This is an open access article published under an ACS AuthorChoice License, which permits
`copying and redistribution of the article or any adaptations for non-commercial purposes.
`
`Cite This: ACS Med. Chem. Lett. 2018, 9, 300−305
`
`Letter
`
`Discovery of AG-120 (Ivosidenib): A First-in-Class Mutant IDH1
`Inhibitor for the Treatment of IDH1 Mutant Cancers
`†,#
`†,∇
`†,⊥
`†,⊥
`René M. Lemieux,
`Janeta Popovici-Muller,
`Erin Artin,
`Jeffrey O. Saunders,
`‡
`†,▲
`†,□
`†
`Ding Zhou,
`Francesco G. Salituro,
`Jeremy Travins,
`Giovanni Cianchetta,
`Zhenwei Cai,
`‡
`†,∞
`†
`‡
`†,⊥
`∥
`Dawei Cui,
`Ping Chen,
`Kimberly Straley,
`Erica Tobin,
`Fang Wang,
`Muriel D. David,
`∥
`∥
`∥
`∥
`Véronique Saada,
`Stéphane de Botton,
`Virginie Penard-Lacronique,
`Cyril Quivoron,
`Stefan Gross,
`†
`†
`†,@ Yue Chen,†
`
`†
`†
`§
`Lenny Dang,
`Hua Yang,
`Luke Utley,
`Hyeryun Kim,
`Shengfang Jin,
`Zhiwei Gu,
`†,+ Lee Silverman,
`§
`§
`§
`§
`§
`Gui Yao,
`Zhiyong Luo,
`Xiaobing Lv,
`Cheng Fang,
`Liping Yan,
`Andrew Olaharski,
`†
`†,∇
`and Katharine Yen*,†
`Scott Biller,
`Shin-San M. Su,
`†
`Agios Pharmaceuticals Inc., Cambridge, Massachusetts 02139, United States
`‡
`PharmaResources, Shanghai 201201, China
`§ChemPartner, Shanghai 201203, China
`∥
`INSERM U1170 and Gustave Roussy, Villejuif 94800, France
`*S Supporting Information
`
`‡,⊗
`
`†
`
`†
`
`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 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.
`KEYWORDS: isocitrate dehydrogenase, mutant IDH1, AG-120, ivosidenib, differentiation therapy, 2-hydroxyglutarate
`
`P oint mutations in isocitrate dehydrogenase (IDH) 1 and 2
`
`including glioma,
`are found in multiple tumors,
`cholangiocarcinoma, chondrosarcoma, and acute myeloid
`leukemia (AML).1 Mutant IDH (mIDH) enzymes have a
`gain-of-function activity that results in accumulation of the
`oncometabolite D-2-hydroxyglutatrate (2-HG),2 which is
`structurally similar to α-ketoglutarate (α-KG). 2-HG com-
`petitively inhibits α-KG-dependent dioxygenases, which partic-
`ipate in many cellular processes such as histone and DNA
`demethylation, and adaption to hypoxia, and their inhibition
`leads to a block in normal cellular differentiation and oncogenic
`transformation.1,3−5
`mIDH inhibitors represent a novel class of targeted cancer
`metabolism therapy that induces differentiation of proliferating
`cancer cells. The mIDH2 inhibitor enasidenib,
`recently
`approved by the FDA for relapsed/refractory AML, as well as
`all-trans retinoic acid for the treatment for acute promyelocytic
`leukemia,
`support
`the potential of
`such differentiation
`therapy.6−8 We previously reported that
`the prototype
`mIDH1 inhibitor AGI-5198 inhibited both biochemical and
`cellular production of 2-HG.9 AGI-5198 showed robust tumor
`
`2-HG inhibition in an in vivo mIDH1 xenograft model,
`impaired growth of mIDH1 glioma cells in vivo, and induced
`epigenetic alterations leading to the expression of genes
`associated with gliogenic differentiation.5 However, the poor
`pharmaceutical properties of AGI-5198 precluded its use in
`clinical studies. Although several additional mIDH1 inhibitors
`have been disclosed,1,10,11 AG-120 is the first inhibitor of the
`mIDH1 enzyme to achieve clinical proof of concept in human
`trials. Lead optimization of AGI-5198 leading to the discovery
`of AG-120 is described here. The mIDH1-R132H enzyme was
`utilized for primary biochemical evaluation. Routine profiling in
`cells was done in the HT1080 chondrosarcoma cell line, which
`endogenously expresses mIDH1-R132C, and in our experience
`the potency for mIDH1-R132C is very similar to mIDH1-
`R132H, as previously reported.9
`
`Received: October 13, 2017
`Accepted:
`January 19, 2018
`Published:
`January 19, 2018
`
`© 2018 American Chemical Society
`
`300
`
`DOI: 10.1021/acsmedchemlett.7b00421
`ACS Med. Chem. Lett. 2018, 9, 300−305
`
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`In vitro profiling of AGI-5198 in kinetic solubility and liver
`microsomal assays pointed to reasonable physicochemical
`properties but poor metabolic stability across
`species.
`Metabolite identification studies conducted in human liver
`microsomal S9 fraction revealed extensive NADPH-dependent
`oxidation of the cyclohexyl (R1) and imidazole ring (R4). The
`following strategies were therefore employed to decrease
`metabolic clearance (Table 1). At R4, the imidazole ring was
`replaced with moieties that emerged from broad structure−
`activity relationship profiling and had similar potency to AGI-
`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 o-Me (X)
`group was replaced by an o-Cl group.
`
`Table 1. Optimization of Microsome Stability and Potency
`Leading to AGI-14100
`
`aEnzymatic IC50 values for the mIDH1-R132H homodimer are the
`mean of at least two determinations performed as described in the
`Supporting Information. bCellular IC50 from HT1080 chondrosarco-
`ma cell line. cMicrosome stability recorded as the hepatic extraction
`ratio in human liver microsomes. dRacemic. eNot determined.
`
`Letter
`
`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 o-
`Me group on R2 to o-Cl and the cyclohexyl in R1 to difluoro
`cyclobutyl in 2 incurred only a 5-fold 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 mono- and dioxidation of
`the proline carbamate moiety were the major metabolic
`pathways, allowing us to stabilize the R1 site of oxidative
`metabolism. Eliminating oxidative liabilities at R4 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 metabolic stability.
`Removal of the pyrimidine ring in 4 in concert with oxidation
`of the proline ring at the 2-position 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.
`A scan of heterocycles at R4 revealed that pyridines
`substituted with electron-withdrawing groups at the 4-position
`could achieve the desired potency and metabolic stability
`profile as shown for 7 and 8. Finally, additional fluorine
`substitution at the 5-position of the R3 aromatic group provided
`the compound AGI-14100, with a good balance of single-digit
`nM potency in enzyme and cell-based assays and desirable
`metabolic stability.
`To further assess the suitability of AGI-14100 as a potential
`development candidate, additional pharmacokinetic (PK)
`properties were evaluated. Low clearance in liver microsomal
`incubations was observed across species, which was also
`observed in the rat, dog, and cynomolgus monkey in vivo
`(Table S1). However, assessment in the human pregnane X
`receptor (hPXR) screen indicated that AGI-14100 was
`potentially a cytochrome P450 (CYP) 3A4 inducer. hPXR
`activation by AGI-14100 was approximately 70% that of
`rifampicin, a known strong CYP 3A4 inducer. CYP induction
`studies using human hepatocytes confirmed the results (data
`not shown).
`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
`focused 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.
`the introduction of additional
`Starting from AGI-14100,
`polarity (hydroxyl group) on the pyrrolidinone ring of R4 in 9
`maintained similar potency,
`somewhat decreased hPXR
`activation 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
`heterocycle in 10 abolished the hPXR activation but led to poor
`cellular potency and decreased metabolic stability.
`
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`Table 2. Reduction of hPXR Activation Leading to AG-120
`
`Letter
`
`aHuman pregnane X receptor activation was determined as the fold activation relative to reference compound (rifampicin). bThe cell-permeability
`coefficient (Papp) was determined in both directions (apical to basolateral [A−B] and basolateral to apical [B−A]) across the Caco2 cell monolayer.
`The efflux ratio was estimated as Papp[B−A]/Papp[A−B]. cTotal polar surface area.
`
`Table 3. Biochemical and Cell Biology Profiling of AG-120
`
`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 C−F bonds at R3 with an N
`atom embedded in the ring led to AG-120, 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 AG-120
`and all related analogues was accomplished as described in
`Scheme S1 and the Supporting Information.
`Biochemical and cell biology profiling revealed that AG-120
`inhibited several IDH1-R132 mutants with potency similar 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).
`AG-120 at 100 μM did not inhibit multiple dehydrogenases
`tested (Table S3).
`In vitro, AG-120 exhibited rapid-equilibrium inhibition
`against
`the mIDH1-R132 homodimer. Kinetic studies of
`binding to demonstrate mode of action were inconclusive
`due to persistent prebound NADP(H) in all soluble mIDH1
`enzyme preparations (Supporting Information, Figures S1 and
`S2). Surprisingly, AG-120 demonstrated slow-tight binding
`inhibition against the IDH1-WT homodimer (Figure S3 and
`S4).
`
`mutationa
`
`b
`IC50
`(nM)
`12
`13
`8
`13
`12
`12
`
`5
`
`assay
`type
`enzyme
`
`cell-
`based
`
`IDH1-R132H
`IDH1-R132C
`IDH1-R132G
`IDH1-R132L
`IDH1-R132S
`IDH1-R132H/IDH1-WT heterodimer + NADP+/
`NADPH @ 1 h
`IDH1-R132H/IDH1-WT heterodimer + NADP+/
`NADPH @ 16 h
`71
`IDH1-WT + NADP+ @ 1h
`24
`IDH1-WT + NADP+ @ 16h
`19
`U87 MG (R132H)
`3
`neurospheres (R132H)
`8
`HT1080 (R132C)
`15
`COR-L105 (R132C)
`12
`HCCC-9810 (R132S)
`aAll cell lines described here express mIDH1 endogenously, except
`U87 MG, which is an overexpression system. bFor activity against
`enzyme, the enzyme and compound were preincubated for 1 or 16 h
`either in the presence or absence of cofactor as described in the
`Supporting Information.
`
`AG-120 also showed good cellular potency across multiple
`mIDH1-R132 endogenous and overexpressing cell lines (Table
`3),
`indicating its potential
`for use across all mIDH1-R132
`
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`cancers. AG-120 has a low turnover rate in liver microsomes
`derived from multiple species, including humans. PK studies
`performed in Sprague−Dawley rats, beagle dogs, and
`cynomolgus monkeys showed rapid oral absorption, low total
`body plasma clearance (CLp) and moderate to long half-life
`(t1/2) (Table S4). Although moderate exposure reduction was
`observed in a repeat-dose study in rodents (data not shown),
`no exposure reduction occurred in cynomolgus monkeys, and
`in patients with cancer a long t1/2 and accumulation of AG-120
`following multiple doses were observed.13,14
`Following a single oral dose of 50 mg/kg to rats with an
`intact blood−brain barrier, AG-120 exhibited brain penetration
`of 4.1% (AUC0−8h [brain]/AUC0−8h [plasma]). However, brain
`penetration is likely to be higher in glioma patients who have a
`compromised blood−brain barrier. Given that AG-120 is very
`potent and well
`tolerated,
`it has the potential
`to achieve
`therapeutic concentration in the brain, and its therapeutic
`benefit in glioma is being evaluated in clinical trials.
`AG-120 showed robust tumor 2-HG reduction in female
`nude BALB/c mice inoculated with HT1080 cells. Each mouse
`received a single oral dose of vehicle or AG-120 at 50 or 150
`mg/kg by gavage. Tumor 2-HG 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 h post
`dose. Tumor 2-HG concentrations approached baseline levels
`48−72 h following a single dose of AG-120 (Figure 1),
`consistent with the reversible nature of AG-120 inhibition.
`
`Figure 1. Mean ± SD concentrations of AG-120 in plasma and 2-HG
`in tumor after single oral administration of AG-120 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.1,3−5 To
`determine the effect of mIDH1 inhibition in primary human
`AML blast cells, mIDH1-R132H, mIDH1-R132C, and IDH1-
`WT, bone marrow or peripheral blood samples from patients
`(Table S5) were treated with AG-120 in an ex vivo assay. Living
`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 AG-120. In mIDH1 samples, AG-120 reduced the
`level of intracellular 2-HG by 96% at the lowest tested dose
`(0.5 μM) and by 98.6% and 99.7%, respectively, at 1 and 5 μM
`(Figure 2). 2-HG was not measurable in multiple IDH1-WT
`patient samples assessed. AG-120 induced differentiation of
`primary mIDH1-R132H and mIDH1-R132C (but not IDH1-
`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 cell-surface markers
`of differentiation, and increases in the proportion of mature
`myeloid cells (Figure S5).
`
`Letter
`
`Figure 2. Percent intracellular 2-HG remaining relative to DMSO
`control after 6 days’ treatment with AG-120 in mIDH1-R132H or
`mIDH1-R132C patient samples (mean ± SEM from cells from four
`patients with mIDH1 AML).
`
`Together, these compelling preclinical data provided the
`rationale to advance AG-120 into clinical development.
`The discovery of enasidenib, which is active against mIDH2,
`and now AG-120 (ivosidenib) against mIDH1 as described
`here, presents a novel class of cancer therapy based on cellular
`differentiation. AG-120 is a potent mIDH1 inhibitor with
`favorable nonclinical and clinical safety profiles that has shown
`promising clinical activity in phase 1 clinical trials for both solid
`and hematologic malignancies.
`In patients with relapsed/
`refractory mIDH1 AML,
`interim results from the ongoing
`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 Long-term stable disease has
`been observed in patients with previously treated nonenhancing
`mIDH1 gliomas,16 and in heavily pretreated patients with
`mIDH1 cholangiocarcinoma, where the median progression-
`free survival was 3.8 months and the 6-month progression-free
`survival rate was 40%.17 In these two single arm, phase 1
`studies, AG-120 has demonstrated an acceptable safety profile
`to date.15−18 AG-120 is currently in late-stage clinical
`development in adults with mIDH1 AML (ClinicalTrials.gov
`NCT03173248), and with previously treated advanced mIDH1
`cholangiocarcinoma (NCT02989857).
`
`■ ASSOCIATED CONTENT
`*S Supporting Information
`The Supporting Information is available free of charge on the
`ACS Publications website at DOI: 10.1021/acsmedchem-
`lett.7b00421.
`Synthesis and profiling of AG-120, experimental
`procedures, synthetic details and characterization of
`compounds, and abbreviations (PDF)
`
`■ AUTHOR INFORMATION
`Corresponding Author
`*E-mail: katharine.yen@agios.com.
`ORCID
`Francesco G. Salituro: 0000-0003-1172-7064
`Katharine Yen: 0000-0003-2054-9108
`Present Addresses
`∇
`(J.P.-M., S.-S.M.S.) Decibel Therapeutics, Cambridge, MA.
`⊥
`(R.L.M., E.A., E.T.) KSQ Therapeutics, Cambridge, MA.
`#
`(J.O.S.) JOSC LLC Consulting, Lincoln, MA.
`▲
`(F.G.S.) Sage Therapeutics, Cambridge, MA.
`
`303
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`ACS Medicinal Chemistry Letters
`□
`(J.T.) Shire, Lexington, MA.
`⊗
`(D.Z.) GSK R&D Shanghai, Shanghai, China.
`∞
`(K.S.) Vertex Pharmaceuticals, Boston, MA.
`@(L.U.) Spero Therapeutics, Cambridge, MA.
`+(A.O.) Akebia Therapeutics, Cambridge, MA.
`Author Contributions
`The manuscript was written through contributions of all
`authors. All authors have given approval to the final version of
`the manuscript.
`Funding
`These studies were funded by Agios Pharmaceuticals Inc., the
`French National Institute of Health (INSERM-AVIESAN; to
`M.D. David and V. Penard-Lacronique), French National
`Cancer League (LNCC),
`the Institut National du Cancer
`(INCa-DGOS-Inserm_6043 and INCa 2012−1-RT- 09), and
`the Fondation Association pour la Recherche sur le Cancer
`(ARC, SL220130607089 Programme Labellisé to V. Penard-
`Lacronique and S. de Botton). M.D. David was funded by a
`fellowship from the Institut National du Cancer (INCa-
`DGOS_5733).
`Notes
`The authors declare the following competing financial
`interest(s): S.d.B. serves on advisory boards for Agios and
`Celgene. S.S.M.S is a consultant for Agios.
`
`■ ACKNOWLEDGMENTS
`
`Writing assistance was provided by Christine Ingleby, Ph.D., of
`Excel Scientific Solutions, Horsham, U.K., and supported by
`Agios Pharmaceuticals, Inc. We thank Jean-Baptiste Micol and
`Christophe Willekens for clinical specimens, Nathalie Auger for
`cytogenetic analyses, and Zenon Konteatis for
`insightful
`discussions during the optimization of hPXR activation.
`
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