Discovery of the first potent inhibitors of mutant IDH1 that lower tumor 2-HG in vivo

Article abstract of DOI:10.1021/ml300225h

Optimization of a series of R132H IDH1 inhibitors from a high throughput screen led to the first potent molecules that show robust tumor 2-HG inhibition in a xenograft model. Compound 35 shows good potency in the U87 R132H cell based assay and ～90% tumor 2-HG inhibition in the corresponding mouse xenograft model following BID dosing. The magnitude and duration of tumor 2-HG inhibition correlates with free plasma concentration.

Full text of DOI:10.1021/ml300225h

Letter
pubs.acs.org/acsmedchemlett
Discovery of the First Potent Inhibitors of Mutant IDH1 That Lower
Tumor 2‑HG in Vivo
Janeta Popovici-Muller,*,† Jeffrey O. Saunders,‡ Francesco G. Salituro,§ Jeremy M. Travins,† Shunqi Yan,∥
Fang Zhao,⊥ Stefan Gross,† Lenny Dang,† Katharine E. Yen,† Hua Yang,† Kimberly S. Straley,†
Shengfang Jin,† Kaiko Kunii,† Valeria R. Fantin,∇ Shunan Zhang,# Qiongqun Pan,# Derek Shi,#
Scott A. Biller,† and Shinsan M. Su†
†Agios Pharmaceuticals, 38 Sidney Street, Cambridge, Massachusetts 02139, United States
‡Ember Therapeutics, 855 Boylston Street, 11th Floor, Suite B, Boston, Massachusetts 02116, United States
§Sage Therapeutics, 215 First Street, Cambridge, Massachusetts 02141, United States
∥Schrodinger, Inc., 120 West 45th Street, New York, New York 10036, United States
̈
⊥Sundia MediTech Company, Ltd., Building 8, 388 Jialilue Road, Zhangjiang High-Tech Park, Shanghai 201203, China
∇Oncology Research Unit, Pfizer Worldwide Research and Development, La Jolla Laboratories, San Diego, California 92121, United
States
#Shanghai ChemPartner Co., LTD, 998 Halei Road, Zhangjiang Hi-tech Park, Pudong New Area, Shanghai 201203, China
S
* Supporting Information
ABSTRACT: Optimization of a series of R132H IDH1
inhibitors from a high throughput screen led to the first
potent molecules that show robust tumor 2-HG inhibition in a
xenograft model. Compound 35 shows good potency in the
U87 R132H cell based assay and ∼90% tumor 2-HG inhibition
in the corresponding mouse xenograft model following BID
dosing. The magnitude and duration of tumor 2-HG inhibition
correlates with free plasma concentration.
KEYWORDS: Mutant IDH1, tumor 2-HG, R132H IDH1 inhibitors
he family of isocitrate dehydrogenases (IDHs) includes
two NADP dependent isoforms IDH1 and IDH2, which
DNA demethylases,7,8 and several studies have shown that 2-
HG producing IDH mutants are involved in global histone and
DNA methylation alterations which may contribute to
tumorigenesis through epigenetic rewiring.9,10 Taken together,
these findings implicate mutant IDH1 as an oncogene and a
compelling drug target for new therapies for glioma and AML
patients.
T
catalyze the oxidative decarboxylation of isocitrate to produce
carbon dioxide, α-ketoglutarate (α-KG), and NADPH.1,2,14
The implication of a role for IDH in cancer was revealed after
somatic mutations in IDH1 were identified through a genome
wide mutation analysis in glioblastoma.3 This landmark study
was followed by high throughput sequencing, which revealed
the presence of mutations in IDH1 in more than 70% of grade
II−III gliomas and secondary glioblastomas,4 as well as in
approximately 10−15% of patients with acute myeloid leukemia
(AML).5 These somatic mutations were found at a key arginine
residue belonging to the catalytic triad found in the enzyme’s
active site (R132 for IDH1). This active site mutation results in
loss-of-function for the oxidative decarboxylation of isocitrate
and confers a novel gain-of-function for the production of the
oncometabolite D-2-hydroxyglutarate (2-HG).6 Further charac-
terization of the mutation showed that overexpression of
mutant IDH1 in U87-MG, a human glioblastoma cell line,
resulted in 100-fold elevated levels of 2-HG relative to the same
cells expressing vector alone (data not shown).6 Recently, it
was demonstrated that 2-HG is a competitive inhibitor of
multiple α-KG-dependent dioxygenases, including histone and
In order to identify small molecule inhibitors of IDH1,11,12
we conducted a high-throughput screening (HTS) campaign
against R132H IDH1 mutant protein homodimer. Library
screen followed by confirmation of the active hits provided
phenyl-glycine inhibitor 1. Detailed kinetic mechanism-of-
action studies showed compound 1 binding to be reversible and
behaving as competitive inhibitor with respect to α-KG and
uncompetitive with respect to NADPH (data not shown).
Given its attractive chemical structure and well-defined
inhibitory properties, we selected this compound as a starting
point for further optimization.
Received: August 3, 2012
Accepted: September 1, 2012
© XXXX American Chemical Society
A
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ACS Medicinal Chemistry Letters
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Figure 1. HTS hit 1 and phenyl-glycine scaffold synthesis.
Figure 2. Key structural elements that influence the binding affinity of the phenyl-glycine scaffold.
Table 1. C-Terminus R1 SAR
a
The IC50 values for the R132H homodimer are the mean of at least two determinations performed as described in the Supporting Information.
We report herein that optimization of 1 led to the
identification of 35, the first reported R132H IDH1 inhibitor
to show robust in vivo reduction of 2-HG levels in a tumor
xenograft model.
The phenyl-glycine scaffold was readily assembled via four
component Ugi reaction,13 as depicted retrosynthetically in
Figure 1. Compound 1 was synthesized using cyclopentyl
isocyanide, o-methyl benzaldehyde, m-fluoroaniline, and (2-
thiophen-2-yl) acetic acid as starting materials. If 2-chloroacetic
acid is used for the Ugi acid component, intermediate 2 (R4 =
Cl) is readily obtained and can be used for further
functionalization at R4 through nucleophilic displacement of
the chlorine.
protein (Figure 2). The molecule displays mostly hydrophobic
features, with three aromatic rings positioned around two
amide carbonyl groups, with a rather high clogP (5.6). Starting
from a closely related analog 3 (IC50 = 0.08 μM), we first
initiated a substitution pattern investigation of the phenyl-
glycine backbone. The eutomer/distomer relationship of the α-
carbon stereocenter was established by chiral synthesis of
analog 3 starting from D-and L-mandelic acid,14 which provided
4 (S) and 5 (R) enantiomers, respectively, with compound 4
(IC50 = 0.06 μM) possessing essentially all of the activity found
in the racemate. The enantiospecificity of this enzyme
inhibition held true in many analogs subsequently investigated
(data not shown).
Upon identification of 1 as a screening hit, we set out to
understand the key structural elements that were responsible
for the binding affinity of this compound to the R132H IDH1
For rapid exploration of structure−activity relationships
(SARs), all subsequent compounds were profiled in their
racemic form. Geminal substitution at the α-carbon as depicted
B
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Table 2. N-Terminus R4 SAR
a
The IC50 values for R132H homodimer are the mean of at least two determinations performed as described in the Supporting Information.
for 6 incurred an 18-fold potency loss compared to the case of
3. Next, alkylation of the secondary amide nitrogen as shown
for 7 caused a 45-fold loss in potency compared to the case of
3, while replacement of either the C-terminus or N-terminus
carbonyl groups (compounds 8 and 9) with a CH2 moiety
resulted in significant loss of biochemical activity, highlighting
the importance of both amide moieties for binding affinity.
We then started a systematic investigation of SAR for the N-
and C-terminus regions of the scaffold, as well as the central
aromatic moieties, with a key objective to improve properties,
including decreasing the lipophilicity of the initial hit 1, while
improving biochemical potency.
R1 functional group exploration (Table 1) revealed that
carbocycles were well tolerated, with cyclohexyl 10 slightly
better (IC50 = 0.05 μM) than the starting HTS hit 1. As the
C
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Table 3. Selectivity and Cell Based Profiling of Potent Phenyl-Glycine Analogs
R132H
IC50(μM)
U87
IC50 (μM)
U87
GI50 (μM)
R132C
IC50 (μM)
HT1080
IC50 (μM)
HT1080
GI50 (μM)
IDH1wt
b
a
a
compd
cLogP
IC50 (μM)
1
5.6
6.2
4.9
5.0
6.5
4.7
6.3
7.1
0.09
0.05
0.10
0.05
0.06
0.07
0.08
0.07
0.58
0.19
0.29
0.21
0.36
0.07
0.24
0.37
>20
>20
>20
>20
>20
>20
>20
>20
0.05
0.03
0.06
0.05
0.03
0.16
0.04
0.04
0.39
0.15
0.22
0.26
0.09
0.48
0.11
0.17
>20
>20
>20
>20
>3
7.7 (32%)
2.9 (22%)
19.7 (32%)
19.3 (34%)
6.3 (39%)
>100
10
18
19
20
35
36
37
>20
>20
>20
>100
>100
a
The IC50 values for R132H and R132C and wt homodimers are the mean of at least two determinations performed as described in the Supporting
b
Information. For compounds with less than 100% enzyme inhibition, the maximum inhibition achieved is shown.
Figure 3. Tumor 2-HG inhibition following one and three BID doses of 150 mg/kg of 35 via IP route in the U87 R132H tumor xenograft model.
ring size decreased from cyclohexyl 10 to cyclopropyl 13,
potency decreased gradually to low micromolar values.
Replacement of cyclohexyl with aromatic rings (o-tolyl, benzyl)
as shown for 14 and 15 led to a 10−30-fold decrease in
biochemical potency compared to the case of 10. In an attempt
to improve the properties of these compounds by decreasing
the clogP through heteroatom substitution in the cyclohexyl
ring, we found that pyran 16 was 10-fold less potent than 10,
while piperidine 17 suffered a nearly 100-fold loss of
biochemical potency.
Replacement of thiophene in compound 1 by other carbon-
linked heterocycles, such as thiazole 18, 4-pyridyl 19, or 3-
indole 20 analogs, provided similar biochemical potency to 1 in
the 0.05−0.1 μM range. Modification of the pyridine 19 to
pyrimidine 21 caused a 22-fold drop in potency. Our
investigation next focused on nitrogen linked systems directly
prepared from intermediate 2 (R4 = Cl) via chlorine
displacement (Figure 1). Replacement of chlorine in compound
22 with amino group in analog 23 caused a potency drop from
0.9 to 7.8 μM. A small set of cycloalkyl amines with an
adjustment of ring size led to diminishing biochemical potency
from cyclopropyl 24 (0.19 μM) to cyclohexyl 26 (1.27 μM).
Interestingly, when the cyclohexyl group in 26 was replaced by
a phenyl ring in compound 27, biochemical potency was
substantially enhanced from 1.27 μM to 0.06 μM. Alkylation of
the aniline nitrogen as shown in analog 28 maintained the
potency at 0.05 μM. Use of aromatic rings for R4 did improve
the potency compared to the aliphatic analogs (24−26);
however, clogP increased as well, retaining their highly
hydrophobic character. Encouraged by the good potency of
aromatic tertiary amine 28, we next tested a small set of tertiary
aliphatic amines, with the aim of decreasing the lipophilicity of
the scaffold by introduction of basic solubilizing groups. Among
the examples that were evaluated, morpholine 30 displayed the
best biochemical potency (0.24 μM), while pyrrolidine 29 and
piperazine 31 afforded weakly active single digit micromolar
analogs. Addition of a fused phenyl ring to pyrrolidine as shown
in 32 improved the potency by 10-fold at the expense of an
Evaluation of R2 substituents revealed that for the α-aromatic
ring ortho-substitution was most favored, while replacement of
the phenyl group with heterocycles or carbocycles afforded only
low micromolar potency analogs.14 A preliminary survey of R3
pointed to meta-substituted aromatic groups being most
favorable, while aliphatic moieties, acyclic or cyclic, or
heteroatom containing carbocycles provided analogs with a
significant drop in biochemical potency.14 These observations
coupled with the C-terminus amide SAR results shown in Table
1 suggested that the phenyl-glycine scaffold was binding in a
highly lipophilic region of the enzyme.
Having elucidated SAR on three areas of the scaffold, we
continued our exploration on the N-terminus R4 substituents in
an additional approach to improve the compound physical
chemical properties and decrease the overall lipophilicity of the
original hit. Synthetic chemistry readily amenable to parallel
arrays allowed us to rapidly explore a variety of functional
groups at the N-terminus (Table 2).
D
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increased clogP value. We then continued exploration of
nitrogen heterocycles from intermediate 2. Replacing the
pyrrolidine ring in compound 29 with pyrazole 33 improved
biochemical potency by 4-fold, while triazole 34 offered a slight
improvement in binding affinity. Gratifyingly, N-(2-methyl)-
imidazole 35 restored the biochemical potency to 0.07 μM,
while fused nitrogen linked heterocycles (benzimidazole 26,
indole 37) maintained the same potency at the expense of
increased clogP values. Overall, R4-substitution allowed
introduction of a diverse set of substituents that were well
tolerated, possibly indicating that this part of the phenyl glycine
scaffold may be binding in a solvent exposed area of the
protein.
As the SAR investigation revealed functional group
modifications that provided potent inhibitors in the R132H
enzymatic assay, we selected a focused set of analogs for
evaluation against R132C IDH1 mutant15 and wild-type IDH1
enzymes. Additionally, compounds were profiled in the
glioblastoma U87 cells that overexpress mutant R132H
IDH1, as well as the HT1080 chondrosarcoma cell line,
which expresses the endogenous R132C IDH1 mutant.16 These
cell lines produce significant levels of 2-HG compared to vector
cells alone. Upon treatment with inhibitor for 48 h, the levels of
2-HG were measured in the media by LCMS, to generate IC50
values.14 Within the same experiment, 50% growth inhibition
(GI50) was determined by measuring total cellular ATP after 72
h of compound treatment.
IC50) while the Cmax of 35 was similar following single and BID
dosing. Better tumor 2-HG inhibition was achieved following
BID dosing compared to a single dose, where the maximum
tumor 2-HG inhibition was 89.4% and 69%, respectively. These
results demonstrated that tumor 2-HG inhibition correlated
with the duration of drug exposure and that robust tumor 2-HG
inhibition is achievable with adequate and sustainable drug
exposure.
In conclusion, we have discovered the first class of potent
IDH1 mutant inhibitors through optimization of HTS hits.
Compound 35 is a potent inhibitor of 2-HG production in U87
R132H cells and shows ∼90% tumor 2-HG inhibition in vivo
following three BID doses. As high levels of 2-HG have been
shown to alter the epigenetic state and biology of cells,9,10,17 the
utility of this molecule will be important to assess the biological
consequences of IDH mutations and the potential of IDH
inhibitors for treating IDH mutant tumors.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures for assay protocols, in vivo studies,
and synthesis and characterization of compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*Tel: (617) 649-8604. Fax: (617) 649-8618. E-mail: janeta.
popovici-muller@agios.com.
As shown in Table 3, the majority of compounds showed
similar biochemical potency against the R132C IDH1 mutant
and displayed cellular IC50 values less than 0.5 μM in both U87
and HT1080 cell lines, with a 3−5-fold shift in enzyme to cell
potency in most cases. Exquisite selectivity for R132H and
R132C IDH1 mutant isoforms was demonstrated by the poor
biochemical activity against the wild-type IDH1 and the lack of
induction of nonspecific cell death (GI50 > 20 μM).
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Dr. Nageshwara Rao KV and Dr. Sarma BVNBS at
SAI Advantium for their contribution to the synthesis of
compound 8.
Compound 35, equipotent in both enzyme R132H and U87
cellular assays, was selected for additional in vivo profiling in the
U87 R132H tumor xenograft mouse model (Figure 3). In vitro
and in vivo DMPK studies were conducted for compound 35.
This analog showed rapid turnover in human and rat
microsomal incubations with an estimated hepatic extraction
ratio of 0.93 and 0.85, respectively. Plasma protein binding was
95.7% in mouse using the equilibrium dialysis method.
Reasonable plasma exposure was achieved via intraperitoneal
dosing at 50 mg/kg (AUC0−24h = 20800 h·ng/mL), enabling
the use of inhibitor 35 for further in vivo studies. Female nude
mice bearing U87 R132H tumor xenografts14 were dosed via IP
route with 150 mg/kg of 35 formulated in 0.5% MC and 0.2%
Tween 80, and then they were compared to the vehicle control
animals. Blood and tumor samples were taken at different time
points following compound administration. The plasma and
tumor concentrations of inhibitor 35, as well as the
corresponding tumor 2-HG concentrations were determined
using sensitive and specific LC/MS/MS methods. The
unbound plasma concentration of 35 was calculated using the
total plasma concentration of 35 and free fraction of 35 in
mouse plasma (4.3%).
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