice-daily (BID). All of the doses were well
tolerated for the length of the study. The results from this
experiment are shown in Figure 5, where the trough exposure
represents the Cmin at 12 h after the first dose on day 7 of test
article administration. The dose of EPZ011989 that achieves
complete coverage over the predicted efficacious plasma level
was determined to be 500 mg/kg BID (Figure 5a). The
exposures at 500 mg/kg BID (mean Cmin = 150 ng/mL)
correspond well with the above PK experiment and with the
PD results in bone marrow, where we observed complete
ablation of the methyl mark by the end of day 7 (Figure 5b).
The above results demonstrate that formulation of the free
base of EPZ011989 in HCl-acidified vehicle was suitable to
complete target engagement proof-of-concept studies. After
completion of this initial PK/PD study, we performed a salt
screen, which identified the D-tartrate salt (DTAL), an
amorphous solid with low hygroscopicity, as an alternative for
future work. We conducted a rat PK experiment at 30, 100, and
300 mg/kg (Table 2) and found that this optimized salt form
provided sustained oral exposure over the rat predicted
efficacious plasma exposure (135 ng/mL) for approximately
10 h after a single dose (Figure 6).
Through SAR studies on the pyridone-benzamide scaffold we
have discovered an in vivo tool compound with which to
further the study of the role of the PRC2 complex in biology
and in preclinical models of disease. We have characterized
EPZ011989, a compound with oral exposure and metabolic
stability that is able to elicit robust methyl mark inhibition and
antitumor activity. The PK/PD and in vivo activity data for this
compound were highlighted to enable collaborative research in
the field. Samples of EPZ011989 can be made available upon
request.
ASSOCIATED CONTENT
■
S
* Supporting Information
Detailed biological assay information, and procedures and
characterization data for the synthesis of EPZ011989. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*Tel: 617-500-0691. E-mail: jcampbell@epizyme.com.
Present Addresses
∥Genentech, Inc., 1 DNA Way, South San Francisco, California
94080, United States.
⊥Raze Therapeutics, Suite 303, 25 First Street, Cambridge,
Massachusetts 02141, United States.
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
Notes
To demonstrate further the utility of EPZ011989 as an in
vivo tool compound, we evaluated the antitumor activity of the
optimized D-tartrate salt form in the treatment of subcutaneous
EZH2 mutant KARPAS-422 human DLBCL xenografts.
Homogenous suspensions of 250 and 500 mg/kg in 0.5%
methyl cellulose and 0.1% Tween-80 were dosed orally to
implanted SCID mice for 21 days, BID. On the basis of the PD
study, we expected to see tumor regression with the 500 mg/kg
dose; however, EPZ011989 administration induced significant
tumor regression at both doses, with nominal effect on mean
body weights over the course of the study period (Figure 7).
Evaluation of PD in tumor samples on day 7 demonstrated
robust H3K27 methyl mark reduction for EPZ011989 at the
250 and 500 mg/kg dose over the 12 h time-course (Figure 8).
Notably, the exposure for EPZ011989 at 3 h postdose is an
order of magnitude higher in this experiment, using the DTAL
salt, than for the corresponding dose in the PK/PD study
(Figure 9). As a result, at a dose of 250 mg/kg, EPZ011989
remains over the predicted efficacious plasma levels for a
minimum of 6 h, though not for the full 12 h time interval.
Examination of the data in Figure 8 reveals that, even though
plasma exposure does not remain over the LCC, tumor methyl
mark levels do not rebound during the dosing interval at 500
nor 250 mg/kg. This suggests that the observed efficacious
exposure of EPZ011989 required for tumor growth inhibition
is even lower than the level predicted by the LCC and that
persistent methyl mark inhibition likely accounts for the
resultant antitumor activity at lower exposure. Additional PK
and xenograft studies are underway to see if this observation
with EPZ011989 holds in the exploration of an expanded set of
cancer types associated with EZH2 mutation and dysfunction.
The authors declare the following competing financial
interest(s): J.E.C., K.W.K., S.K.K., N.M.W., H.K., T.J.W., A.R.,
C.R.K., N.R., M.P.S., N.J.W., J.J.S., R.C., M.P.M., and R.A.C.
have ownership interest (including patents) in Epizyme.
ACKNOWLEDGMENTS
■
We thank Rahul Nagawade for his contribution to the synthesis
of EPZ011989.
ABBREVIATIONS
■
EZH2, enhancer of zeste Homolog 2; PRC2, polycomb
repressive complex 2; H3K27, histone 3 lysine 27; NHL,
non-Hodgkin lymphoma; DLBCL, diffuse large B cell
lymphoma; SAR, structure−activity relationship; %Eh, percent
hepatic extraction; LCC, lowest cytotoxic concentration;
HMTs, histone methyltransferases; HLM, human liver micro-
somes; RLM, rat liver microsomes; SCID, severe combined
immune deficiency; BID, twice-daily dosing; PK, pharmacoki-
netics; PD, pharmacodynamics; DTAL, D-tartrate salt; p.o., oral
dosing; SEM, standard error of the mean; H3K27me3, histone
3 lysine 27 trimethyl
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