Synthesis of NVS-BPTF-1 and evaluation of its biological activity

Article abstract of DOI:10.1016/j.bmcl.2021.128208

BPTF (bromodomain and PHD finger containing transcription factor) is a multidomain protein that plays essential roles in transcriptional regulation, T-cell homeostasis and stem cell pluripotency. As part of the chromatin remodeling complex hNURF (nucleoso

Full text of DOI:10.1016/j.bmcl.2021.128208

Bioorg. Med. Chem. Lett. 47 (2021) 128208
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis of NVS-BPTF-1 and evaluation of its biological activity
a
b
b
b
a,*
L ´e a M ´e lin , Cyrus Calosing , Olesya A. Kharenko , Henrik C. Hansen , Alexandre Gagnon
a
D ´e partement de chimie, Universit ´e du Qu ´e bec a` Montr ´e al, C.P. 8888, Succ. Centre-Ville, Montr ´e al, Qu ´e bec H3C 3P8, Canada
b
Zenith Epigenetics Ltd, Suite 300, 4820 Richard Road SW, Calgary, AB T3E 6L1, Canada
A R T I C L E I N F O
A B S T R A C T
Keywords:
NVS-BPTF-1
BPTF
BPTF (bromodomain and PHD finger containing transcription factor) is a multidomain protein that plays
essential roles in transcriptional regulation, T-cell homeostasis and stem cell pluripotency. As part of the chro-
matin remodeling complex hNURF (nucleosome remodeling factor), BPTF epigenetic reader subunits are
particularly important for BPTF cellular function. Here we report the synthesis of NVS-BPTF-1, a previously
reported highly potent and selective BPTF-bromodomain inhibitor. Evaluation of the impact of the inhibition of
BPTF-bromodomain using NVS-BPTF-1 on selected proteins involved in the antigen processing pathway revealed
that exclusively targeting BPTF-bromodomain is insufficient to observe an increase of PSMB8, PSMB9, TAP1 and
TAP2 proteins.
NURF
Synthesis
Gene expression is highly regulated by chromatin topology. Even in
the euchromatin state, transcription factors can hardly access the cis-
sequences of DNA and usually require the combined action of both
epigenetic enzymes and chromatin remodelers beforehand. Covalent
modifications of histone tails, increased exposition of naked DNA or
alteration of nucleosomes organization in a promoter region can
strongly impact gene expression and, ultimately, cell phenotypes.1
NURF (nucleosome remodeling factor) is one of the conserved ATP-
dependent chromatin remodeling factors belonging to the ISWI family.
Rather than binding to naked DNA or histones, NURF preferentially
interacts with nucleosomes through the positively charged N-terminal
histone tails2 and catalyzes nucleosome sliding.3 By doing so, NURF is
able to assist the binding of transcription factors and is therefore key for
bromodomain, two PHD domains and a glutamine-rich acidic domain.11
These epigenetic readers are particularly important for BPTF cellular
function as they serve as recognition units for acetylated or methylated
lysine residues. It has therefore been demonstrated that BPTF binds to
acetylated H3 and H4 histone tails via its bromodomain and to
H3K4Me3 via its second PHD finger.12
As lysine acetylation of histone tails is one of the most dynamic post-
translation modification associated with chromatin accessibility and
increased gene expression,13 mutation and overexpression of bromo-
domain containing proteins (BCPs) have been associated with many
1
4
diseases, such as cancer, inflammation or neurological disorders. In
particular, aberrant expression of BPTF has been implicated in the
development and progression of multiple types of cancer, including
4
15
16
17
gene activation initiation. Human NURF (hNURF) is composed of three
colorectal cancer, lung adenocarcinomas, melanoma, and neuro-
blastomas.18 Slowly emerging as a potential target for novel anti-cancer
subunits: the conserved ISWI ATPase core SNF2L, BPTF (bromodomain
and PHD finger containing transcription factor, also known as FALZ for
fetal alzheimer antigen) and RbAP48/46 (retinoblastoma associated
proteins 46 and 48), two mammalian orthologs of Drosophila NURF301
and NURF55, respectively.5
1
9,20
drugs because of its required recruitment for c-MYC activation,
it is
+
interesting to note that BPTF knockdowns enhance CD8 T-cell and NK-
cells mediated antitumor immunity,2
1,22
therefore also highlighting
BPTF as a potential target for the development of immunotherapies.
Despite BPTF biological pertinence in cancer and the fact that
inhibiting the bromodomain of BCPs has been successful in the past for
treating BCPs-related diseases (as illustrated by the numerous BET in-
hibitors currently in clinical trials), only few chemical probes targeting
BPTF-bromodomain have been developed (Fig. 1). AU1, the first small
BPTF, the largest and most essential component of the hNURF
complex, is critical for transcriptional regulation during embryogen-
6
,7
esis.
Outside of this specific developmental stage, BPTF maintains
8
chromatin accessibility, allowing stem cell pluripotency, T-cell ho-
9
10
meostasis and function, and transcriptional regulation. In order to do
so, BPTF harbors multiple motifs characteristic of transcriptional coac-
tivators: one non-BET (bromodomain and extra-terminal domain)
2
3
molecule showing some selectivity for BPTF, was reported in 2015.
Discovered during an 19F NMR dual screening against BPTF and BRD4,
*
Corresponding author.
E-mail address: gagnon.alexandre@uqam.ca (A. Gagnon).
https://doi.org/10.1016/j.bmcl.2021.128208
Received 29 April 2021; Received in revised form 9 June 2021; Accepted 13 June 2021
Available online 16 June 2021
0
960-894X/© 2021 Elsevier Ltd. All rights reserved.

L. M ´e lin et al.
Bioorganic & Medicinal Chemistry Letters 47 (2021) 128208
O
F
NH
O
I
OMe
H
N
H
N
N
N
OMe
N
O
H
2
N
O
AU1
DCB29
O
O
S
O
N
H
H
N
Me
2
N
N
O
N
N
O
HN
N
O
N
N
C620-0696
TP-238
Me
O
N
N
N
Me
O
O
O
N
Me
S
N
N
N
H
N
N
N
N
H
Me
F
1
NVS-BPTF-1
Fig. 1. Reported BPTF inhibitors.
Scheme 1. Retrosynthetic analysis of NVS-BPTF-1.
AU1 displays a K
d
value of 2.8 M for BPTF as determined by isothermal
μ
N
an halide, a triflate or a tosylate could allow an S Ar transformation or a
titration calorimetry (ITC), while no binding against BRD4 was
observed. In 2019, DCB29, a dialkoxy iodo benzamide derivative, was
developed through structure-based virtual screening as a selective BPTF-
metal-catalyzed N-arylation reaction with 3. Although complications
could arise from the anticipated low nucleophilicity of aniline 3, we
hypothesized that this approach would have a higher chance of success
bromodomain inhibitor with an IC50 value of 13.2
homogenous time-resolved fluorescence resonance energy transfer
HTRF) assays.24 The same year, compound C620-0696 was reported
with a K value of 35.5 M against BPTF as assessed by a biolayer
μM, obtained by
than the complementary C
preparation of an intriguing and poorly-characterized amino-pyr-
imidinone version of 2 (i.e. X = NH ). Left-hand side fragment 2 could
–
N disconnection that would require the
(
2
d
μ
then be prepared by a palladium-catalyzed cross-coupling reaction be-
tween an N-cyclopropylboron species 4, either in the form of a boronic
acid or ester, and a halo or triflyl pyridopyrimidinone core of type 5.
Should this cross-coupling be challenging, we assumed that the role of
the partners could be inverted, that is, the boron function would be
installed on 5. The installation of the cyclopropyl unit on the pyrazole’s
NH would be performed through a copper-catalyzed N-cyclopropylation
reaction on 6 via one of the numerous conditions involving boron or
bismuth reagents. The boron would be installed on 6 via a lith-
ium–halogen exchange reaction or a metal-catalyzed cross-coupling
process. A search of the literature revealed a paucity of methods to form
the densely functionalized central core 5. It was our hope that this
scaffold could be obtained by a condensation reaction between 7 and a
properly activated malonic system 8. Finally, the aniline portion 3
would be prepared from 9 and 10 through conventional sulfonamide
bond construction and nitro reduction.
interferometry (BLI) assay. C620-0696 exhibits cytotoxicity to BPTF
overexpression in non-small-cell lung cancer (NSCLC) cell lines and also
inhibits the binding between the BPTF bromodomain and H4K16Ac,
which leads to repression of c-MYC transcription activation.25
Finally, the SGC, in collaboration with Takeda, reported on their
website TP-238, the first chemical probe with low nanomolar potency
against BPTF bromodomain. However, TP-238 inhibited both CECR2
and BPTF in an AlphaScreen assay with IC50 values of 30 nM and 350
nM, respectively.26 This lack of selectivity was countered with the
release of NVS-BPTF-1. Produced through a collaboration between the
SGC and Novartis, NVS-BPTF-1 is the first highly potent, selective and
cell active chemical probe for BPTF-bromodomain. NVS-BPTF-1 gave an
d
IC50 value of 56 nM in an AlphaScreen assay and a K value of 71 nM in a
2
7
BLI assay. A DSF screen and a BROMOscan revealed no significant
interaction with a panel of other human bromodomains. In HEK293
cells, NVS-BPTF-1 showed on-target activity with an IC50 of 16 nM, as
measured by a nanoBRET assay. While writing this manuscript, com-
We first prepared aniline 3 by reacting 3-fluoro-4-nitrobenzenesul-
fonyl chloride 9 with 1-methylpiperazine 10, followed by reduction of
the nitro group in 11 under B ´e champ’s conditions (Scheme 2). Quick
attempt at improving the yield of this transformation, for example by
increasing the reaction time or the temperature, or pre-forming the so-
dium amide of 10 proved unsuccessful and therefore, we continued with
the synthesis of the western portion of our target molecule.
pound 1 was published as a new BPTF-bromodomain inhibitor with a K
d
value of 428 nM for BPTF as determined by ITC. Compound 1 down-
regulated both c-MYC and BPTF expression in A549 cells.28
Even though NVS-BPTF-1 is currently the most potent and selective
chemical probe against BPTF, to the best of our knowledge, its synthesis
has not been reported yet. We would like to disclose herein a rapid and
modular chemical route to access this tool compound. Preliminary
evaluation of the biological activity of NVS-BPTF-1 is also described.
The retrosynthetic analysis of NVS-BPTF-1 invited a disconnection
on the central aniline function, leading to the left-hand side pyr-
idopyrimidinone synthon 2 and the right-hand side 1-((3-fluoro-4-ami-
nophenyl)sulfonyl)-4-methylpiperazine fragment 3 (Scheme 1). We
envisioned that the presence of a suitable leaving group X on 2 such as
Thus, we prepared the N-cyclopropyl-4-borylpyrazolyl synthon 4 (c.
f. Scheme 1) by first installing the cyclopropyl moiety onto 1-cyclo-
propyl-4-iodo-1H-pyrazole 12 via
a
copper-catalyzed N-cyclo-
propylation reaction (Scheme 3). After testing various conditions, we
found that this transformation could be efficiently accomplished using
2
.0 equivalents of cyclopropylboronic acid in the presence of a stoi-
chiometric amount of cupric acetate and a mixture of dimethylamino-
pyridine and pyridine in refluxing dioxane under an oxygen atmosphere.
2

L. M ´e lin et al.
Bioorganic & Medicinal Chemistry Letters 47 (2021) 128208
Scheme 2. Synthesis of aniline 3.
O
O
O
O
B
B
c-PrB(OH)
2
(2.0 equiv)
H
N
N
I
Cu(OAc)
(1.0 equiv)
(1.4 equiv)
KOAc (4.0 equiv)
2
DMAP (4.0 equiv)
N
N
N
N
Pyridine (2.5 equiv)
Dioxane
Pd(dppf)Cl
2
•CH
2
Cl
2
B
O
I
(5 mol%)
DMSO, 80 °C, 3 h
82%
O
101 °C, O
2
, o.n.
12
13
14
95%
Scheme 3. Synthesis of 1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxabor-
olan-2-yl)-1H-pyrazole 14.
Scheme 4. Synthesis of the 7-bromo-2-hydroxy-3-methyl-4H-pyrido[1,2-a]
pyrimidin-4-one core 17.
Attempts at transforming the iodide in 13 into a boron functionality
through a lithium–halogen exchange process followed by reaction with
trimethylborate proved difficult. Consequently, iodide 13 was converted
into the corresponding 1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)-1H-pyrazole 14 via a palladium-catalyzed cross-
coupling reaction with bis(pinacolato)diboron. Rapid optimization of
′
the reaction conditions led us to use [1,1 -bis(diphenyl-phosphino)
ferrocene]-dichloropalladium(II) as the catalyst in combination with
potassium acetate as the base and DMSO as the solvent.
We next turned our attention to the preparation of the pyridopyr-
imidinone scaffold 5 (c.f. Scheme 1). A quick search of the literature
indicated a lack of methods to prepare compounds of this type with a
methyl group in position 3. Attempts at directly coupling 5-bromoami-
nopyridine 15 with 2-methylmalonic dimethylester 16 under smooth
or forcing conditions failed to deliver the desired condensation product
1
7, but provided instead a mixture of the mono-condensation adduct 18
and its corresponding decarboxylation product 19 (Scheme 4a).
We hypothesized that a more reactive malonic system could poten-
tially facilitate this apparently difficult condensation reaction. Thus, 2-
methylmalonic acid 20 was preactivated with HATU in the presence
of Hünig’s base and then reacted with 15 (Scheme 4b). Again, product
1
7 could not be isolated using this approach, even when conducted
Scheme 5. Synthesis of pyridopyrimidinone 27.
under drastic conditions. Ultimately, the cyclization problem was solved
by transforming 2-methylmalonic acid 21 into its corresponding bis
transformation would occur with some level of selectivity on the bro-
mide over the chloride. Happily, this strategy delivered 27, albeit in a
moderate 19% yield. Since other catalysts or conditions failed to
improve the efficiency of the process, we decided to continue with the
union of 27 with 3.
(
2,4,6-trichlorophenyl)ester derivative 23 through reaction with 2,4,6-
trichlorophenol 22 in neat phosphorus oxychloride (Scheme 4c).
Reacting 23 with 5-bromo-2-aminopyridine 15 in hot toluene over 2 h
finally afforded the desired cyclized product 17 in 83% yield (Scheme
4
c).
Direct reaction of N-cyclopropylpyrazolylboronic pinacol ester 14
N
Attempts at coupling 3 and 27 through a S Ar reaction under various
conditions failed to provide the desired product NVS-BPTF-1. We
assumed that the deactivation of the aniline 3 by the combined electron-
withdrawing effects of the fluoride in ortho position and the sulfonamide
in para were responsible (at least partially) for this lack of reactivity.
Therefore, we turned our attention to a metal-catalyzed approach and
found that key intermediates 3 and 27 could be coupled under
Buchwald-Hartwig conditions using palladium(II) acetate, racemic
BINAP in refluxing toluene in the presence of cesium carbonate,
affording NVS-BPTF-1 in 56% yield with greater than 99% purity
with bromopyrimidinone 17 was then attempted with the aim of
generating 24 (Scheme 5). After testing numerous conditions, we could
not obtain the desired product and we thus opted to convert the OH
(
which might also exist in the tautomeric keto-form) into the corre-
sponding chloride. This chloride would serve as a valuable handle for a
subsequent S Ar reaction with aniline 3. In the event, 17 was converted
into 25 through heating in a mixture of phosphoryl chloride and phos-
phorus pentachloride. Unfortunately, all attempts to realize the S Ar
N
N
reaction between 25 and 3 failed, even under harsh conditions. Thus, 25
was engaged in a cross-coupling reaction with 14 with the hope that this
(
Scheme 6).
The structure of synthetic NVS-BPTF-1 was confirmed through X-ray
3

L. M ´e lin et al.
Bioorganic & Medicinal Chemistry Letters 47 (2021) 128208
N
N
O
N
Me
Cl
N
Pd(OAc)2 (6 mol%)
Rac-BINAP (9 mol%)
Cs2CO3 (2.4 equiv)
N
N
O
N
O
O
2
7
Me
S
N
N
+
N
Toluene, argon
N
H
Me
O
S
O
110 °C, o.n.
F
56%
N
NVS-BPTF-1
N
H2N
Me
F
3
Scheme 6. Synthesis of NVS-BPTF-1 through Buchwald-Hartwig coupling be-
tween 27 and 3.
= 5.7 ◦C) assays
Fig. 3. a) AlphaScreen (IC50 = 30 nM; n = 4) and b) DSF (ΔT
m
using resynthesized NVS-BPTF-1 against BPTF and BRD4(BD1).
diffraction analysis on crystals obtained from methylene chloride via the
solvent diffusion technique (Fig. 2).
Mayes and collaborators have shown that depletion of BPTF in
B16F10 models leads to upregulation of PSMB8 and PSMB9 which are
part of the immunoproteasome, as well as TAP1 and TAP2 which belong
to the transporter associated with antigen-processing complex.21 They
observed that this upregulation results in enhanced antigenicity and
improved T-cell antitumor activity. With our resynthesized NVS-BPTF-1
in hand, we thus aimed to evaluate if inhibition of BPTF would result in a
similar upregulation of these four specific proteins as in the knockdown
model, thus allowing us to determine the potential therapeutic perti-
nence of BPTF-bromodomain in the context of immunotherapies for the
treatment of cancer.
First, we confirmed the activity and the selective profile of NVS-
BPTF-1 using both an AlphaScreen assay and a DSF thermal shift assay
Fig. 4. Proliferation assay in B16F10 model.
(
(
differential scanning fluorimetry) against BPTF and BRD4(BD1)
can enhance the proteasome subunit beta type-9 protein (PSMB9) in
B16F10 cells (Fig. S2). However, when NVS-BPTF-1 was used, this
activation was not detected in B16F10 mouse melanoma cell lines
◦
Fig. 3). In the event, an IC50 of 30 nM and a ΔT
m
of 5.7 C were ob-
tained, which are in good agreement with values presented online by the
SGC (i.e. IC50 of 56 nM against BPTF in an AlphaScreen assay and ΔT of
m
(
(
Fig. 5), nor in A549 (lung) or BT549 (breast) human cancer cell lines
Fig. S3).
◦
27
6
.16 C).
Since the selectivity of the probe was already assessed by the SGC via
Since NVS-BPTF-1 did not affect the level of PSMB8 and PSMB9 or
a DSF screen and a BROMOscan assay,27 we then evaluated the effect of
our compound on proliferation in various cancer cell lines. Contrary to
AU1 and C620-0696, NVS-BPTF-1 did not affect the proliferation of
B16F10 mouse melanoma cell lines (Fig. 4). While AU1 and C620-0696
are low micromolar inhibitors of the BPTF bromodomain, this difference
could be attributed to off-target effects, previously reported in the
literature.29 In a similar fashion, NVS-BPTF-1 did not inhibit the pro-
liferation of multiple human cancer cell lines (Fig. S1), while siRNA
knockdowns of BPTF were previously reported as reducing proliferation
of various cancer cell lines.1
TAP1 and TAP2, we hypothesized that targeting BPTF-bromodomain
alone is not sufficient to observe any impact on the expression of these
proteins.
In conclusion, a modular synthetic route was developed for NVS-
BPTF-1, the first potent and selective inhibitor of BPTF bromodomain.
Binding of resynthesized NVS-BPTF-1 to BPTF was confirmed using a
DSF assay while inhibition was demonstrated using an AlphaScreen
assay. No impact on B16F10 cell proliferation was observed upon
exposure to NVS-BPTF-1. Contrary to BPTF knockdown models, inhi-
bition of BPTF with NVS-BPTF-1 did not lead to increased levels of
TAP1, TAP2, PSMB8 or PSMB9. These results suggest that only targeting
BPTF-bromodomain might not be a viable strategy for the development
of immunotherapies.
6,30,31
3
2
Previous reports revealed that interferon gamma (IFNγ)
and
shRNA knockdown of BPTF21 can increase the amount of immunopro-
teasome proteins PSMB8 and PSMB9 and antigen transport proteins
TAP1 and TAP2. Our results also indicate that BPTF siRNA knockdown
Declaration of Competing Interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
Fig. 5. Effects of NVS-BPTF-1 on PSMB8, PSMB9, TAP1 and TAP2. a) Western
blot of B16F10 mouse melanoma cell lines treated with NVS-BPTF-1 or 20 ng/
mL IFNg for 72 h; b) effects on PSMB9 mRNA in B16F10 mouse melanoma
cell lines.
Fig. 2. Thermal atomic displacement ORTEP ellipsoid plot for NVS-BPTF-1
(
CCDC number: 2080173). Ellipsoids are drawn at the 50% probability level
and hydrogen atoms are shown as spheres of arbitrary size.
4

L. M ´e lin et al.
Bioorganic & Medicinal Chemistry Letters 47 (2021) 128208
the work reported in this paper.
13 Shahbazian MD, Grunstein M. Functions of site-specific histone acetylation and
deacetylation. Annu Rev Biochem. 2007;76(1):75–100. https://doi.org/10.1146/
annurev.biochem.76.052705.162114.
Acknowledgments
14 Muller S, Filippakopoulos P, Knapp S. Bromodomains as therapeutic targets. Expert
Rev Mol Med. 2011;13. https://doi.org/10.1017/S1462399411001992.
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We would like to thank the Natural Sciences and Engineering
Research Council of Canada (NSERC) and Zenith Epigenetics Ltd for a
Collaborative Research and Development Grant. C.C., O.K., and H.H. are
salaried employees of Zenith Epigenetics Ltd.
1
465–1474. https://doi.org/10.1007/s00432-015-1937-y.
1
1
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prognosis in lung adenocarcinomas. Oncotarget. 2015;6(32):33878–33892.
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Appendix A. Supplementary data
1
0.1073/pnas.1606027113.
1
1
2
2
8
9
0
1
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