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Details

Stereochemistry ACHIRAL
Molecular Formula C30H42N8O3.3H2O
Molecular Weight 616.7521
Optical Activity UNSPECIFIED
Defined Stereocenters 6 / 6
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of PINOMETOSTAT TRIHYDRATE

SMILES

O.O.O.CC(C)N(C[C@H]1O[C@H]([C@H](O)[C@@H]1O)N2C=NC3=C(N)N=CN=C23)[C@@H]4C[C@H](CCC5=NC6=CC(=CC=C6N5)C(C)(C)C)C4

InChI

InChIKey=UQPFPXXVGVCSCX-MIFIOKNMSA-N
InChI=1S/C30H42N8O3.3H2O/c1-16(2)37(13-22-25(39)26(40)29(41-22)38-15-34-24-27(31)32-14-33-28(24)38)19-10-17(11-19)6-9-23-35-20-8-7-18(30(3,4)5)12-21(20)36-23;;;/h7-8,12,14-17,19,22,25-26,29,39-40H,6,9-11,13H2,1-5H3,(H,35,36)(H2,31,32,33);3*1H2/t17-,19+,22-,25-,26-,29-;;;/m1.../s1

HIDE SMILES / InChI

Description
Curator's Comment: Description was created based on several sources, including https://www.ncbi.nlm.nih.gov/pubmed/26385168

Pinometostat, also known as EPZ-5676, is a small molecule inhibitor of histone methyltransferase with potential antineoplastic activity. Upon intravenous administration, EPZ-5676 specifically blocks the activity of the histone lysine-methyltransferase DOT1L, thereby inhibiting the methylation of nucleosomal histone H3 on lysine 79 (H3K79) that is bound to the mixed lineage leukemia (MLL) fusion protein which targets genes and blocks the expression of leukemogenic genes. Epizyme is developing pinometostat, a small molecule inhibitor of DOT1L, for the treatment of patients with MLL-r, a genetically defined acute leukemia. Epizyme is conducting a phase 1 clinical trial in pediatric patients. Epizyme is evaluating preclinical combinations of pinometostat with other anti-cancer agents in MLL-r leukemia. Pinometostat is being developed in collaboration with Celgene. Epizyme retains all U.S. rights to pinometostat and has granted Celgene an exclusive license to pinometostat outside of the U.S.

Originator

Approval Year

Unknown
139594
Targets

Targets

Primary TargetPharmacologyConditionPotency
Inhibitor
8297
 80.0 pM [Ki]
Conditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
Phase I
428
Unknown

Approved Use

Unknown
Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
412 ng/mL
EXPERIMENT
https://pubmed.ncbi.nlm.nih.gov/26645404
30 mg/kg single, intravenous
dose: 30 mg/kg
route of administration: Intravenous
experiment type: SINGLE
co-administered:
PINOMETOSTAT plasma
Rattus norvegicus
population: HEALTHY
age: ADULT
sex: MALE
food status: UNKNOWN
507 ng/mL
EXPERIMENT
https://pubmed.ncbi.nlm.nih.gov/26645404
30 mg/kg single, intravenous
dose: 30 mg/kg
route of administration: Intravenous
experiment type: SINGLE
co-administered:
PINOMETOSTAT plasma
Rattus norvegicus
population: HEALTHY
age: ADULT
sex: FEMALE
food status: UNKNOWN
AUC

AUC

ValueDoseCo-administeredAnalytePopulation
9005 ng × h/mL
EXPERIMENT
https://pubmed.ncbi.nlm.nih.gov/26645404
30 mg/kg single, intravenous
dose: 30 mg/kg
route of administration: Intravenous
experiment type: SINGLE
co-administered:
PINOMETOSTAT plasma
Rattus norvegicus
population: HEALTHY
age: ADULT
sex: MALE
food status: UNKNOWN
9400 ng × h/mL
EXPERIMENT
https://pubmed.ncbi.nlm.nih.gov/26645404
30 mg/kg single, intravenous
dose: 30 mg/kg
route of administration: Intravenous
experiment type: SINGLE
co-administered:
PINOMETOSTAT plasma
Rattus norvegicus
population: HEALTHY
age: ADULT
sex: FEMALE
food status: UNKNOWN
T1/2

T1/2

ValueDoseCo-administeredAnalytePopulation
1.29 h
EXPERIMENT
https://pubmed.ncbi.nlm.nih.gov/26645404
30 mg/kg single, intravenous
dose: 30 mg/kg
route of administration: Intravenous
experiment type: SINGLE
co-administered:
PINOMETOSTAT plasma
Rattus norvegicus
population: HEALTHY
age: ADULT
sex: MALE
food status: UNKNOWN
0.63 h
EXPERIMENT
https://pubmed.ncbi.nlm.nih.gov/26645404
30 mg/kg single, intravenous
dose: 30 mg/kg
route of administration: Intravenous
experiment type: SINGLE
co-administered:
PINOMETOSTAT plasma
Rattus norvegicus
population: HEALTHY
age: ADULT
sex: FEMALE
food status: UNKNOWN
Funbound

Funbound

ValueDoseCo-administeredAnalytePopulation
4%
EXPERIMENT
https://pubmed.ncbi.nlm.nih.gov/27160567
unknown, unknown
 PINOMETOSTAT plasma
Homo sapiens
population: UNKNOWN
age: UNKNOWN
sex: UNKNOWN
food status: UNKNOWN
Doses

Doses

DosePopulationAdverse events​
90 mg/m2 1 times / day multiple, intravenous (unknown)
Highest studied dose
Dose: 90 mg/m2, 1 times / day
Route: intravenous
Route: multiple
Dose: 90 mg/m2, 1 times / day
Sources:
https://pubmed.ncbi.nlm.nih.gov/29724899/
unhealthy
n = 6
Health Status: unhealthy
Condition: acute leukemia
Sex: M+F
Food Status: UNKNOWN
Population Size: 6
Sources:
https://pubmed.ncbi.nlm.nih.gov/29724899/
DLT: cardiac failure...
Other AEs: Cardiac failure congestive, Ejection fraction decreased...
Dose limiting toxicities:
cardiac failure (grade 4, 1 pt)
Other AEs:
Cardiac failure congestive (grade 3-4, 4%)
Ejection fraction decreased (grade 3-4, 2%)
Cardiorespiratory arrest (grade 3-4, 2%)
Hypophosphatemia (grade 3-4, 2%)
Sources:
https://pubmed.ncbi.nlm.nih.gov/29724899/
AEs

AEs

AESignificanceDosePopulation
Cardiorespiratory arrest grade 3-4, 2%
90 mg/m2 1 times / day multiple, intravenous (unknown)
Highest studied dose
Dose: 90 mg/m2, 1 times / day
Route: intravenous
Route: multiple
Dose: 90 mg/m2, 1 times / day
Sources:
https://pubmed.ncbi.nlm.nih.gov/29724899/
unhealthy
n = 6
Health Status: unhealthy
Condition: acute leukemia
Sex: M+F
Food Status: UNKNOWN
Population Size: 6
Sources:
https://pubmed.ncbi.nlm.nih.gov/29724899/
Ejection fraction decreased grade 3-4, 2%
90 mg/m2 1 times / day multiple, intravenous (unknown)
Highest studied dose
Dose: 90 mg/m2, 1 times / day
Route: intravenous
Route: multiple
Dose: 90 mg/m2, 1 times / day
Sources:
https://pubmed.ncbi.nlm.nih.gov/29724899/
unhealthy
n = 6
Health Status: unhealthy
Condition: acute leukemia
Sex: M+F
Food Status: UNKNOWN
Population Size: 6
Sources:
https://pubmed.ncbi.nlm.nih.gov/29724899/
Hypophosphatemia grade 3-4, 2%
90 mg/m2 1 times / day multiple, intravenous (unknown)
Highest studied dose
Dose: 90 mg/m2, 1 times / day
Route: intravenous
Route: multiple
Dose: 90 mg/m2, 1 times / day
Sources:
https://pubmed.ncbi.nlm.nih.gov/29724899/
unhealthy
n = 6
Health Status: unhealthy
Condition: acute leukemia
Sex: M+F
Food Status: UNKNOWN
Population Size: 6
Sources:
https://pubmed.ncbi.nlm.nih.gov/29724899/
Cardiac failure congestive grade 3-4, 4%
90 mg/m2 1 times / day multiple, intravenous (unknown)
Highest studied dose
Dose: 90 mg/m2, 1 times / day
Route: intravenous
Route: multiple
Dose: 90 mg/m2, 1 times / day
Sources:
https://pubmed.ncbi.nlm.nih.gov/29724899/
unhealthy
n = 6
Health Status: unhealthy
Condition: acute leukemia
Sex: M+F
Food Status: UNKNOWN
Population Size: 6
Sources:
https://pubmed.ncbi.nlm.nih.gov/29724899/
cardiac failure grade 4, 1 pt
DLT
90 mg/m2 1 times / day multiple, intravenous (unknown)
Highest studied dose
Dose: 90 mg/m2, 1 times / day
Route: intravenous
Route: multiple
Dose: 90 mg/m2, 1 times / day
Sources:
https://pubmed.ncbi.nlm.nih.gov/29724899/
unhealthy
n = 6
Health Status: unhealthy
Condition: acute leukemia
Sex: M+F
Food Status: UNKNOWN
Population Size: 6
Sources:
https://pubmed.ncbi.nlm.nih.gov/29724899/
PubMed

PubMed

TitleDatePubMed
MLL-rearranged leukemia is dependent on aberrant H3K79 methylation by DOT1L.
2011 Jul 12
The pathogenesis of mixed-lineage leukemia.
2012
Potent inhibition of DOT1L as treatment of MLL-fusion leukemia.
2013 Aug 8
Patents

Patents

20120142625
3
20140051654
3

Sample Use Guides

In Vivo Use Guide
28-day continuous IV infusion of each 28-day cycle
Route of Administration: Intravenous
In Vitro Use Guide
Pinometostat reduces H3K79 dimethylation with a cellular IC50 of 2.6 nM in MV4-11 cells. Pinometostat treatment results in concentration- and time-dependent reduction of H3K79 methylation without effect on the methylation status of other histone sites, which leads to inhibition of key MLL target genes and selective, apoptotic cell killing in MLL-rearranged leukemia cells. Pinometostat inhibits proliferation of MLL-AF4 rearranged cell line MV4-11 with an IC50 of 9 nM.
Name Type Language
PINOMETOSTAT TRIHYDRATE
Common Name English
ADENOSINE, 5'-DEOXY-5'-((CIS-3-(2-(6-(1,1-DIMETHYLETHYL)-1H-BENZIMIDAZOL-2-YL)ETHYL)CYCLOBUTYL)(1-METHYLETHYL)AMINO)-, HYDRATE (1:3)
Systematic Name English
Code System Code Type Description
CAS
1643929-61-6
Created by admin on Sat Dec 16 07:42:57 GMT 2023 , Edited by admin on Sat Dec 16 07:42:57 GMT 2023
NON-SPECIFIC STOICHIOMETRY
FDA UNII
RHP89XVN70
Created by admin on Sat Dec 16 07:42:57 GMT 2023 , Edited by admin on Sat Dec 16 07:42:57 GMT 2023
PRIMARY
PUBCHEM
91617704
Created by admin on Sat Dec 16 07:42:57 GMT 2023 , Edited by admin on Sat Dec 16 07:42:57 GMT 2023
PRIMARY
SMS_ID
300000006060
Created by admin on Sat Dec 16 07:42:57 GMT 2023 , Edited by admin on Sat Dec 16 07:42:57 GMT 2023
PRIMARY
CAS
1628338-78-2
Created by admin on Sat Dec 16 07:42:57 GMT 2023 , Edited by admin on Sat Dec 16 07:42:57 GMT 2023
PRIMARY
ACTIVE MOIETY
Structure of PINOMETOSTAT
NIH
NCATS
PRIVACY ACT
ACCESSIBILITY
DISCLAIMER
HHS VULNERABILITY DISCLOSURE
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