Discovery and Evaluation of Clinical Candidate IDH305, a Brain Penetrant Mutant IDH1 Inhibitor

Article abstract of DOI:10.1021/acsmedchemlett.7b00342

Inhibition of mutant IDH1 is being evaluated clinically as a promising treatment option for various cancers with hotspot mutation at Arg¹³². Having identified an allosteric, induced pocket of IDH1^R132H, we have explored 3-pyrimidin-4-yl-oxazolidin-2-ones as mutant IDH1 inhibitors for in vivo modulation of 2-HG production and potential brain penetration. We report here optimization efforts toward the identification of clinical candidate IDH305 (13), a potent and selective mutant IDH1 inhibitor that has demonstrated brain exposure in rodents. Preclinical characterization of this compound exhibited in vivo correlation of 2-HG reduction and efficacy in a patient-derived IDH1 mutant xenograft tumor model. IDH305 (13) has progressed into human clinical trials for the treatment of cancers with IDH1 mutation.

Full text of DOI:10.1021/acsmedchemlett.7b00342

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Letter
Discovery and Evaluation of Clinical Candidate
IDH305, a Brain Penetrant Mutant IDH1 Inhibitor
Young Shin Cho, Julian Levell, Gang Liu, Thomas Caferro, James Sutton, Cynthia M. Shafer, Abran Costales,
James R Manning, Qian Zhao, Martin Sendzik, Michael David Shultz, Gregg Chenail, Julia Dooley, Brian
Villalba, Ali Farsidjani, Jinyun Chen, Raviraj Kulathila, Xiaoling Xie, Stephanie Dodd, Ty Gould, Guiqing Liang,
Tycho Heimbach, Kelly Slocum, Brant Firestone, Minying Pu, Raymond Pagliarini, and Joseph D. Growney
ACS Med. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/acsmedchemlett.7b00342 • Publication Date (Web): 18 Sep 2017
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Discovery and Evaluation of Clinical Candidate IDH305, a Brain
Penetrant Mutant IDH1 Inhibitor
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Young Shin Cho,* Julian R. Levell, Gang Liu, Thomas Caferro, James Sutton, Cynthia M. Shafer,
Abran Costales, James R. Manning, Qian Zhao, Martin Sendzik, Michael Shultz, Gregg Chenail,
Julia Dooley, Brian Villalba, Ali Farsidjani, Jinyun Chen, Raviraj Kulathila, Xiaoling Xie, Stepha-
nie Dodd, Ty Gould, Guiqing Liang, Tycho Heimbach, Kelly Slocum, Brant Firestone, Minying
Pu, Raymond Pagliarini and Joseph D. Growney*
Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139
KEYWORDS mutant IDH1, inhibition of 2-HG production, in vivo anticancer activity, brain penetration, clinical can-
didate
ABSTRACT: Inhibition of mutant IDH1 is being evaluated clinically as a promising treatment option for various cancers
with hotspot mutation at Arg132. Having identified an allosteric, induced pocket of IDH1R132H, we have explored 3-
pyrimidin-4-yl-oxazolidin-2-ones as mutant IDH1 inhibitors for in vivo modulation of 2-HG production and potential
brain penetration. We report here optimization efforts towards the identification of clinical candidate IDH305 (13), a po-
tent and selective mutant IDH1 inhibitor which has demonstrated brain exposure in rodents. Preclinical characterization
of this compound exhibited in vivo correlation of 2-HG reduction and efficacy in a patient-derived IDH1 mutant xenograft
tumor model. IDH305 (13) has progressed into human clinical trials for the treatment of cancers with IDH1 mutation.
Isocitrate dehydrogenase 1 (IDH1) is a NADP+, metal
97/98/98%), and poor solubility (39 ꢀM at pH 6.8) which
we anticipated to entail very high human efficacious dose
dependent oxidoreductase active in cellular metabolism.1-5
Wild-type IDH1 catalyzes the oxidative decarboxylation of
isocitrate to give α-ketoglutarate (α-KG), while NADP+ is
converted to NADPH. Heterozygous mutations in IDH1 at
Arg132 have been tightly linked to various cancers includ-
ing glioma, glioblastoma, AML, chondrosarcoma, and
cholangiocarcinoma.6-9 This gain-of-function mutation
reduces α-KG to R-2-hydroxyglutarate (2-HG) resulting in
significantly elevated levels of this metabolite.10 Recently,
both preclinical11-17 and clinical18-19 inhibition of mutant
IDH1 have shown efficacy in various cancers, potentially
offering a new treatment option to many patients with
IDH1 mutation.
(>10 g BID). These considerable challenges to clinical de-
velopment required additional optimization to identify a
viable clinical candidate. Efforts focused on maintaining
mutant IDH1 potency while optimizing the overall in vitro
profile and subsequent translation to in vivo activity. The
high unmet medical needs for glioma and glioblastoma
patients justified additional selection criteria to identify
inhibitors with potentially efficacious brain exposure.
Initial modifications were focused on the amine
sidechain. It was rationalized that increased polarity may
reduce the brain penetration observed with 1,20 whereas
reduction of the polarity would increase the lipophilicity,
resulting in increased clearance and higher predicted
dose for efficacy. Concomitant maintenance of the opti-
mized biaryl system of 120 necessitated either retaining 2
nitrogens in the first aryl ring and none in the second, or
transposing one nitrogen from the pyrimidine ring to the
second ring to give a bipyridyl moiety. Pyrazine 2 was
Previously, we have reported hit-to-lead optimization
efforts to identify a mutant specific inhibitor of IDH1.20
Compound 1 (IDH889) was shown to bind to an alloster-
ic, induced-fit pocket of IDH1R132H with potent inhibition
of 2-HG production as well as selectivity over the wild-
type protein. Oral dosing of 1 in a mouse xenograft model
demonstrated robust in vivo reduction of 2-HG tumor
tissue levels in engineered HCT116 colon carcinoma cells
expressing mutant IDH1R132H. While 1 is a potent and se-
lective inhibitor that modulates 2-HG in xenograft mod-
els, it showed relatively high in vitro intrinsic clearance
(Clint) across different species (rat/mouse/dog/human Clint
588/143/548/205 ꢀl min-1 mg-1), high plasma protein bind-
ing (rat/mouse/human plasma protein binding
identified as
a tolerated replacement for the 2,5-
pyrimidine ring, but this did not attenuate the high Clint
or improve the solubility (<5 ꢀM at pH 6.8). Alternative 6-
membered ring systems containing 2 nitrogens as the
internal aryl ring gave significant loss of potency. The
crystal structure of 120 showed a hydrogen bond between
one of the ortho nitrogens of the pyrimidine to Ser278, so
one ortho nitrogen was maintained in the first pyridine
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(trifluoromethyl)pyridin-4-yl)boronic acid23 and following
ring for subsequent exploration of bipyridyl systems.
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8
While terminal rings without a meta-substituent lost po-
tency, the various 3,2’-, and 3,3’-bipyridyl systems exhibit-
ed increased Clint in rat liver microsomes. On the other
hand, the 3,4’-bipyridine analog 3 lost about 10-fold cellu-
lar potency compared to 1, but showed significant reduc-
tion of Clint in rat and improvement of solubility (430 ꢀM
at pH 6.8). Modifications of the meta-substituent on the
terminal ring were explored to regain the activity. Larger
substituents generally led to improved potency, but also
increased Clint in rat likely due to the increased lipophilic-
ity. For example, the bulky tert-butyl group of 4 increased
both biochemical and cellular potency, however, at the
expense of increased rat Clint. The CF3 group provided the
best balance of potency and in vitro clearance, as shown
with compound 5. Reducing Clint in rat liver microsomes
through this stage of the optimization resulted in ~8 fold
increase of AUC after a single oral dose of 5 in rats at 10
mg/kg when compared to 1 (1.6 ꢀM.h vs. 0.2 ꢀM.h, respec-
tively). Mutant IDH1 inhibitory potency was further
boosted by installation of a methyl at the 2- or 4-position
of the internal pyridine ring (6 and 8, respectively), but
not at the 5-position (7) without significant impact on rat
Clint.
deprotection of the amine to give 20. Coupling of 18 and
20 in DIPEA and DMSO provided 13 in 28% yield.
Table 1. Biochemical, cellular potency and Clint in rat
liver microsomes
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With the best amine sidechain in-hand (8), the C(4)
substituent of the oxazolidinone was evaluated to deter-
mine whether it could be used as a handle to reduce the
clearance further. Truncation of the isopropyl to a methyl
(9) and ethyl (10) reduced rat Clint effectively. However,
this came with a loss of potency compared to the isopro-
pyl 8. Increasing polarity by addition of a hydroxy to 10
resulted in reduced cellular potency without any further
improvement of metabolic stability as shown with 11. Ad-
dition of a fluorine to 9 enhanced potency (12) while
maintaining low in vitro clearance. A further boost in po-
tency was observed with 13 (IDH305). Having previously
established chirality preference on C(4) of the oxazoli-
dinone and the S-amine,20 we examined a C(1’)-R dia-
stereomer (14) and found that 14 lost not only potency in
both biochemical and cellular assays but also rat micro-
somal stability. Overall, 13 demonstrated an improved
balance of mutant IDH1 inhibitory potency, rat in vitro
clearance and solubility (130 ꢀM at pH 6.8) compared to 1.
We also observed lower plasma protein binding of com-
pound 13 (rat/mouse/human 83/88/83%) than that of 1
which we attributed to reduction of logD at pH 7.4 (1: 3.4
vs. 13: 2.8). While similar optimization with 6 also result-
ed in reduced clearance, overall cellular potency of the
analogs was not retained (data not shown).
Cm Biochemical
pd
Cellular HCT116- Rat liver mi-
IDH1R132H+/- IC50 crosomal Clint
IDH1R132H+/+
IC50 (ꢀM)
(ꢀM)
(ꢀl min-1 mg-1)
1
0.020
0.014
0.047
0.145
588
641
68
235
101
141
128
125
36
2
0.062
0.339
0.004
0.077
0.015
0.084
0.013
0.116
3
4
<0.002
0.041
0.013
5
6
7
0.067
0.014
0.258
0.042
0.102
0.069
0.024
0.316
8
9
10
11
12
13
14
0.035
0.033
0.028
0.018
0.073
58
84
27
45
157
Compound 13 was evaluated for specificity against mu-
tant IDH1 relative to wild-type (WT) IDH1 in a biochemi-
cal assay measuring consumption (mutant) or production
(WT) of NADPH.20,21 Compound 13 exhibited greater than
200 fold selectivity for mutant IDH1 isoforms vs. WT
(IDH1R132H IC50: 0.027 ꢀM, IDH1R132C IC50: 0.028 ꢀM, IDH1WT
IC50: 6.14 ꢀM). This potent in vitro biochemical activity
correlated with efficient 2-HG reduction in HCT116-
IDH1R132H+/- cells. Furthermore, in the MCF10A-IDH1R132H+/-
cell line, which depends on IDH1R132H activity for growth
in EGF-depleted conditions,21 2-HG inhibition was corre-
lated with inhibition of EGF-independent proliferation
Synthesis of 13 is described in Scheme 1. Reduction of
methyl ester 15 and cyclization followed by PMB protec-
tion gave oxazolidinone 16 in 96% yield over two steps.
Removal of tert-butyl and conversion of the resulting hy-
droxy into a fluorine using perfluoro-1-butanesulfonyl
fluoride and NEt3(HF)3 provided 17 efficiently.22 Removal
of PMB and subsequent SNAr reaction with 2,4-
difluoropyrimidine yielded 18 in 59% overall yield. Amine
19 was protected with Boc and subjected to palladium-
catalyzed
cross-coupling
reaction
with
(2-
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trajectory as the phenyl-pyrimidine of 1, extending out
with an IC50 0.020 ꢀM (Figure 1). The effects of 13 on pro-
liferation are not due to off-target activity, as 13 had no
effect on the EGF-independent growth of a mutant
PIK3CA-dependent derivative of MCF10A at doses up to 10
µM (maximum dose tested). Compound 13 was not effec-
tive at lowering 2-HG concentration in engineered
HCT116 cells with IDH2 mutation of R172K and R140Q
(IC50 10 ꢀM and 3.8 ꢀM, respectively) demonstrating se-
lectivity against mutant IDH2.
1
2
3
4
5
6
7
8
towards the dimer interface. The regulatory segment
(α10) is folded next to 13, with the sidechain of Ser278 posi-
tioned in the vicinity of the ortho nitrogen of the pyridine
ring, potentially forming a hydrogen bond.
Figure 2. X-ray co-crystal structure of 13 (IDH305) in
IDH1R132H+/+ (PDB 6B0Z)
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Scheme 1. Synthesis of 13 (IDH305)
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13
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(a) TFA, CH2Cl2
r.t. 20 min
79%
O
(a) NaBH4, THF
-25 oC to r.t.
NHCbz
CO2Me
PMBN
O
(b) PFBSF, TEA.(HF)3
TEA, CH3CN
OtBu
(b) NaH, PMBCl
TBAI, DMF
0 oC to r.t., 16 h
OtBu
15
16
0
oC, 1 h, 96%
96% over two steps
O
(a) TFA, 65 o
16 h, 88%
C
N
O
PMBN
O
F
N
N
O
(b) NaH, DMF
2,4-difluoropyrimidine
oC to r.t., 67%
F
F
0
17
18
(a) Boc2O, CH2Cl2
NH2
TEA, r.t., overnight
no purification
NH2
N
N
B(OH)
2
(b) PdCl2(dppf).CH2Cl2,
Na2CO3, dioxane
90 oC, 16 h, 83%
Br
Pharmacokinetic profiling of 13 across multiple species
was performed, including assessment of brain penetrant
exposure (Table 2). Moderate clearance both in vitro and
in vivo was observed in all species examined. In response
to a single 10 mg/kg oral dose in rats, plasma exposure of
13 (AUC 6.2 ꢀM.h) was improved ~30 fold compared to 1.
The brain to plasma (total/unbound) ratio of 13 in mouse
was 0.29/0.17 at 1 hour post oral dosing at 30 mg/kg. Fol-
lowing intravenous administration of 13 at 5 mg/kg in
rats, the brain to plasma exposure ratio was 0.61, suggest-
ing 13 is brain penetrant (AUCbrain 3.4 ꢀM.h vs AUCplasma
5.5 ꢀM.h). High passive permeability of compound 13 in
both an artificial membrane (PAMPA calculated %FA:
99.3%) and a cellular system (Caco-2 Papp(B-A)/(A-B):
23/19) seemed sufficient to limit the impact of the p-
glycoprotein driven efflux mechanism (MDR1-MDCK ef-
flux ratio 4.9) and demonstrate rodent brain exposure.
N
N
CF
3
CF3
19
20
(c) TFA, CH2Cl2, -78 oC to r.t.
1 h, no purification
N
O
HN
N
N
O
DIPEA, DMSO
N
+
18
20
110 oC, 1 h, 28%
F
N
CF3
13 (IDH305)
Figure 1. Cell growth inhibition of MCF10A-IDH1R132H+/- by 13
(IDH305) (Mean ± SD)
Table 2. In vitro and in vivo PK parameters of 13
(IDH305)
PK parameter
In vitro
Mouse
liver 61
Rat
45
Dog Human
28
18
56
14
An X-ray structure of 13 bound to IDH1R132H homodimer
revealed similar interactions as observed with 1 in the
allosteric binding pocket and subsequent stabilization of
the catalytically inactive conformation (Figure 2).20,21 Con-
sistent with 1, the aminopyrimidine moiety forms a pair of
hydrogen bonds with the backbone atoms of Ile128, while
the carbonyl of the oxazolidinone forms a hydrogen bond
with the backbone amide of Leu120, and the alpha-methyl
fits into the methyl nook. Compound 13 demonstrated a
hydrophobic collapse conformation in which the fluoro-
ethyl is in van der Waals contact with the pyridine of the
amine side chain. The bipyridine moiety adopts a similar
microsomal Clint (ꢀl
min-1 mg-1)
in vitro predicted liver 65
microsomal Cl (ml
min-1 kg-1)
33
In vivo plasma clear- 29
34
83
95
24
89
n.d.
83
ance (ml min-1 kg-1)
Plasma protein bind- 88
ing (%)
Brain
homogenate 93
n.d. n.d.
binding (%)
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To determine if the exposure dependent 2-HG reduc-
Brain to plasma ratio 0.29/
0.61/ n.d. n.d.
0.18
tion observed in the mechanistic HCT116-IDH1R132H+/-
model would be similar in an endogenous IDH1R132C or
IDH1R132G mutant tumor model, we evaluated 13 induced
2-HG suppression in two patient derived xenograft (PDX)
melanoma tumor models propagated in nude mice.24 In
the IDH1R132C mutant HMEX2838 PDX model, 13 led to
dose dependent 2-HG inhibition, with greater than 98%
maximal inhibition for 16-20 h following a single 300
mg/kg dose (Figure 4A). Plasma exposures were compa-
rable to those observed in the HCT116-IDH1R132H+/- model
(Table SI-3), with AUC8h of 10.1 ꢀM.h, AUC8h of 71.9 ꢀM.h
and AUC24h of 212 ꢀM.h following doses of 30, 100 and 300
1
2
3
4
5
6
7
8
9
(total/unbound)
0.17
*n.d. not determined
Compound 13 was profiled in the HCT116-IDH1R132H+/-
mechanistic xenograft model to evaluate whether robust
in vivo inhibition of 2-HG production could be observed.
Following a single oral dose of 200 mg/kg, AUC48h and
Cmax of 13 were 149 ꢀM.h and 16.2 ꢀM, respectively.
Mouse plasma protein binding of 88.4% was used to ap-
proximate unbound plasma AUC48h of 17.3 ꢀM.h and Cmax
of 1.88 ꢀM which suggested unbound plasma concentra-
tions above the HCT116-IDH1R132H+/- cellular IC50 for great-
er than 12 h. This resulted in reduction of tumor 2-HG
concentration (Figure 3A) with maximal 2-HG inhibition
of 87.2 ± 1.5% (mean ± SEM) relative to the vehicle treated
tumors 8 h post treatment (Table SI-1). Tumor 2-HG lev-
els recovered above baseline by 48 h post treatment.
The relationship between unbound plasma exposure of 13
and percent inhibition of 2-HG suggested an estimated
unbound EC50 value of 0.02 – 0.03 ꢀM, similar to the in
vitro IC50 of 0.024 ꢀM (Figure 3B). This was consistent
with our previous observation that inhibition of 2-HG
production was correlated with unbound plasma drug
concentration. Additional dose escalation studies demon-
strated dose-dependent exposure and 2-HG inhibition
(Figure 3C) and further supported our PK/PD model.
Pharmacokinetic parameters (AUC, Cmax) values were not
calculated for this study due to insufficient data points.
Notably, 300 mg/kg dosed orally (po) achieved greater
than 95% 2-HG production inhibition 12 h post treatment
(Table SI-2). These data suggested a BID dosing regimen
would achieve maximal and sustained 2-HG inhibition.
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mg/kg, respectively.
Similarly, in the IDH1R132G mutant
HMEX2700 melanoma PDX model, 13 at 100 and 300
mg/kg achieved maximal 2-HG inhibition 8 h post treat-
ment of 92% and 97% relative to vehicle treatment, re-
spectively (Figure SI-1, Table SI-4)
.
Figure 4. In vivo 2-HG reduction and efficacy of 13 (IDH305)
in HMEX2838-IDH1R132C+/-. (a) % 2-HG inhibition in tumors
relative to vehicle treatment by single dose of 13 at indicated
doses. (b) % 2-HG inhibition in tumors in correlation with
total and unbound 13 plasma concentration following 30, 100
or 300 mg/kg BID for 21 days. (c) Tumor volume of
HMEX2838 xenograft tumors treated as in (b).
Figure 3. 2-HG reduction in 13 (IDH305) treated HCT116-
IDH1R132H+/- xenograft tumor tissue. (a) Tumor 2-HG levels
following a 200 mg/kg dose. (b) % 2-HG inhibition in tumors
relative to vehicle treatment in correlation with total and
calculated unbound 13plasma concentration following a 200
mg/kg dose. (c) % 2-HG inhibition in tumors in correlation
with total and calculated unbound 13 plasma concentration
following a 30, 100 or 300 mg/kg dose.
We next evaluated 2-HG reduction in the IDH1R132C
HMEX2838 PDX model in a multi-dose PK/PD/efficacy
study. Compound 13 was well tolerated for 21 days of
treatment, with no body weight loss at 30, 100 or 300
mg/kg po BID (Figure SI-2). Exposures at the steady state
were reduced relative to single dose treatment (Table SI-
5), with AUC12h of 5.4 ꢀM.h, AUC12h of 19.2 ꢀM.h and
AUC12h of 88.9 ꢀM.h at doses of 30, 100 and 300 mg/kg,
respectively. Despite reduced exposure, dose-dependent
inhibition of 2-HG levels in tumor tissue was achieved
(Figure 4B) and correlated with anti-tumor activity (Fig-
ure 4C). A dose of 30 mg/kg po BID resulted in 22-25% 2-
HG reduction and no significant tumor growth inhibition
(%T/C = 63%). In contrast, 100 mg/kg po BID resulted in
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efficacy study protocols and data (PDF). This material is
available free of charge on the ACS Publications website.
62-67% 2-HG reduction and significant anti-tumor activi-
ty (%T/C = 38%, P<0.05), consistent with the robust PD
observed after a single dose (Figure 3C). Furthermore, 300
mg/kg of 13 dosed po BID resulted in 97-99% 2-HG reduc-
tion and partial tumor regression of 32% (P<0.05). As the
HMEX2838 model was propagated by in vivo tumor pas-
sage, an in vitro IC50 for 2-HG inhibition for this model
was not determined. It is notable that in both the engi-
neered HCT116-IDH1R132H+/- and the endogenously mutant
PDX xenograft models, maintenance of unbound plasma
concentration of 13 above the in vitro IC50 for the engi-
neered model (0.024 ꢀM) was required to achieve greater
than 50% 2-HG inhibition in vivo. This observation sug-
gested that the engineered HCT116-IDH1R132H+/- was useful
for predicting efficacious unbound plasma concentrations
required to inhibit 2-HG in solid tumor models.
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AUTHOR INFORMATION
Corresponding Author
* Tel: (617) 871-3495. Email: youngshin.cho@novartis.com.
* Tel: (617) 871-3474. Email: joseph.growney@novartis.com.
Present Addresses
9
(J.R.L.) Constellation Pharmaceuticals, 215 First Street, Suite
200, Cambridge, MA 02142; (J.S.) Ideaya Biosciences, 280
Utah Avenue, Suite 250, South San Francisco, CA 94080
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ACKNOWLEDGMENT
The authors would like to thank Bill Sellers, Karin Briner,
Tim Ramsey, Juliet Williams and Travis Stams for their sup-
port.
Based on PK/PD studies of 13 in the HCT116-IDH1R132H+/-
mechanistic xenograft mouse model above, maintaining
unbound concentrations of 13 above the cell IC50 range
(0.024 ꢀM) was anticipated to be sufficient for inhibition
of 2-HG. Human pharmacokinetics was predicted from in
vitro and preclinical in vivo data based on allometric scal-
ing approaches.25 With predicted clearance of 7.9 ml min-1
kg-1, Vdss of 3.8 l kg-1, and an oral bioavailability value of
70% (average of mouse, rat, dog, and monkey values), the
resulting efficacious dose of 13 for a 70 kg human was
predicted to be 500 mg QD or 150 mg BID to maintain
unbound concentration above the in vitro IC50. Using a
150 mg BID dose, the anticipated Cmax after a single dose
was 1.0 μM and the AUC was 6.6 μM*h. For a 500 mg QD
dose, Cmax was predicted to be 3.2 μM and AUC was 22
μM. The pharmacokinetics of 13 has been investigated in
patients with gliomas, AML, chondrosarcomas and intra-
hepatic cholangiocarcinomas, who have documented
IDH1R132 mutations. After a single oral dose of 13 at 150 mg
in human, the geometric mean Cmax and AUC were 1.2
µM and 6.6 µM*h with a moderate inter subject variabil-
ity (CV% of geometric mean: 49% and 57%, respectively),
which was within 1.5 fold from the predicted values.
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In conclusion, optimization of 1 focusing on potency
and PK properties led to the discovery of 13, an oral inhib-
itor of mutant IDH1 that efficiently inhibited 2-HG pro-
duction in various xenograft models and inhibited 2-HG-
dependent tumor growth of an IDH1 mutant PDX mela-
noma model. Robust dose-dependent 2-HG inhibition in
preclinical models by 13 enabled development of an expo-
sure-response relationship. Based on these data, 13 was
selected for evaluation in clinical trials in humans to treat
IDH1 mutant tumors, such as AML, chondrosarcoma and
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ASSOCIATED CONTENT
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Discovery and Evaluation of Clinical Candidate IDH305, a Brain
Penetrant Mutant IDH1 Inhibitor
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Young Shin Cho,* Julian R. Levell, Gang Liu, Thomas Caferro, James Sutton, Cynthia M. Shafer, Abran
Costales, James R. Manning, Qian Zhao, Martin Sendzik, Michael Shultz, Gregg Chenail, Julia Dooley,
Brian Villalba, Ali Farsidjani, Jinyun Chen, Raviraj Kulathila, Xiaoling Xie, Stephanie Dodd, Ty Gould,
Guiqing Liang, Tycho Heimbach, Kelly Slocum, Brant Firestone, Minying Pu, Raymond Pagliarini and Jo-
seph D. Growney*
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