OLUTASIDENIB

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C18H15ClN4O2
Molecular Weight	354.79
Optical Activity	UNSPECIFIED
Defined Stereocenters	1 / 1
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

C[C@H](NC1=CC=C(C#N)N(C)C1=O)C2=CC3=CC(Cl)=CC=C3NC2=O

InChI

InChIKey=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

HIDE SMILES / InChI

Description
Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/215814s000lbl.pdf|https://pubmed.ncbi.nlm.nih.gov/35639513

Olutasidenib (FT-2102) is a highly potent, orally bioavailable, brain-penetrant, and selective inhibitor of mutant IDH1. Olutasidenib was designed to reduce R-2-HG and revert pathologic epigenetic modifications that impair cellular differentiation to restore regulatory enzyme function. In patients with AML, susceptible IDH1 mutations are defined as those leading to increased levels of 2-hydroxyglutarate (2-HG) in the leukemia cells and where efficacy is predicted by 1) clinically meaningful remissions with the recommended dose of olutasidenib and/or 2) inhibition of mutant IDH1 enzymatic activity at concentrations of olutasidenib sustainable at the recommended dosage according to validated methods. The most common of such mutations in patients with AML are R132H and R132C substitutions. In vitro, olutasidenib inhibited mutated IDH1 R132H, R132L, R132S, R132G, and R132C proteins; wild-type IDH1 or mutated IDH2 proteins were not inhibited. Olutasidenib inhibition of mutant IDH1 led to decreased 2-HG levels in vitro and in in vivo xenograft models. On December 1, 2022, the FDA approved olutasidenib (brand name Rezlidhia) capsules for adult patients with relapsed or refractory acute myeloid leukemia with a susceptible IDH1 mutation as detected by an FDA-approved test.

CNS Activity

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Isocitrate dehydrogenase [NADP] cytoplasmic 5 Target ID: CHEMBL2007625 Sources: https://pubmed.ncbi.nlm.nih.gov/31971798\|https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/215814s000lbl.pdf	Inhibitor 8504		21.1 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Acute myeloid leukemia 141 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/215814s000lbl.pdf	Primary		Approved 8583	REZLIDHIA Approved Use REZLIDHIA is an isocitrate dehydrogenase-1 (IDH1) inhibitor indicated for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with a susceptible IDH1 mutation as detected by an FDA-approved test. Launch Date 2022

C_max

Value	Dose	Co-administered	Analyte	Population
3573 ng/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/215814s000lbl.pdf	150 mg 2 times / day steady-state, oral dose: 150 mg route of administration: Oral experiment type: STEADY-STATE co-administered:		OLUTASIDENIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

AUC

Value	Dose	Co-administered	Analyte	Population
43050 ng × h/mL DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/215814s000lbl.pdf	150 mg 2 times / day steady-state, oral dose: 150 mg route of administration: Oral experiment type: STEADY-STATE co-administered:		OLUTASIDENIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
67 h DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/215814s000lbl.pdf	150 mg 2 times / day steady-state, oral dose: 150 mg route of administration: Oral experiment type: STEADY-STATE co-administered:		OLUTASIDENIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

F_unbound

Value	Dose	Co-administered	Analyte	Population
7% DRUG LABEL https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/215814s000lbl.pdf	150 mg 2 times / day steady-state, oral dose: 150 mg route of administration: Oral experiment type: STEADY-STATE co-administered:		OLUTASIDENIB plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: UNKNOWN food status: UNKNOWN

Doses

Dose	Population	Adverse events
150 mg 2 times / day steady, oral Highest studied dose Dose: 150 mg, 2 times / day Route: oral Route: steady Dose: 150 mg, 2 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/215814Orig1s000MultidisciplineR.pdf	unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: FED Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/215814Orig1s000MultidisciplineR.pdf	Disc. AE: Transaminitis, Pneumonia... AEs leading to discontinuation/dose reduction: Transaminitis (3%) Pneumonia (2%) Differentiation syndrome (2%) Febrile neutropenia (2%) Intracranial hemorrhage (1%) Gallbladder disorders (1%) Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/215814Orig1s000MultidisciplineR.pdf

AEs

AE	Significance	Dose	Population
Gallbladder disorders	1% Disc. AE	150 mg 2 times / day steady, oral Highest studied dose Dose: 150 mg, 2 times / day Route: oral Route: steady Dose: 150 mg, 2 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/215814Orig1s000MultidisciplineR.pdf	unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: FED Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/215814Orig1s000MultidisciplineR.pdf
Intracranial hemorrhage	1% Disc. AE	150 mg 2 times / day steady, oral Highest studied dose Dose: 150 mg, 2 times / day Route: oral Route: steady Dose: 150 mg, 2 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/215814Orig1s000MultidisciplineR.pdf	unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: FED Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/215814Orig1s000MultidisciplineR.pdf
Differentiation syndrome	2% Disc. AE	150 mg 2 times / day steady, oral Highest studied dose Dose: 150 mg, 2 times / day Route: oral Route: steady Dose: 150 mg, 2 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/215814Orig1s000MultidisciplineR.pdf	unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: FED Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/215814Orig1s000MultidisciplineR.pdf
Febrile neutropenia	2% Disc. AE	150 mg 2 times / day steady, oral Highest studied dose Dose: 150 mg, 2 times / day Route: oral Route: steady Dose: 150 mg, 2 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/215814Orig1s000MultidisciplineR.pdf	unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: FED Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/215814Orig1s000MultidisciplineR.pdf
Pneumonia	2% Disc. AE	150 mg 2 times / day steady, oral Highest studied dose Dose: 150 mg, 2 times / day Route: oral Route: steady Dose: 150 mg, 2 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/215814Orig1s000MultidisciplineR.pdf	unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: FED Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/215814Orig1s000MultidisciplineR.pdf
Transaminitis	3% Disc. AE	150 mg 2 times / day steady, oral Highest studied dose Dose: 150 mg, 2 times / day Route: oral Route: steady Dose: 150 mg, 2 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/215814Orig1s000MultidisciplineR.pdf	unhealthy, ADULT Health Status: unhealthy Age Group: ADULT Sex: M+F Food Status: FED Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/215814Orig1s000MultidisciplineR.pdf

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inducer 1087 substrate 1946	substrate 1193 inducer 440 inhibitor 2438	inhibitor 2507	inhibitor 2217

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
Cav1.2 58 OATP1B1 1079 CYP3A4/5 296 Nav1.5 116 OATP1B3 961 OAT3 747 BSEP 550 OCT2 779 P-gp 1741 BCRP 910 CYP1A2 2153 CYP2B6 926 CYP2C8 1057 CYP2C19 2057 MRP2 499 MATE1 415 MATE2K 17 MRP3 246 MRP4 290 OAT1 725	BCRP 697 CYP2C19 1119 MRP2 252 MRP3 58 MRP4 91 P-gp 2052 BSEP 63 CYP2C8 810	CYP2B6 669 CYP1A2 832 CYP2C8 198

Drug as perpetrator

Target	Modality	Activity
BSEP 554	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/215814Orig1s000MultidisciplineR.pdf Page: 63.0	no
CYP1A2 2333	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/215814Orig1s000MultidisciplineR.pdf Page: 62.0	no
CYP2B6 1160	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/215814Orig1s000MultidisciplineR.pdf Page: 62.0	no
CYP2C19 2141	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/215814Orig1s000MultidisciplineR.pdf Page: 62.0	no
CYP2C8 1117	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/215814Orig1s000MultidisciplineR.pdf Page: 62.0	no
CYP2C9 2497	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/215814Orig1s000MultidisciplineR.pdf Page: 62.0	no
CYP2D6 2546	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/215814Orig1s000MultidisciplineR.pdf Page: 62.0	no
CYP3A4/5 357	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/215814Orig1s000MultidisciplineR.pdf Page: 62.0	no
MRP2 625	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/215814Orig1s000MultidisciplineR.pdf Page: 63.0	no
MRP3 326	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/215814Orig1s000MultidisciplineR.pdf Page: 63.0	no
MRP4 345	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/215814Orig1s000MultidisciplineR.pdf Page: 63.0	no
OAT1 730	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/215814Orig1s000MultidisciplineR.pdf Page: 63.0	no
BCRP 985	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/215814Orig1s000MultidisciplineR.pdf Page: 63.0	yes
CYP1A2 2333	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/215814Orig1s000MultidisciplineR.pdf Page: 62.0	yes
CYP2B6 1160	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/215814Orig1s000MultidisciplineR.pdf Page: 62.0	yes
CYP2C8 1117	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/215814Orig1s000MultidisciplineR.pdf Page: 62.0	yes
CYP2C9 2497	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/215814Orig1s000MultidisciplineR.pdf Page: 62.0	yes
CYP3A4 2633	inducer 1966 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/215814Orig1s000MultidisciplineR.pdf Page: 62.0	yes
MATE1 416	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/215814Orig1s000MultidisciplineR.pdf Page: 63.0	yes
MATE2K 17	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/215814Orig1s000MultidisciplineR.pdf Page: 63.0	yes
OAT3 749	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/215814Orig1s000MultidisciplineR.pdf Page: 63.0	yes
OATP1B1 1095	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/215814Orig1s000MultidisciplineR.pdf Page: 63.0	yes
OATP1B3 970	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/215814Orig1s000MultidisciplineR.pdf Page: 63.0	yes
OCT2 782	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/215814Orig1s000MultidisciplineR.pdf Page: 63.0	yes
P-gp 1932	inhibitor 4027 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/215814Orig1s000MultidisciplineR.pdf Page: 63.0	yes

Drug as victim

Target	Modality	Activity	Clinical evidence
CYP3A4 1946	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/215814Orig1s000MultidisciplineR.pdf Page: 61 \| 62	major	yes (co-administration study) Comment: Multiple doses of rifampicin decreased Cmax by 43% and AUC by 80%. However, multiple doses of itraconazole made no clinically meaningful differences in Cmax and AUC. Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/215814Orig1s000MultidisciplineR.pdf Page: 61 \| 62
CYP2C19 1119	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/215814Orig1s000MultidisciplineR.pdf Page: 61.0	minor
CYP2C8 810	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/215814Orig1s000MultidisciplineR.pdf Page: 61.0	minor
CYP2C9 1193	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/215814Orig1s000MultidisciplineR.pdf Page: 61.0	minor
BCRP 697	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/215814Orig1s000MultidisciplineR.pdf Page: 63.0	no
BSEP 63	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/215814Orig1s000MultidisciplineR.pdf Page: 63.0	no
MRP2 252	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/215814Orig1s000MultidisciplineR.pdf Page: 63.0	no
MRP3 58	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/215814Orig1s000MultidisciplineR.pdf Page: 63.0	no
MRP4 91	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/215814Orig1s000MultidisciplineR.pdf Page: 63.0	no
P-gp 2052	substrate 4014 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/215814Orig1s000MultidisciplineR.pdf Page: 63.0	yes

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
Cav1.2 63	inhibitor 2237 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/215814Orig1s000MultidisciplineR.pdf Page: 32 \| 37
Nav1.5 119	inhibitor 2237 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/215814Orig1s000MultidisciplineR.pdf Page: 32.0
hERG 2263	inhibitor 2237 Sources: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/215814Orig1s000MultidisciplineR.pdf Page: 32 \| 36

PubMed

Title	Date	PubMed
Olutasidenib.	2006	36701506
Olutasidenib alone or with azacitidine in IDH1-mutated acute myeloid leukaemia and myelodysplastic syndrome: phase 1 results of a phase 1/2 trial.	2023 Jan	36370742
Olutasidenib (FT-2102) in patients with relapsed or refractory IDH1-mutant glioma: A multicenter, open-label, phase Ib/II trial.	2023 Jan 5	35639513
Olutasidenib (FT-2102) induces durable complete remissions in patients with relapsed or refractory IDH1-mutated AML.	2023 Jul 11	36724515

Patents

Sample Use Guides

In Vivo Use Guide

Recommended dosage: 150 mg orally twice daily, until disease progression or unacceptable toxicity. Take on an empty stomach at least 1 hour before or 2 hours after a meal.

Route of Administration: Oral

In Vitro Use Guide

Olutasidenib is an inhibitor of mutant isocitrate dehydrogenase 1 (IDH1; IC50s = 0.021 and 0.114 uM for IDH1R132H and IDH1R132C, respectively). It is selective for mutant IDH1 over wild-type IDH1 and mutant IDH2 (IC50s = 22.4, 27.3, and >100 μM for wild-type IDH1, IDH2R172K, and IDH2R140Q, respectively). Olutasidenib inhibits production of ɑ-hydroxyglutaric acid in U87 cells expressing mutant IDH1R132H, IDH1R132C, IDH1R132L, IDH1R132G, and IDH1R132S with IC50 values of 0.009, 0.039, 0.042, 0.006, and 0.009 uM, respectively.

Name

Type

Language

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

Preferred Name

English

OLUTASIDENIB

Official Name

English

olutasidenib [INN]

Common Name

English

(S)-5-((1-(6-CHLORO-2-OXO-1,2-DIHYDROQUINOLIN-3-YL)ETHYL)AMINO)-1-METHYL-6-OXO-1,6-DIHYDROPYRIDINE-2-CARBONITRILE

Systematic Name

English

REZLIDHIA

Brand Name

English

FT-2102

Code

English

Olutasidenib [WHO-DD]

Common Name

English

2-PYRIDINECARBONITRILE, 5-(((1S)-1-(6-CHLORO-1,2-DIHYDRO-2-OXO-3-QUINOLINYL)ETHYL)AMINO)-1,6-DIHYDRO-1-METHYL-6-OXO-

Systematic Name

English

OLUTASIDENIB [USAN]

Common Name

English

Classification Tree Code System Code

EU-Orphan Drug

EU/3/19/2159