Novel 3-methylindoline inhibitors of EZH2: Design, synthesis and SAR

Article abstract of DOI:10.1016/j.bmcl.2016.11.080

EZH2 (enhancer of zeste homologue 2) is the catalytic subunit of the polycomb repressive complex 2 (PRC2) that catalyzes the methylation of lysine 27 of histone H3 (H3K27). Dysregulation of EZH2 activity is associated with several human cancers and theref

Full text of DOI:10.1016/j.bmcl.2016.11.080

Accepted Manuscript
Novel 3-methylindoline inhibitors of EZH2: design synthesis and SAR
Amantullah Ansari, Sharad Satalkar, Varshavekumar Patil, Amit Shete,
Simranjeet Kaur, Ashu Gupta, Siddhartha Singh, Mohd. Raja, Daniel L.
Severance, Sebastián Bernales, Sarvajit Chakravarty, David T. Hung, Son M.
Pham, Francisco Herrera, Roopa Rai
PII:
S0960-894X(16)31235-5
DOI:
http://dx.doi.org/10.1016/j.bmcl.2016.11.080
BMCL 24475
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
29 September 2016
22 November 2016
23 November 2016
Please cite this article as: Ansari, A., Satalkar, S., Patil, V., Shete, A., Kaur, S., Gupta, A., Singh, S., Raja, Mohd.,
Severance, D.L., Bernales, S., Chakravarty, S., Hung, D.T., Pham, S.M., Herrera, F., Rai, R., Novel 3-methylindoline
inhibitors of EZH2: design synthesis and SAR, Bioorganic & Medicinal Chemistry Letters (2016), doi: http://
dx.doi.org/10.1016/j.bmcl.2016.11.080
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Bioorganic & Medicinal Chemistry Letters
Novel 3-methylindoline inhibitors of EZH2: design synthesis and SAR
Amantullah Ansaria, Sharad Satalkara, Varshavekumar Patila, Amit Shetea, Simranjeet Kaura, Ashu Guptaa,
Siddhartha Singha, Mohd. Rajaa, Daniel L. Severanceb, Sebastián Bernalesc, Sarvajit Chakravartyc, David T.
Hungc, Son M. Phamc, Francisco Herrerac and Roopa Raic*
aIntegral BioSciences Pvt. Ltd., C-64, Hosiery Complex Phase II Extension, Noida Uttar Pradesh, 201306 India
bSchrodinger, Inc.: Portland, OR, USA
cMedivation, 525 Market Street, 36th Floor, San Francisco, CA 94105 USA
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Accepted
Available online
EZH2 (enhancer of zeste homologue 2) is the catalytic subunit of the polycomb repressive
complex 2 (PRC2) that catalyzes the methylation of lysine 27 of histone H3 (H3K27).
Dysregulation of EZH2 activity is associated with several human cancers and therefore EZH2
inhibition has emerged as a promising therapeutic target. Several small molecule EZH2
inhibitors with different chemotypes have been reported in the literature many of which use a
bicyclic heteroaryl core.
Several small molecule EZH2 inhibitors representing diverse
chemotypes have been reported in literature, many of which use a bicyclic heteroaryl core.
Herein, we report the design and synthesis of EZH2 inhibitors containing an indoline core.
Partial saturation of an indole to an indoline provided lead compounds with nanomolar activity
against EZH2, while also improving solubility and oxidative metabolic stability.
Keywords:
EZH2
Indoline
Anticancer
Methyltransferases
2009 Elsevier Ltd. All rights reserved.
Covalent modifications of histones play pivotal roles in the
organization of the chromatin structure and the regulation of gene
expression.1,2 A large number of enzymes are known to catalyze
the addition or removal of covalent groups from specific amino
acids in histone proteins including histone methyltransferases
(HMTs).3 Enhancer of Zeste Homologue 2 (EZH2) is the
catalytic subunit of Polycomb repressive complex 2 (PRC2),
which catalyzes the methylation of lysine 27 of histone 3
(H3K27).4 Tri-methylation of the lysine-27 of histone 3
(H3K27) is associated with the silencing of specific genes,
including many tumor suppressor genes.5 EZH2 has been found
to be significantly overexpressed in a variety of human cancers
and its expression level correlates with cancer progression and
poor prognosis.6,7 In addition, point mutations of residues, such
as Y641, A677 and A687, within the catalytic domain of EZH2
have been found in follicular lymphomas and diffuse large cell B
lymphomas (DLBCL).8 Several studies have revealed that EZH2
knockdown in tumor cell lines can cause decreased cell
proliferation, migration angiogenesis and increased apoptosis.9–11
Collectively, this evidence supports EZH2 as an important target
for cancer therapy and its inhibitors to be potential anticancer
agents. Therefore significant efforts have been made on the
discovery and optimization of small molecule EZH2 inhibitors.
Through these efforts various small molecule EZH2 inhibitors
have been reported with demonstrated efficacy both in vitro and
in vivo.12–14
An analysis of EZH2 inhibitors reported in the literature13 led
to the recognition that a substituted pyridone-methyl amide
fragment constituted a highly optimized moiety for binding to
EZH2. Examples of published molecules which have the
pyridone group are shown in Figure 1. Of these, EPZ643815 (7)
and GSK12616 (2) are currently being evaluated in human clinical
trials. We noted that EPZ6438 and EPZ11989 are exceptions in
the pyridone containing EZH2 inhibitors; the pyridone-methyl
amide is attached to a phenyl core in place of a bicyclic hetero-
aryl core. It has been demonstrated that increased fraction of sp3
carbons (Fsp3 = number of sp3 hybridized carbons/total carbon
count) correlates with improved solubility, an experimental
physical property important to success in drug discovery.17
These observations prompted us to use a bicyclic non-planar
indoline core for making novel EZH2 inhibitors, where the core
consists of a phenyl residue fused with a saturated 5-membered
ring. Our design is drawn in Figure 2, where we show that the
indoline can be derived from the EPZ6438 (7) core by C7-C8
cyclization or by saturation of indole core at C-2 and C-3 present
in Ei1 (1) and GSK126 (2). We envisaged that the new molecules
with non-planar indoline core might have improved solubility
and pharmacokinetic properties due to higher degree of saturation
and non-planarity of the core.

Figure 1. Reported EZH2 inhibitors13
Figure 2. Design of indoline core for making EZH2 inhibitors
We started our lead generation effort by preparing compounds
16, 17, 18 and 19 incorporating an indoline core (Scheme 1).
Key intermediates 12a-c were synthesized by a reductive
amination of various ketones with 11, which was obtained by
reduction of commercially available indole 10. Intermediates
12a and 12b were then converted to 15a and 15b using
trimethyaluminium as the coupling agent. Cyanation of 15a, 15b
and 15c afforded 16, 17 and 18 respectively. Alternatively,
intermediate 12c was transformed to 19 via Suzuki coupling
followed by hydrolysis and amide bond formation.
Compounds were tested in vitro for their ability to inhibit the
enzymatic activity of EZH2, mutant EZH2 (Y641F) and the
homolog EZH1. The enzymatic activity was determined using
3
the indicated HMT complexes incubated with H-SAM (tritiated
S-adenosenyl L-methionine) and histone H3 and IC50 curves were
determined for each compound (see supplemental information) .
The IC50 results for inhibition of EZH2 are shown in Table 1.
Scheme 1. Synthesis of 16, 17 18 and 19. Reagents and conditions: (a) TFA,
triethylsilane, CH2Cl2, RT; (b) AcOH, ketone, Na(OAc)3BH, CH2Cl2, 0-RT,
16 h; (c) 2M AlMe3 in toluene, THF, 80 °C, 18 h; (d) Zn, Zn(CN)2,
PdCl2(dppf)•CH2Cl2, DMA, 135 °C, 18 h; (e) Boronic ester, Na2CO3,
Pd(PPh3)4, dioxane-water, 90 °C, 15 h; (f) 6N HCl, 95 °C, 16 h; (g) PyBOP,
TEA, DMSO, RT, 16 h. Further details are in the Supplemental Information.
Based on reported compounds and published SAR,13 we
maintained the 4,6-dimethylpyridone methyl amide as a constant.
Our first analogs scoped out the effect of substitution at the 1-
and 6-positions of the indoline. The isopropyl substituted 16 was
inactive (EZH2 IC50 = 26.6 M) while the cyclopentyl
substituted 17 had a 47-fold improvement in potency (EZH2 IC50
= 571 nM). However, a tetrahydropyran (THP) substitution led
to a drastic loss of potency (18 EZH2 IC50 = 15.7 M). We also
made compound 19 with a large phenyl-methyl morpholine at the
6-position, and surprisingly, while this compound has a THP
group at the 1-position, its activity improved to EZH2 IC50 = 237

nM. With some uncertainty about our SAR conclusions at this
point, we turned our attention to substitution at the 3-position.
Table 1 EZH2 inhibitory activity of compounds 16-19
a
EZH2 IC50
R1
R2
(nM)
Compound
16
26,600
571
17
18
15,700
237
19
aExperimental details are in the Supplemental Information.
For compounds containing a 3-position methyl substituent,
we synthesized several analogs using different R1 and R2 groups,
including those reported in the literature13 for molecules having
an indole core. R2 groups included nitrile, phenyl-methyl
morpholine, piperazino-pyridine, piperazino-pyrimidine and
Scheme 2. Synthesis of 27, 28, 30, 31, 33 and 34. Reagents and conditions:
(a) NaH, alkyl bromide, DMF, 0-RT, 16 h; (b) (i) POCl3,DMF, 2.5 h (ii) 2N
NaOH; (c) (i) ZnI2, NaCNBH3, DCE, RT, 16 h (ii) TFA, triethylsilane, DCE,
RT, 16 h; (d) AcOH, aldehyde/ketone, Na(OAc)3BH, 0-RT, 16 h (e) Zn,
Zn(CN)2, PdCl2(dppf).DCM, DMA, 135 °C, 18 h; (f) LiOH, THF, MeOH,
piperazino-isoquinoline.
R1 groups included isopropyl,
Water, RT,
6 h; (g) 3-(Aminomethyl)-4,6-dimethylpyridin-2(1H)-one,
PyBOP, TEA, DMSO, RT, 16 h; (h) 3-(Aminomethyl)-4,6-dimethylpyridin-
2(1H)-one, 2M AlMe3 in toluene, THF, 80 °C, 18 h; (i) Boronic ester,
Na2CO3, Pd(PPh3)4, dioxane, water, 90 °C, 15 h. Further details are in the
Supplemental Information.
cyclopentyl, cyclopropylmethyl and THP. The 3-position methyl
group resulted in enantiomeric pairs of compounds after
separation by chiral chromatography.
Scheme 2 describes the synthesis of compounds 27, 28, 30,
31, 33 and 34. Briefly, intermediate 24a and 24b were
synthesized from 10 by alkylation followed by formylation and
reduction while 24c and 24d were synthesized by reductive
amination of 23 which was obtained from 10 via 22. Cyanation
of 24a and 24b resulted in 25a and 25b which after hydrolysis
followed by amide bond formation with 3-(aminomethyl)-4,6-
dimethylpyridin-2(1H)-one gave 27 and 28, respectively.
Compound 29a, 29b and 29c were obtained by amide bond
formation of 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one
with 24a, 24d and 24c respectively, using trimethylaluminium as
coupling agent. Suzuki coupling of 29a and 29b with arylboronic
ester yielded 30 and 31 respectively. Suzuki coupling of 24b and
24c respectively gave 32a and 32b which after amidation
afforded 33 and 34 respectively.
Scheme 3 describes the synthesis of compounds 36, 39, 40, 41
and 45. Boc-piperazine-isoquinoline boronic ester (synthesized
by a method described in Supplemental Information) was coupled
with 29c to give 35 which after Boc-deprotection afforded 36.
Compound 24a, 24b and 24c were coupled with commercially
available Boc-piperazine-pyridine boronic ester to afford 37a,
37b and 37c which after amide bond formation followed by Boc-
deprotection afforded 39, 40 and 41 respectively. Suzuki
coupling of Boc-piperazine-pyrimidine boronic ester with 24c
resulted 42 which was converted to 45 via 43 and 44.

compound 34 (see Supplemental Information). This pair of
enantiomers presented the dimethyl pyridone moiety to the
protein in a manner identical to the published bound inhibitor,
forming 2 H-bonds with the backbone of W624. The active
enantiomer (34e1, predicted to be the R enantiomer based on
docking) indeed has the methyl group sitting in a groove lined by
T678, F665, and the face of R685, possibly displacing an isolated
water molecule. The inactive enantiomer (34e2) is seen to rotate
the indoline group by 180o, while still anchored to the protein
through the pyridone. This likely happens in an attempt to avoid
a steric clash with the protein. In this state, R685 and F665
interactions with the ligand are lost, and a high entropy stranded
water is likely interacting with R685 thus explaining the potency
loss.
We probed the role of substituent at the N1 position of
indoline (R1) and found that compounds with cyclopentyl (28e1,
33e1) and THP group (34e1) had better potency compared to their
corresponding isopropyl analogs 27e1 and 30e1 (Table 2). These
results indicated that bulkier groups are needed at this position
for better potency. The compound with cyclopropylmethyl group
at N1 (31e1) was found to be 8 fold less potent compared to its
isopropyl analog (30e1) (Table 2). This result highlights the role
of α-branching at this position on potency.
Next, we decided to study effect of substituent at C-6 position
of indoline on activity (Table 2). We used different substituents
at this position and pyridine-2-yl-piperizine residue was found to
be the best substituent at this position as far as the biological
activity against WT EZH2 inhibition is concerned (Compounds
39-41, Table 2).
Scheme 3. Synthesis of 36, 39, 40, 41 and 45. Reagents and conditions: (a)
PdCl2(dppf).dcm, K2CO3, boronic ester, dioxane, water, 90°C, 16 h; (b) TFA,
DCM, RT, 16 h; (c) 3-(Aminomethyl)-4,6-dimethylpyridin-2(1H)-one, 2M
AlMe3 in toluene, THF, 80 °C, 18 h; (d) LiOH, THF, MeOH, water, RT, 6 h;
(e) 3-(Aminomethyl)-4,6-dimethylpyridin-2(1H)-one, PyBOP, TEA, DMSO,
RT, 16 h. Further details are in the Supplemental Information.
The pyrimidine analog of 41e1 (45e1) was found to be 9-fold
less potent than 41e1. We also explored a 3-ethyl substituted
With this set of methyl-substituted compounds in hand, we
tested for activity against EZH2; the active analogs were
additionally tested for activity against EZH1 and the Y641F
EZH2 mutant. The Y641 residue is frequently mutated in certain
lymphomas. Moreover, lymphomas with this mutation have
increased H3K27 methylation.16 The SAR is illustrated in Table
2.
analog of 41e1 and found it to be 13-fold less potent (EZH2 IC50
=
145 nM, data not shown).
While these compounds maintained relatively good potency
for EZH2, they did not display appreciable inhibitory activity
against EZH1 (IC50 > 1.35 µM), indicating their relative
selectivity for EZH2 versus the homolog EZH1. Regarding
Y641F EZH2 activity, overall, this series suffered a 7-40 fold
loss in potency relative to WT EZH2. Compound 28e1 with a
cyano group at the R2 position had the best potency against
Y641F EZH2.
The methyl substituent had a dramatic effect on potency in
the series. As an illustrative example, 16 has EZH2 IC50 of 26.6
M, while the methyl substituted active enantiomer 27e1 has
EZH2 IC50 of 88 nM - a 302 fold improvement. The inactive
enantiomer 27e2 has no measurable activity against EZH2. This
interesting phenomenon is an example of the “magic methyl”
effect that has been described in the literature.18 During the
prosecution of this program, a patent application describing
indoline core containing EZH2 inhibitors was published.19 While
the broad claims included multiple 3- substituted indolines and
some compounds containing 3,3-dimethyl substituted indolines
were described, no compounds containing 3-monomethyl
substituted indolines were exemplified.
We found that for all R1 and R2 groups, the 2 enantiomers of a
pair had very disparate activity. This difference in activity in an
enantiomeric pair was more pronounced in the case of a small R2
substituent (-CN, in 27e1, 27e2, 28e1 and 28e2). In these examples,
the difference in activity between enantiomers is >100 fold, with
the less potent enantiomer (27e2 and 28e2) having no measurable
IC50 against EZH2 up to 100 µM. With the larger R2 substituents
shown in Table 2, the less active enantiomer had measurable
activity, albeit in the micromolar range. This indicates that in the
3-methyl substituted indoline series, there appears to be some
cross talk between the 3- and 6-position substituents. In an effort
to understand the “magic methyl” effect, we used the published
crystal structure of EZH220 to dock both enantiomers of

Table 2. SAR of 3-methlindoline based compounds
a
a
EZH1 IC50
EZH2 IC50
EZH2 (Y641F)
Compound
R1
R2
(nM)
(nM)
IC50a (nM)
27e1
27e2
28e1
28e1
7,750
ND
88
478
ND
185
ND
>100,000
27
4,440
ND
>100,000
30e1
30e2
31e1
31e2
33e1
33e2
34e1
34e2
39e1
39e2
40e1
40e2
41e1
41e2
45e1
45e2
36e1
2,710
ND
47
4,140
375
15,200
24
448
29
6,980
17
1,082
21
378
11
2,150
98
2,160
17
518
ND
ND
ND
902
ND
975
ND
622
ND
505
ND
578
ND
ND
ND
304
ND
ND
2,650
ND
3,340
ND
1,870
ND
1,350
ND
1,980
ND
ND
ND
1,560
36e2
ND
540
ND
e1/e2 Active/inactive enantiomer; ND: not determined; aExperimental details are in the Supplemental Information.
We tested EPZ6438 (7, EZH2 IC50 = 2 nM in our assay) and two of our lead compounds with the indoline core (34e1 and 41e1) in
solubility and microsomal stability assays; the data are shown in Table 3. These two compounds demonstrated superior kinetic
solubility in PBS (pH 7.5) and improved oxidative stability in human and mouse liver microsomes (HLM and MLM) compared to
EPZ6438 (7).
Table 3. In vitro ADME dataa for 7, 15e1 and 21e1

Compound
Sol (μM)b
hLM (% R)c mLM (% R)c
28
75
75
25
62
83
39
58
95
7
34e1
41e1
aExperimental details are in the Supplemental Information; bKinetic solubility; cPercent parent remaining after 30 min.
In conclusion, we describe the indoline as a novel core for making EZH2 inhibitors. These findings provide a foundation for
future analoging and SAR; lead compounds will be tested in cell assays, in vivo for optimization of pharmacokinetic properties and
evaluation in pharmacology models.
Funding: This research did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectors.
It was funded solely by Medivation.
Acknowledgements: The authors thank Kevin Quinn for his advice and expertise on the in vitro metabolism experiments and the
Analytical and Purification group at Integral Bioscience for purification of compounds and for acquiring NMR data.
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Novel 3-methylindoline inhibitors of EZH2:
design synthesis and SAR
Leave this area blank for abstract info.
Amantullah Ansari, Sharad Satalkar, Varshavekumar Patil, Amit Shete, Simranjeet Kaur, Ashu Gupta,
Siddhartha Singh, Mohd. Raja, Daniel L. Severance, Sebastián Bernales, Sarvajit Chakravarty, David T. Hung,
Son M. Pham, Francisco Herrera and Roopa Rai