Discovery of AG-120 (Ivosidenib): A First-in-Class Mutant IDH1 Inhibitor for the Treatment of IDH1 Mutant Cancers

Article abstract of DOI:10.1021/acsmedchemlett.7b00421

Somatic point mutations at a key arginine residue (R132) within the active site of the metabolic enzyme isocitrate dehydrogenase 1 (IDH1) confer a novel gain of function in cancer cells, resulting in the production of d-2-hydroxyglutarate (2-HG), an oncometabolite. Elevated 2-HG levels are implicated in epigenetic alterations and impaired cellular differentiation. IDH1 mutations have been described in an array of hematologic malignancies and solid tumors. Here, we report the discovery of AG-120 (ivosidenib), an inhibitor of the IDH1 mutant enzyme that exhibits profound 2-HG lowering in tumor models and the ability to effect differentiation of primary patient AML samples ex vivo. Preliminary data from phase 1 clinical trials enrolling patients with cancers harboring an IDH1 mutation indicate that AG-120 has an acceptable safety profile and clinical activity.

Full text of DOI:10.1021/acsmedchemlett.7b00421

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Letter
Discovery of AG-120 (Ivosidenib): A First-in-Class Mutant
IDH1 Inhibitor for the Treatment of IDH1-Mutant Cancers
Janeta Popovici-Muller, René M. Lemieux, Erin Artin, Jeffrey O. Saunders, Francesco G. Salituro,
Jeremy Travins, Giovanni Cianchetta, Zhenwei Cai, Ding Zhou, Dawei Cui, Ping Chen, Kimberly
Straley, Erica Tobin, Fang Wang, Muriel D. David, Virginie Penard-Lacronique, Cyril Quivoron,
Véronique Saada, Stéphane de Botton, Stefan Gross, Lenny Dang, Hua Yang, Luke Utley, Yue
Chen, Hyeryun Kim, Shengfang Jin, Zhiwei Gu, Gui Yao, Zhiyong Luo, Xiaobing Lv, Cheng Fang,
Liping Yan, Andrew Olaharski, Lee Silverman, Scott Biller, Shin-San M. Su, and Katharine E. Yen
ACS Med. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/acsmedchemlett.7b00421 • Publication Date (Web): 19 Jan 2018
Downloaded from http://pubs.acs.org on January 20, 2018
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Discovery of AG-120 (Ivosidenib): A First-in-Class Mutant IDH1 In-
hibitor for the Treatment of IDH1-Mutant Cancers
Janeta PopoviciꢀMuller,†,‡ René M. Lemieux,†,§ Erin Artin,†,§ Jeffrey O. Saunders,†,ǁ Francesco G.
Salituro,†,▲ Jeremy Travins,†,□ Giovanni Cianchetta,† Zhenwei Cai,≡ Ding Zhou,≡,◊ Dawei Cui,≡ Ping
Chen,≡ Kimberly Straley,†,∞ Erica Tobin,†,§ Fang Wang,† Muriel D. David,• Virginie Penardꢀ
Lacronique,• Cyril Quivoron,• Véronique Saada,• Stéphane de Botton,• Stefan Gross,† Lenny Dang,† Hua
Yang,† Luke Utley,†,∩ Yue Chen,† Hyeryun Kim,† Shengfang Jin,† Zhiwei Gu,« Gui Yao,« Zhiyong
Luo,« Xiaobing Lv,« Cheng Fang,« Liping Yan,« Andrew Olaharski,†,+ Lee Silverman,† Scott Biller,†
ShinꢀSan M. Su,†,‡ and Katharine Yen†,*
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†Agios Pharmaceuticals Inc., Cambridge, Massachusetts 02139, United States
≡PharmaResources, Shanghai 201201, China
«ChemPartner, Shanghai 201203, China
•INSERM U1170 and Gustave Roussy, Villejuif 94800, France
KEYWORDS Isocitrate dehydrogenase; mutant IDH1; AG-120; ivosidenib; differentiation therapy; 2-hydroxyglutarate
ABSTRACT: Somatic point mutations at a key arginine residue (R132) within the active site of the metabolic enzyme isocitrate
dehydrogenase 1 (IDH1) confer a novel gain of function in cancer cells, resulting in the production of Dꢀ2ꢀhydroxyglutarate (2ꢀ
HG), an oncometabolite. Elevated 2ꢀHG levels are implicated in epigenetic alterations and impaired cellular differentiation. IDH1
mutations have been described in an array of hematologic malignancies and solid tumors. Here, we report the discovery of AGꢀ120
(ivosidenib), an inhibitor of the IDH1 mutant enzyme that exhibits profound 2ꢀHG lowering in tumor models and the ability to efꢀ
fect differentiation of primary patient AML samples ex vivo. Preliminary data from phase 1 clinical trials enrolling patients with
cancers harboring an IDH1 mutation indicate that AGꢀ120 has an acceptable safety profile and clinical activity.
Point mutations in isocitrate dehydrogenase (IDH) 1 and 2
are found in multiple tumors, including glioma, cholangiocarꢀ
cinoma, chondrosarcoma, and acute myeloid leukemia
(AML).1 Mutant IDH (mIDH) enzymes have a gainꢀofꢀ
function activity that results in accumulation of the onꢀ
cometabolite Dꢀ2ꢀhydroxyglutatrate (2ꢀHG),2 which is strucꢀ
turally similar to alphaꢀketoglutarate (αꢀKG). 2ꢀHG competiꢀ
tively inhibits αꢀKGꢀdependent dioxygenases, which particiꢀ
pate in many cellular processes such as histone and DNA deꢀ
methylation, and adaption to hypoxia, and their inhibition
leads to a block in normal cellular differentiation and oncoꢀ
genic transformation.1, 3ꢀ5
properties of AGIꢀ5198 precluded its use in clinical studies.
Although several additional mIDH1 inhibitors have been disꢀ
closed,1, 10ꢀ11 AGꢀ120 is the first inhibitor of the mIDH1 enꢀ
zyme to achieve clinical proof of concept in human trials.
Lead optimization of AGIꢀ5198 leading to the discovery of
AGꢀ120 is described here. The mIDH1ꢀR132H enzyme was
utilized for primary biochemical evaluation. Routine profiling
in cells was done in the HT1080 chondrosarcoma cell line,
which endogenously expresses mIDH1ꢀR132C, and in our
experience the potency for mIDH1ꢀR132C is very similar to
mIDH1ꢀR132H, as previously reported.9
In vitro profiling of AGIꢀ5198 in kinetic solubility and liver
microsomal assays pointed to reasonable physicoꢀchemical
properties but poor metabolic stability across species. Metaboꢀ
lite identification studies conducted in human liver microsoꢀ
mal S9 fraction revealed extensive NADPHꢀdependent oxidaꢀ
tion of the cyclohexyl (R1) and imidazole ring (R4). The folꢀ
lowing strategies were therefore employed to decrease metaꢀ
bolic clearance (Table 1). At R4, the imidazole ring was reꢀ
placed with moieties that emerged from broad structureꢀ
activity relationship profiling and had similar potency to AGIꢀ
5198, as previously described.9 R1 modifications focused on
blocking metabolism using fluorinated cycloalkyl groups, and
to mitigate any potential oxidative metabolism at R2, the oꢀMe
(X) group was replaced by an oꢀCl group.
mIDH inhibitors represent a novel class of targeted cancer
metabolism therapy that induce differentiation of proliferating
cancer cells. The mIDH2 inhibitor enasidenib, recently apꢀ
proved by the FDA for relapsed/refractory AML, as well as
allꢀtrans retinoic acid for the treatment for acute promyelocytic
leukemia, support the potential of such differentiation theraꢀ
py.6ꢀ8 We previously reported that the prototype mIDH1 inhibꢀ
itor AGIꢀ5198 inhibited both biochemical and cellular producꢀ
tion of 2ꢀHG.9 AGIꢀ5198 showed robust tumor 2ꢀHG inhibiꢀ
tion in an in vivo mIDH1 xenograft model, impaired growth of
mIDH1 glioma cells in vivo, and induced epigenetic alteraꢀ
tions leading to the expression of genes associated with glioꢀ
genic differentiation.5 However, the poor pharmaceutical
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oxidative metabolism. Eliminating oxidative liabilities at R4
1
2
3
4
5
6
7
8
was the next focus. Replacing the methyl carbamate with a
heterocyclic “mimic” gave the pyrimidine analog 4, which
maintained biochemical potency but did not improve metabolꢀ
ic stability. Removal of the pyrimidine ring in 4 in concert
with oxidation of the proline ring at the 2ꢀposition eliminated
nearly all biochemical potency but resulted in much improved
metabolic stability for 5, giving another important insight into
stabilization of oxidative metabolism at R4. Addition of the
pyrimidine ring on the oxidized proline moiety at R4 provided
6, which maintained low metabolic clearance and restored
enzyme potency. Optimization then focused on improving the
biochemical/cellular potency while maintaining low metabolic
clearance.
Table 1. Optimization of microsome stability and potency
leading to AGI-14100
9
c
Cmpd
X
Y
H
R1
R4
Enz. Cell. Eh
IC50 IC50
10
11
12
13
14
15
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60
(nM)a (nM)b
AGIꢀ
Me
70
497
0.93
A scan of heterocycles at R4 revealed that pyridines substiꢀ
tuted with electronꢀwithdrawing groups at the 4ꢀposition could
achieve the desired potency and metabolic stability profile as
shown for 7 and 8. Finally, additional fluorine substitution at
the 5ꢀposition of the R3 aromatic group provided the comꢀ
pound AGIꢀ14100, with a good balance of singleꢀdigit nM
potency in enzyme and cellꢀbased assays and desirable metaꢀ
bolic stability.
5198d
1d
2d
Me
Cl
H
H
46
155
605
0.94
0.45
230
Cl
Cl
H
H
44
34
279
53
0.91
0.93
3
4
To further assess the suitability of AGIꢀ14100 as a potential
development candidate, additional pharmacokinetic (PK)
properties were evaluated. Low clearance in liver microsomal
incubations was observed across species, which was also obꢀ
served in the rat, dog, and cynomolgus monkey in vivo (Table
S1). However, assessment in the human pregnane X receptor
(hPXR) screen indicated that AGIꢀ14100 was potentially a
cytochrome P450 (CYP) 3A4 inducer. hPXR activation by
AGIꢀ14100 was approximately 70% that of rifampicin, a
known strong CYP 3A4 inducer. CYP induction studies using
human hepatocytes confirmed the results (data not shown).
Cl
Cl
H
H
13310 NDe 0.18
5
6
45
40
73
66
0.03
0.15
To mitigate the CYP induction liabilities, further medicinal
chemistry optimization was conducted to eliminate hPXR
activation (Table 2). Since the R1 and R2 substituents require
hydrophobic character to maintain potency, our strategy foꢀ
cused on introducing polarity at R3 and R4 to decrease hPXR
activation12 while maintaining enzymatic and cellular potency,
good metabolic stability, and avoiding efflux that may affect
in vivo clearance.
7
8
Cl
H
Cl
Cl
H
F
9
6
3
1
0.37
0.23
AGIꢀ
14100
Starting from AGIꢀ14100, the introduction of additional poꢀ
larity (hydroxyl group) on the pyrrolidinone ring of R4 in 9
maintained similar potency, somewhat decreased hPXR actiꢀ
vation at 1 µM, but also decreased overall permeability and
increased the efflux ratio. Further increasing the polarity at R4
by transitioning from cyanopyridine to cyanopyrimidine hetꢀ
erocycle in 10 abolished the hPXR activation but led to poor
cellular potency and decreased metabolic stability.
aEnzymatic IC50 values for the mIDH1ꢀR132H homodimer are the
mean of at least two determinations performed as described in the
b
Supporting Information. Cellular IC50 from HT1080 chondrosarꢀ
c
coma cell line. Microsome stability recorded as the hepatic exꢀ
d
e
traction ratio in human liver microsomes. Racemic. Not deterꢀ
mined.
Replacing the R4 imidazole group with glycine carbamate in
1 slightly improved the enzymatic potency but maintained the
same high metabolic clearance. Simultaneously switching the
oꢀMe group on R2 to oꢀCl and the cyclohexyl in R1 to diꢀfluoro
cyclobutyl in 2 incurred only a 5ꢀfold potency loss, but
brought the metabolic stability into the medium clearance
range. Next, replacement of the glycine carbamate group at R4
with proline carbamate (3) restored the biochemical potency
but lost the improvement in the hepatic extraction ratio (Eh). A
metabolite identification study of 3 revealed that monoꢀ and
diꢀoxidation of the proline carbamate moiety were the major
metabolic pathways, allowing us to stabilize the R1 site of
Next, functional group changes at R3 (replacing one of the F
atoms with a sulfonamide group in 11) dramatically increased
the polarity of the molecule, leading to low hPXR activation
values, but coupled with high microsomal clearance and efflux
ratio. Lastly, changing one of the CꢀF bonds at R3 with an N
atom embedded in the ring led to AGꢀ120, with a balance of
desirable properties: good enzyme and cellular potency, good
stability in human liver microsomes, reduced hPXR activation,
good permeability, and low efflux ratio. Synthesis of AGꢀ120
and all related analogs was accomplished as described in
Scheme S1 and the Supporting Information.
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Table 2. Reduction of hPXR activation leading to AG-120
3
4
5
6
7
8
Cmpd
R3
R4
Enz.
IC50
(nM)
Cell. Eh
IC50
(nM)
hPXR actiꢀ Papp[AꢀB] (10ꢀ6
vation, (% cm/s)/Efflux ratiob
of rifampicꢀ
tPSA (Å)c
F
O
R3
N
F
R4
in at 1/10
N
µM)a
H
Cl
O
9
AGIꢀ
14100
6
1
0.23 69/70
14.2/2.3
105.9
10
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12
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9
10
7
1
0.37 21/61
1.9/26
ND
126.1
138.5
10
297
0.54 2/10
11
11
12
13
8
0.62 2/3
0.19/129
15/2
166.0
118.2
AGꢀ120
0.15 2/21
aHuman pregnane X receptor activation was determined as the fold activation relative to reference compound (rifampicin). The cell perꢀ
meability coefficient (Papp) was determined in both directions (apical to basolateral [AꢀB] and basolateral to apical [BꢀA]) across the Caꢀ
co2 cell monolayer. The efflux ratio was estimated as Papp[BꢀA]/Papp[AꢀB]. cTotal polar surface area.
b
Biochemical and cell biology profiling revealed that AGꢀ
120 inhibited several IDH1ꢀR132 mutants with potency simiꢀ
lar to that seen for R132H (Table 3), and was highly selective
for IDH1 isoforms, showing no inhibition of IDH2 (WT or
mutant) isoforms at micromolar concentrations (Table S2).
AGꢀ120 at 100 µM did not inhibit multiple dehydrogenases
tested (Table S3).
Table 3. Biochemical and cell biology profiling of AG-120
Assay
type
Mutationa
IC50 (nM)b
Enzyme IDH1ꢀR132H
IDH1ꢀR132C
12
13
8
IDH1ꢀR132G
In vitro, AGꢀ120 exhibited rapidꢀequilibrium inhibition
against the mIDH1ꢀR132 homodimer. Kinetic studies of bindꢀ
ing to demonstrate mode of action were inconclusive due to
persistent preꢀbound NADP(H) in all soluble mIDH1 enzyme
preparations (Supporting Information, Figures S1ꢀS2). Surꢀ
prisingly, AGꢀ120 demonstrated slowꢀtight binding inhibition
against the IDH1ꢀWT homodimer (Figure S3ꢀS4).
IDH1ꢀR132L
13
12
IDH1ꢀR132S
IDH1ꢀR132H/IDH1ꢀWT heterodimer
+ NADP+/NADPH @ 1 h
12
IDH1ꢀR132H/IDH1ꢀWT heterodimer
+ NADP+/NADPH @ 16 h
5
AGꢀ120 also showed good cellular potency across multiple
mIDH1ꢀR132 endogenous and overexpressing cell lines (Taꢀ
ble 3), indicating its potential for use across all mIDH1ꢀR132
cancers. AGꢀ120 has a low turnover rate in liver microsomes
derived from multiple species, including humans. PK studies
performed in SpragueꢀDawley rats, beagle dogs, and cynoꢀ
molgus monkeys showed rapid oral absorption, low total body
plasma clearance (CLp) and moderate to long halfꢀlife (t½)
(Table S4). Although moderate exposure reduction was obꢀ
served in a repeatꢀdose study in rodents (data not shown), no
exposure reduction occurred in cynomolgus monkeys, and in
patients with cancer a long t½ and accumulation of AGꢀ120
following multiple doses were observed.13ꢀ14
IDH1ꢀWT + NADP+ @ 1h
71
24
IDH1ꢀWT + NADP+
@ 16h
Cellꢀ
based
U87 MG (R132H)
19
3
Neurospheres (R132H)
HT1080 (R132C)
8
CORꢀL105 (R132C)
HCCCꢀ9810 (R132S)
15
12
aAll cell lines described here express mIDH1 endogenously, exꢀ
cept U87 MG, which is an overexpression system. For activity
against enzyme, the enzyme and compound were preꢀincubated
for 1 h or 16 h either in the presence or absence of cofactor as
described in the Supporting Information.
b
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Following a single oral dose of 50 mg/kg to rats with an inꢀ
1
2
3
4
5
6
7
tact bloodꢀbrain barrier, AGꢀ120 exhibited brain penetration of
4.1% (AUC0ꢀ8h [brain]/AUC0ꢀ8h [plasma]). However, brain
penetration is likely to be higher in glioma patients who have a
compromised bloodꢀbrain barrier. Given that AGꢀ120 is very
potent and well tolerated, it has the potential to achieve theraꢀ
peutic concentration in the brain, and its therapeutic benefit in
glioma is being evaluated in clinical trials.
AGꢀ120 showed robust tumor 2ꢀHG reduction in female
nude BALB/c mice inoculated with HT1080 cells. Each
mouse received a single oral dose of vehicle or AGꢀ120 at 50
or 150 mg/kg by gavage. Tumor 2ꢀHG concentration declined
rapidly, with maximum inhibition (92.0% and 95.2% at the 50
mg/kg and 150 mg/kg doses, respectively) achieved at ~12
hours post dose. Tumor 2ꢀHG concentrations approached
baseline levels 48 to 72 hours following a single dose of AGꢀ
120 (Figure 1), consistent with the reversible nature of AGꢀ
120 inhibition.
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Figure 2. Percent intracellular 2ꢀHG remaining relative to DMSO
control after 6 days’ treatment with AGꢀ120 in mIDH1ꢀR132H or
mIDH1ꢀR132C patient samples (mean ± SEM from cells from
four patients with mIDH1 AML).
The discovery of enasidenib, which is active against
mIDH2, and now ivosidenib against mIDH1 as described here,
presents a novel class of cancer therapy based on cellular difꢀ
ferentiation. AGꢀ120 is a potent mIDH1 inhibitor with favoraꢀ
ble nonꢀclinical and clinical safety profiles that has shown
promising clinical activity in phase 1 clinical trials for both
solid and hematologic malignancies. In patients with reꢀ
lapsed/refractory mIDH1 AML, interim results from the ongoꢀ
ing phase 1 trial have demonstrated an overall response rate of
42% and a complete response rate of 22% (median duration of
complete response 9.3 months).15 Longꢀterm stable disease has
been observed in patients with previously treated nonꢀ
enhancing mIDH1 gliomas,16 and in heavily pretreated patients
with mIDH1 cholangiocarcinoma, where the median progresꢀ
sionꢀfree survival was 3.8 months and the 6ꢀmonth progresꢀ
sionꢀfree survival rate was 40%.17 In these two single arm,
phase 1 studies, AGꢀ120 has demonstrated an acceptable safeꢀ
ty profile to date.16ꢀ18 AGꢀ120 is currently in lateꢀstage clinical
development in adults with mIDH1 AML (ClinicalTrials.gov
NCT03173248), and with previously treated advanced mIDH1
cholangiocarcinoma (NCT02989857).
Figure 1. Mean ± SD concentrations of AGꢀ120 in plasma and 2ꢀ
HG in tumor after single oral administration of AGꢀ120 at 50 or
150 mg/kg in a mouse HT1080 xenograft tumor model (n = 3 at
each time point).
IDH mutations have been shown to block normal cellular
differentiation via epigenetic and metabolic rewiring.1, 3ꢀ5 To
determine the effect of mIDH1 inhibition in primary human
AML blast cells, mIDH1ꢀR132H, mIDH1ꢀR132C, and IDH1ꢀ
WT, bone marrow or peripheral blood samples from patients
(Table S5) were treated with AGꢀ120 in an ex vivo assay. Livꢀ
ing blast cells were sorted and cultured in medium containing
cytokines (at a density of 0.5×106 cells/mL) in the presence or
absence of AGꢀ120. In mIDH1 samples, AGꢀ120 reduced the
level of intracellular 2ꢀHG by 96% at the lowest tested dose
(0.5 ꢁM) and by 98.6% and 99.7%, respectively, at 1 and
5 ꢁM (Figure 2). 2ꢀHG was not measurable in multiple IDH1ꢀ
WT patient samples assessed. AGꢀ120 induced differentiation
of primary mIDH1ꢀR132H and mIDH1ꢀR132C (but not IDH1ꢀ
WT) blast cells from patients with AML treated ex vivo, as
shown by enhanced ability to form differentiated colonies in
methylcellulose assays, increased levels of cellꢀsurface markꢀ
ers of differentiation, and increases in the proportion of mature
myeloid cells (Figure S5).
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: XXX.
Synthesis and profiling of AGꢀ120, experimental procedures,
synthetic details and characterization of compounds, and abbreviꢀ
ations (PDF)
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: katharine.yen@agios.com
Present Addresses
‡Decibel Therapeutics, Cambridge, Massachusetts, United States;
§KSQ Therapeutics, Cambridge, Massachusetts, United States;
ǁJOSC LLC Consulting, Lincoln, Massachusetts, United States;
▲Sage Therapeutics, Cambridge, Massachusetts, United States
□Shire, Lexington, Massachusetts, United States; ◊GSK R&D
Shanghai, Shanghai, China; ∞Vertex Pharmaceuticals, Boston,
Massachusetts, United States; ∩Spero Therapeutics, Cambridge,
Massachusetts, United States; +Akebia Therapeutics, Cambridge,
Massachusetts, United States.
Together, these compelling preclinical data provided the raꢀ
tionale to advance AGꢀ120 (ivosidenib) into clinical developꢀ
ment.
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(6) Stein, E. M.; DiNardo, C. D.; Pollyea, D. A.; Fathi, A. T.; Roboz,
G. J.; Altman, J. K.; Stone, R. M.; DeAngelo, D. J.; Levine, R. L.;
Flinn, I. W.; Kantarjian, H. M.; Collins, R.; Patel, M. R.; Frankel, A.
E.; Stein, A.; Sekeres, M. A.; Swords, R. T.; Medeiros, B. C.;
Willekens, C.; Vyas, P.; Tosolini, A.; Xu, Q.; Knight, R. D.; Yen, K.
E.; Agresta, S.; de Botton, S.; Tallman, M. S. Enasidenib in Mutant
IDH2 Relapsed or Refractory Acute Myeloid Leukemia. Blood 2017,
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(7) Stein, E. M.; Yen, K. Targeted Differentiation Therapy with
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M.; Yan, S.; Zhao, F.; Gross, S.; Dang, L.; Yen, K. E.; Yang, H.;
Straley, K. S.; Jin, S.; Kunii, K.; Fantin, V. R.; Zhang, S.; Pan, Q.;
Shi, D.; Biller, S. A.; Su, S. M. Discovery of the First Potent
Inhibitors of Mutant IDH1 That Lower Tumor 2ꢀHG in Vivo. ACS
Med. Chem. Lett. 2012, 3 (10), 850ꢀ855.
(10) Pusch, S.; Krausert, S.; Fischer, V.; Balss, J.; Ott, M.; Schrimpf,
D.; Capper, D.; Sahm, F.; Eisel, J.; Beck, A. C.; Jugold, M.;
Eichwald, V.; Kaulfuss, S.; Panknin, O.; Rehwinkel, H.;
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Author Contributions
The manuscript was written through contributions of all authors.
All authors have given approval to the final version of the manuꢀ
script.
Funding Sources
These studies were funded by Agios Pharmaceuticals Inc., the
French National Institute of Health (INSERMꢀAVIESAN; to
M.D. David and V. PenardꢀLacronique), French National Cancer
League (LNCC), the Institut National du Cancer (INCaꢀDGOSꢀ
Inserm_6043 and INCa 2012ꢀ1ꢀRTꢀ 09), and the Fondation Assoꢀ
ciation pour la Recherche sur le Cancer (ARC, SL220130607089
Programme Labellisé to V. PenardꢀLacronique and S. de Botton).
M.D. David was funded by a fellowship from the Institut National
du Cancer (INCaꢀDGOS_5733).
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Conflict of Interest Disclosure
MDD: Agios, Celgene ꢀ travel expenses. VPꢀL: Celgene ꢀ travel
expenses. SdB: Agios ꢀ advisory board, research funding, travel
expenses; Celgene ꢀ advisory board member, research funding,
travel expenses; SSMS: Agios ꢀ consultancy.
ACKNOWLEDGMENTS
Writing assistance was provided by Christine Ingleby, PhD, of
Excel Scientific Solutions, Horsham, UK, and supported by Agios
Pharmaceuticals, Inc. The authors thank JeanꢀBaptiste Micol and
Christophe Willekens for clinical specimens, Nathalie Auger for
cytogenetic analyses, and Zenon Konteatis for insightful discusꢀ
sions during the optimization of hPXR activation.
(11) Cho, Y. S.; Levell, J. R.; Liu, G.; Caferro, T.; Sutton, J.; Shafer,
C. M.; Costales, A.; Manning, J. R.; Zhao, Q.; Sendzik, M.; Shultz,
M.; Chenail, G.; Dooley, J.; Villalba, B.; Farsidjani, A.; Chen, J.;
Kulathila, R.; Xie, X.; Dodd, S.; Gould, T.; Liang, G.; Heimbach, T.;
Slocum, K.; Firestone, B.; Pu, M.; Pagliarini, R.; Growney, J. D.
Discovery and Evaluation of Clinical Candidate IDH305, a Brain
Penetrant Mutant IDH1 Inhibitor. ACS Med Chem Lett 2017, 8 (10),
1116ꢀ1121.
(12) Gao, Y. D.; Olson, S. H.; Balkovec, J. M.; Zhu, Y.; Royo, I.;
Yabut, J.; Evers, R.; Tan, E. Y.; Tang, W.; Hartley, D. P.; Mosley, R.
T. Attenuating Pregnane X Receptor (PXR) Activation: A Molecular
Modelling Approach. Xenobiotica 2007, 37 (2), 124ꢀ138.
ABBREVIATIONS
Provided in the Supporting Information.
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Discovery of AG-120 (Ivosidenib): A First-in-Class Mutant IDH1 Inhibitor for the
Treatment of IDH1-Mutant Cancers
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Janeta Popovici-Muller, René M. Lemieux, Erin Artin, Jeffrey O. Saunders, Francesco G.
Salituro, Jeremy Travins, Giovanni Cianchetta, Zhenwei Cai, Ding Zhou, Dawei Cui, Ping Chen,
Kimberly Straley, Erica Tobin, Fang Wang, Muriel D. David, Virginie Penard-Lacronique, Cyril
Quivoron, Véronique Saada, Stéphane de Botton, Stefan Gross, Lenny Dang, Hua Yang, Luke
Utley, Yue Chen, Hyeryun Kim, Shengfang Jin, Zhiwei Gu, Gui Yao, Zhiyong Luo, Xiaobing
Lv, Cheng Fang, Liping Yan, Andrew Olaharski, Lee Silverman, Scott Biller, Shin-San M. Su
and Katharine Yen
Block in cellular
differentiation,
oncogenesis
AG-120
2-HG
2-HG
2-HG
2-HG
Mutant
IDH
Restoration of cell
differentiation
ability
2-HG
a-KG
Isocitrate
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