Mutant Isocitrate Dehydrogenase 1 (mIDH1) [2]
Specifically, mutant IDH1-R132H (IC50 = 0.021 μM) and mutant IDH1-R132C (IC50 = 0.114 μM). [2]

Numerous IDH1-R132 mutants (R132H, R132C, R132G, and R132L) can effectively be inhibited from producing 2-HG by olutasidenib (FT-2102), suggesting that Olutasidenib (FT-2102) is effective against the majority of tumors expressing IDH1-R132 mutants. IDH1 isoforms are the only ones that olintasidenib (FT-2102) significantly inhibits, with no discernible effect on wild-type IDH1 (> 20 µM) or IDH2 mutants (R172K and R140Q, both > 20 µM) [2].

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Olutasidenib (FT-2102) is a potent and selective inhibitor of mutant IDH1 (mIDH1). It inhibits the mIDH1-R132H enzyme with an IC50 of 0.021 μM and the mIDH1-R132C enzyme with an IC50 of 0.114 μM in biochemical assays. [2]
In cellular assays, Olutasidenib (FT-2102) potently inhibits the production of the oncometabolite 2-hydroxyglutarate (2-HG) in various mIDH1-expressing cell lines. In HCT116 cells engineered to express IDH1-R132H, the IC50 for 2-HG inhibition was 0.021 μM, and for IDH1-R132C cells, it was 0.094 μM. [2]
Similar potent inhibition of 2-HG was observed in U87MG glioblastoma cells expressing various IDH1-R132 mutants (R132H IC50 = 0.009 μM, R132C IC50 = 0.039 μM, R132L IC50 = 0.042 μM, R132G IC50 = 0.006 μM, R132S IC50 = 0.009 μM). [2]
Olutasidenib (FT-2102) demonstrates high selectivity for mIDH1, showing no significant inhibition against wild-type IDH1 (IC50 > 20 μM) and mutant IDH2 isoforms (R172K IC50 = 27.3 μM, R140Q IC50 > 100 μM). [2]
Olutasidenib (FT-2102) exhibits a kinetic solubility of 35.4 μM at pH 7.4. [2]
In a Caco-2 permeability assay, Olutasidenib (FT-2102) showed an apical-to-basal (A-B) apparent permeability (Papp) of 9.01 x 10^-6 cm/s and a basal-to-apical (B-A) Papp of 12.12 x 10^-6 cm/s, resulting in an efflux ratio of 1.35. [2]

Three oral doses of olinusidenib (FT-2102; 25 mg/kg, 50 mg/kg, and 12 hours apart) showed strong antitumor activity in xenografted female BALB/c nude mice with the HCT116-IDH1-R132H/+ mutation [2].

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In HCT116-IDH1-R132H/+ xenograft models, oral administration of Olutasidenib (FT-2102) at doses of 12.5, 25, and 50 mg/kg (every 12 hours) led to dose-dependent suppression of 2-HG levels in tumors. At 50 mg/kg, >90% inhibition of tumor 2-HG levels was sustained for up to 24 hours after the last dose. [2]
Similar potent 2-HG suppression was observed in HCT116-IDH1-R132C/+ xenograft models, with significant inhibition sustained for at least 12 hours. [2]
The free drug concentration of Olutasidenib (FT-2102) in tumors was comparable to that in plasma. [2]
The in vivo IC50 values, based on tumor 2-HG suppression versus free tumor drug concentration, were calculated to be 26 nM for the HCT116-IDH1-R132H model and 36 nM for the HCT116-IDH1-R132C model. [2]

The biochemical inhibition of mutant IDH1 enzymatic activity was measured. The assay details are provided in the Supporting Information. Briefly, the activity of purified mutant IDH1 enzymes (R132H, R132C) was assessed in the presence of varying concentrations of the test compounds. The production of NADPH, a co-factor in the reaction catalyzed by IDH1, was monitored to determine enzyme activity and calculate IC50 values. [2]

Cellular potency was determined by measuring the inhibition of 2-hydroxyglutarate (2-HG) production in engineered cell lines expressing specific mutant IDH1 proteins (e.g., HCT116-IDH1-R132H, HCT116-IDH1-R132C, U87MG-IDH1-R132H, etc.). Cells were treated with a range of compound concentrations for a specified period. Intracellular 2-HG levels were then quantified using a suitable analytical method (e.g., LC-MS/MS) to determine the concentration of compound required to inhibit 2-HG production by 50% (IC50). [2]
Cytotoxicity or general cell health was assessed in parallel to ensure that 2-HG inhibition was not due to nonspecific toxicity. [2]

Animal/Disease Models: HCT116-IDH1-R132H/+ xenograft-bearing female BALB/c nude mice [2].
Doses: 12.5, 25 and 50 mg/kg.
Doses: Orally administered 3 times (12.5, 25 and 50 mg/kg) every 12 hrs (hrs (hours)).
Experimental Results: Demonstrated time- and dose-dependent inhibition of 2-HG levels in tumors. At the highest dose tested in these studies (50 mg/kg), FT-2102 treatment inhibited 2-HG levels in tumors by >90% within 24 hrs (hrs (hours)) of the last dose in HCT116-IDH1-R132H/+ Xenograft model.

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For in vivo pharmacokinetic-pharmacodynamic (PK-PD) studies, female BALB/c Nude mice bearing HCT116-IDH1-R132H/+ or HCT116-IDH1-R132C/+ xenograft tumors were used. [2]
Olutasidenib (FT-2102) was administered orally at doses of 12.5, 25, and 50 mg/kg. The dosing regimen consisted of administration every 12 hours. [2]
Plasma and tumor samples were collected at 4, 12, and 24 hours after the last dose to measure compound concentrations and tumor 2-HG levels. [2]
The formulation/solvent used for dosing is not explicitly described in the main text but is detailed in the Supporting Information. [2]

Absorption, Distribution and Excretion
For patients with acute myeloid leukemia (AML) receiving the recommended dose, the steady-state daily plasma concentration-time area under the curve (AUC0-12-h, ss) of oslucidinib is 43050 ng·h/mL, and the steady-state Cmax is 3573 ng/mL. The Cmax and AUC of oslucidinib increase proportionally between 100 mg and 300 mg (0.33 to 1 times the recommended total daily dose), but no adjustment to the recommended dose is required. For patients receiving a single oral dose of 150 mg, the median tmax of oslucidinib is approximately 4 hours. In healthy subjects, a single 150 mg dose of oslucidinib, combined with a high-fat meal (800-1000 calories, 50% of which are from fat), increased Cmax and AUCinf by 191% and 83%, respectively. In healthy subjects, following a single oral dose of 150 mg of radiolabeled osulusidinib, approximately 17% of the osulusidinib was excreted in the urine (1% unchanged) and 75% in the feces (35% unchanged). The apparent volume of distribution of osulusidinib is 319 L. The mean apparent oral clearance (CL/F) of osulusidinib is 4 L/h. Metabolism/Metabolites The metabolic pathway of osulusidinib includes N-dealkylation, demethylation, oxidative deamination, followed by… Orusidinib is primarily metabolized via oxidation and monooxidation, followed by glucuronidation. Approximately 90% of the osulusidinib dose is metabolized by CYP3A4, while the effects of CYP2C8, CYP2C9, CYP1A2, and CYP2C19 are relatively minor.

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Biological Half-Life
Orusidinib has a mean half-life of 67 hours.

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Orusidinib (FT-2102) exhibits excellent metabolic stability in vitro. In human liver microsome (HLM) stability assays, the parent compound was 100% retained after 30 minutes of incubation. Mouse liver microsome (MLM) stability was also high, with 92% retained after 30 minutes. [2]
The compound had a central nervous system multiparameter optimization (CNS MPO) score of 5.5, indicating good brain penetration. [2]
The Caco-2 cell permeability assay showed that the drug had good permeability and a low efflux rate (1.35). [2]
Pharmacokinetic data in a mouse xenograft model showed that the intratumoral free drug concentration was comparable to the plasma concentration, and the drug exposure was dose-dependent. [2]

Hepatotoxicity
In published pre-registration clinical trials of oslucidinib, the incidence of elevated serum ALT or AST was 46% and 47%, respectively. Among these, 13% and 10% of patients had ALT or AST levels exceeding 5 times the upper limit of normal (ULN), leading to dose adjustments in at least 10% of patients, and ultimately, 5% discontinuing treatment. One patient receiving azacitidine in combination with oslucidinib died of liver failure, and another developed clinically significant but spontaneously resolving cholestatic hepatitis. Most hepatic adverse events occurred early in treatment, typically in the first or second month, but there were isolated cases occurring up to 5 months after starting oslucidinib. Since oslucidinib's approval, at least one case of acute hepatitis with jaundice has been reported in clinical trials. In pre-marketing studies, oslucidinib treatment was also associated with differentiation syndrome in 9% to 16% of patients, sometimes severe and occasionally fatal. Differentiation syndrome is caused by a sudden and rapid proliferation of myeloid cells leading to the release of inflammatory cytokines and symptoms of respiratory distress, accompanied by hypoxemia, pulmonary infiltration, and pleural effusion. Other manifestations include fever, renal impairment, lymphadenopathy, bone pain, peripheral edema, and weight gain. Hepatic dysfunction may also occur, but is usually masked by more severe systemic manifestations. Differentiation syndrome typically develops within 2 to 8 weeks of starting treatment and can be quite severe. Treatment involves immediate discontinuation of the drug and, in severe cases, the use of glucocorticoids. Once differentiation syndrome resolves, the patient can restart oslucidinib. The black box warning for oslucidinib includes differentiation syndrome and provides specific recommendations for its timely identification and management. The package insert also warns of the risk of hepatotoxicity and recommends monitoring liver function during treatment; if hepatotoxicity occurs, the drug should be discontinued, the dose reduced, or the drug discontinued.
Probability Score: D (Possible but uncommon, a clinically significant cause of liver injury).

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Effects during pregnancy and lactation
◉ Overview of use during lactation
There is currently no information on the use of oslucidinib during lactation. Because it binds to plasma proteins at a rate of 93%, the concentration in breast milk may be very low. However, the manufacturer recommends that mothers not breastfeed during treatment and for two weeks after the last dose.
◉ Effects on breastfed infants
No relevant published information was found as of the revision date.
◉ Effects on lactation and breast milk
No relevant published information was found as of the revision date.

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Protein binding
Olutasidenib has a plasma protein binding rate of approximately 93%.

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Cytotoxicity assays in cell models showed that potent inhibition of 2-HG occurred at concentrations that did not significantly affect overall cell viability, suggesting a selective mechanism of action. [2]

[1]. A phase 1 dose escalation study of the IDH1m inhibitor, FT-2102, in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS).

[2]. Structure-based design and identification of FT-2102 (olutasidenib), a potent mutant-selective IDH1 inhibitor. J Med Chem. 2020.

Olutasidenib (FT-2102) is a selective and potent isocitrate dehydrogenase-1 (IDH1) inhibitor approved by the U.S. Food and Drug Administration (FDA) in December 2022. It is indicated for the treatment of patients with relapsed or refractory acute myeloid leukemia (AML) who are identified by an FDA-approved testing method as carrying a susceptible IDH1 mutation. IDH1 mutations are common in various cancers, such as glioma, AML, intrahepatic cholangiocarcinoma, chondrosarcoma, and myelodysplastic syndromes (MDS). These mutations lead to elevated levels of 2-hydroxyglutarate (2-HG), a metabolite involved in tumorigenesis. Olutasidenib specifically inhibits mutated IDH1, thus providing therapeutic benefit to cancer patients carrying IDH1 mutations. Other IDH1 inhibitors, such as [ivosidenib], have also been approved for the treatment of relapsed or refractory acute myeloid leukemia (AML). Olutasidenib has oral bioavailability and can cross the blood-brain barrier. Its efficacy in treating myelodysplastic syndromes (MDS) as well as solid tumors and gliomas is currently being evaluated (NCT03684811). Olutasidenib is a small-molecule isocitrate dehydrogenase-1 (IDH1) mutation inhibitor used to treat adult patients with relapsed or refractory acute myeloid leukemia harboring IDH1 mutations. Serum transaminase elevations during olutasidenib treatment are relatively common and can be severe, requiring early discontinuation of the drug, and occasionally even causing clinically significant acute liver injury. Olutasidenib is an oral isocitrate dehydrogenase type 1 (IDH1; IDH-1; IDH1 [NADP+] soluble) inhibitor that targets IDH1 (R132) with a mutation at arginine (R) 132, and has potential antitumor activity. Upon administration, olutacinib specifically inhibits IDH1 (R132), thereby inhibiting the production of the oncogenic metabolite 2-hydroxyglutarate (2HG) from α-ketoglutarate (α-KG). This blocks 2HG-mediated signaling, leading to the induction of differentiation and inhibition of proliferation in IDH(R132)-expressing tumor cells. IDH1 (R132) mutations are highly expressed in certain malignancies, including gliomas; they initiate and drive cancer growth by blocking cell differentiation and catalyzing the production of 2-hydroxyglutarate (2HG).

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Drug Indications
Oluteacinib is indicated for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) diagnosed by an FDA-approved assay as harboring a susceptible isocitrate dehydrogenase-1 (IDH1) mutation.

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Mechanism of Action
Orutasicil is an isocitrate dehydrogenase-1 (IDH1) inhibitor used to treat patients with acute myeloid leukemia (AML) harboring IDH1 gene mutations associated with cancer development. IDH1 catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG). However, IDH1 gene mutations occur at the active catalytic site of arginine residues, promoting the conversion of α-ketoglutarate (α-KG) to 2-hydroxyglutarate (2-HG), a carcinogenic metabolite that can lead to tumorigenesis. This results in elevated 2-HG levels, thereby inhibiting α-KG-dependent mechanisms such as epigenetic regulation, collagen synthesis, and cell signaling. IDH1 gene mutations have been detected in a variety of cancers, including acute myeloid leukemia (AML). The most common IDH1 gene mutations in AML patients are R132H and R132C amino acid substitutions. Olutasidenib is a selective IDH1 inhibitor with affinity only for the mutant enzyme. In vitro studies have shown that olutasidenib inhibits mutant IDH1 proteins R132H, R132L, R132S, R132G, and R132C, but has no inhibitory effect on wild-type IDH1 or mutant IDH2 proteins. Olutasidenib promotes the restoration of normal cell differentiation and provides therapeutic benefits for IDH1-mutant cancers by inhibiting mutant IDH1 and reducing 2-hydroxyglutarate (2-HG) levels.

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Pharmacodynamics
In patients with acute myeloid leukemia (AML) with IDH1 mutations, olutasidenib reduced 2-hydroxyglutarate (2-HG) levels by 59.1% before cycle 2 of treatment. The reduction in 2-HG levels was maintained throughout treatment. In AML patients treated with oxucidinib, increased oxucidinib exposure was also associated with an increased incidence of differentiation syndrome and grade 3 hepatotoxicity. Orusidinib use resulted in a concentration-dependent prolongation of the QTc interval; however, the effect of this increase could not be determined because the effects of higher doses of oxucidinib were not assessed. Orusidinib (FT-2102) was developed using a structure-based drug design approach to be a highly effective, orally bioavailable, blood-brain barrier-crossing drug that selectively inhibits mutant IDH1. [2] The compound binds in an allosteric pocket near the mIDH1 dimer interface. Key interactions include hydrogen bonds between the quinoline core and Arg109/Asp279, hydrogen bonds between the cyano group of the pyridone ring and Leu120, hydrogen bonds between the linked amine and Ile128, and a newly introduced hydrogen bond between the pyridone carbonyl group and the NH group of the Ile128 backbone. [2]
Orutasicib (FT-2102) is used to treat cancers harboring IDH1 mutations, including hematologic malignancies (e.g., acute myeloid leukemia, myelodysplastic syndromes), solid tumors, and gliomas. [2]
As of the time of this publication, clinical trials of olutasicib (FT-2102) for the treatment of patients with mIDH1-dependent cancers are ongoing. [2]

C18H15CLN4O2

354.79030251503

354.09

C, 60.94; H, 4.26; Cl, 9.99; N, 15.79; O, 9.02

1887014-12-1

118955396

Light yellow to yellow solid powder

2.5

2

4

3

25

745

1

C[C@@H](C1=CC2=C(C=CC(=C2)Cl)NC1=O)NC3=CC=C(N(C3=O)C)C#N

NEQYWYXGTJDAKR-JTQLQIEISA-N

InChI=1S/C18H15ClN4O2/c1-10(21-16-6-4-13(9-20)23(2)18(16)25)14-8-11-7-12(19)3-5-15(11)22-17(14)24/h3-8,10,21H,1-2H3,(H,22,24)/t10-/m0/s1

5-[[(1S)-1-(6-Chloro-2-oxo-1,2-dihydroquinolin-3-yl)ethyl]amino]-1-methyl-6-oxo-1,6-dihydropyridine-2-carbonitrile

FT-2102; FT 2102; FT2102

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~125 mg/mL (~352.32 mM)

Solubility in Formulation 1: ≥ 2.08 mg/mL (5.86 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (5.86 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)