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Details

Stereochemistry ABSOLUTE
Molecular Formula C26H33FN4O3S
Molecular Weight 500.629
Optical Activity UNSPECIFIED
Defined Stereocenters 3 / 3
E/Z Centers 0
Charge 0

SHOW SMILES / InChI
Structure of LCL-161

SMILES

CN[C@@H](C)C(=O)N[C@@H](C1CCCCC1)C(=O)N2CCC[C@H]2C3=NC(=CS3)C(=O)C4=CC=C(F)C=C4

InChI

InChIKey=UFPFGVNKHCLJJO-SSKFGXFMSA-N
InChI=1S/C26H33FN4O3S/c1-16(28-2)24(33)30-22(17-7-4-3-5-8-17)26(34)31-14-6-9-21(31)25-29-20(15-35-25)23(32)18-10-12-19(27)13-11-18/h10-13,15-17,21-22,28H,3-9,14H2,1-2H3,(H,30,33)/t16-,21-,22-/m0/s1

HIDE SMILES / InChI
Molecular Formula C26H33FN4O3S
Molecular Weight 500.629
Charge 0
Count
Stereochemistry ABSOLUTE
Additional Stereochemistry No
Defined Stereocenters 3 / 3
E/Z Centers 0
Optical Activity UNSPECIFIED

Description
Curator's Comment: description was created based on several sources, including: http://adisinsight.springer.com/drugs/800031959 | https://www.ncbi.nlm.nih.gov/pubmed/25113756

Ipatasertib (LCL161) binds to inhibitors of apoptosis proteins (IAPs) with high affinity and initiates the destruction of cIAP1 and cIAP2, which further induces apoptosis via caspase activation. Ipatasertib is advancing in clinical development including five Phase 2 trials in patients with Breast cancer, Multiple myeloma, Myelofibrosis, Small cell lung cancer and Ovarian cancer. The most common LCL161-related adverse events were nausea and vomiting.

Originator

Novartis
173
Curator's Comment: synthesized by Novartis Pharma AG, developed by Chen K.F. et al in National Taiwan University Hospital https://www.ncbi.nlm.nih.gov/pubmed/22580047 # Novartis

Approval Year

Unknown
139594
Targets

Targets

Primary TargetPharmacologyConditionPotency
Inhibitor
8297
Inhibitor
8297
Inhibitor
8297
Conditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
Phase II
1132
Unknown

Approved Use

Unknown
Primary
Phase I
428
Unknown

Approved Use

Unknown
Primary
Phase II
1132
Unknown

Approved Use

Unknown
Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
2350 ng/mL
EXPERIMENT
https://pubmed.ncbi.nlm.nih.gov/25113756
1800 mg 1 times / week single, oral
dose: 1800 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
LCL-161 plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
AUC

AUC

ValueDoseCo-administeredAnalytePopulation
32081 ng × h/mL
EXPERIMENT
https://pubmed.ncbi.nlm.nih.gov/25113756
1800 mg 1 times / week single, oral
dose: 1800 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
LCL-161 plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
T1/2

T1/2

ValueDoseCo-administeredAnalytePopulation
6.9 h
EXPERIMENT
https://pubmed.ncbi.nlm.nih.gov/25113756
1800 mg 1 times / week single, oral
dose: 1800 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
LCL-161 plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
Doses

Doses

DosePopulationAdverse events​
3000 mg 1 times / week multiple, oral
Highest studied dose
Dose: 3000 mg, 1 times / week
Route: oral
Route: multiple
Dose: 3000 mg, 1 times / week
Sources:
https://pubmed.ncbi.nlm.nih.gov/25113756
Page: p.3, 4
unhealthy, ADULT
n = 2
Health Status: unhealthy
Condition: cancer
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 2
Sources:
https://pubmed.ncbi.nlm.nih.gov/25113756
Page: p.3, 4
DLT: Cytokine release syndrome...
Dose limiting toxicities:
Cytokine release syndrome (grade 4, 50%)
Sources:
https://pubmed.ncbi.nlm.nih.gov/25113756
Page: p.3, 4
1800 mg 1 times / week multiple, oral
RP2D
Dose: 1800 mg, 1 times / week
Route: oral
Route: multiple
Dose: 1800 mg, 1 times / week
Sources:
https://pubmed.ncbi.nlm.nih.gov/25113756
Page: p.3, 4
unhealthy, ADULT
n = 24
Health Status: unhealthy
Condition: cancer
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 24
Sources:
https://pubmed.ncbi.nlm.nih.gov/25113756
Page: p.3, 4
Sources:
https://pubmed.ncbi.nlm.nih.gov/25113756
Page: p.3, 4
2100 mg 1 times / week multiple, oral
Studied dose
Dose: 2100 mg, 1 times / week
Route: oral
Route: multiple
Dose: 2100 mg, 1 times / week
Sources:
https://pubmed.ncbi.nlm.nih.gov/25113756
Page: p.3, 4
unhealthy, ADULT
n = 2
Health Status: unhealthy
Condition: cancer
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 2
Sources:
https://pubmed.ncbi.nlm.nih.gov/25113756
Page: p.3, 4
DLT: Cytokine release syndrome...
Dose limiting toxicities:
Cytokine release syndrome (grade 3, 50%)
Sources:
https://pubmed.ncbi.nlm.nih.gov/25113756
Page: p.3, 4
AEs

AEs

AESignificanceDosePopulation
Cytokine release syndrome grade 4, 50%
DLT, Disc. AE
3000 mg 1 times / week multiple, oral
Highest studied dose
Dose: 3000 mg, 1 times / week
Route: oral
Route: multiple
Dose: 3000 mg, 1 times / week
Sources:
https://pubmed.ncbi.nlm.nih.gov/25113756
Page: p.3, 4
unhealthy, ADULT
n = 2
Health Status: unhealthy
Condition: cancer
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 2
Sources:
https://pubmed.ncbi.nlm.nih.gov/25113756
Page: p.3, 4
Cytokine release syndrome grade 3, 50%
DLT, Disc. AE
2100 mg 1 times / week multiple, oral
Studied dose
Dose: 2100 mg, 1 times / week
Route: oral
Route: multiple
Dose: 2100 mg, 1 times / week
Sources:
https://pubmed.ncbi.nlm.nih.gov/25113756
Page: p.3, 4
unhealthy, ADULT
n = 2
Health Status: unhealthy
Condition: cancer
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 2
Sources:
https://pubmed.ncbi.nlm.nih.gov/25113756
Page: p.3, 4
Overview

Overview

CYP3A4CYP2C9CYP2D6hERG
inhibitor
1587
inhibitor
1767
inhibitor
1852

OverviewOther

Other InhibitorOther SubstrateOther Inducer
CYP3A
214

P-gp
1461
P-gp
1537
CYP3A
129
Drug as perpetrator​

Drug as perpetrator​

TargetModalityActivityMetaboliteClinical evidence
CYP3A
298
 moderate
CYP2C9
1819
 no
CYP2D6
1891
 no
CYP3A
298
 yes [Ki 0.797 uM]
yes (co-administration study)
Comment: Increased midazolam Cmax and AUCinf by 3.22-fold and 9.32-fold.
CYP3A4
1925
 yes
P-gp
1650
 yes
Drug as victim

Drug as victim

TargetModalityActivityMetaboliteClinical evidence
P-gp
1537
 no
PubMed

PubMed

TitleDatePubMed
Smac mimetics: implications for enhancement of targeted therapies in leukemia.
2010 Dec
Initial testing (stage 1) of LCL161, a SMAC mimetic, by the Pediatric Preclinical Testing Program.
2012 Apr
Benzazepinones and benzoxazepinones as antagonists of inhibitor of apoptosis proteins (IAPs) selective for the second baculovirus IAP repeat (BIR2) domain.
2013 Oct 24
Patents

Patents

20100056467
2
US8906936 B2
2
WO2013043591 A1
2

Sample Use Guides

In Vivo Use Guide
1800 mg dose, administered as a single agent once weekly
Route of Administration: Oral
In Vitro Use Guide
LCL161 showed antiproliferative effects and reduced cell viability significantly in Hep3B (IC50 10.23 uM) and PLC5 (IC50 19.19 uM) cells in a dosedependent manner. However, Sk-Hep1 (IC50 223.55 uM) and Huh-7 cells (IC50 227.77 uM) showed resistance to LCL161 as measured by cell viability.
Substance Class Chemical
Created
by admin
on Sat Dec 16 08:34:45 GMT 2023
Edited
by admin
on Sat Dec 16 08:34:45 GMT 2023
Record UNII
6TNS415Y3P
Record Status Validated (UNII)
Record Version
  • Download
Name Type Language
LCL-161
Common Name English
NVP-LCL 161
Common Name English
PROPANAMIDE, N-((1S)-1-CYCLOHEXYL-2-((2S)-2-(4-(4-FLUOROBENZOYL)-2-THIAZOLYL)-1-PYRROLIDINYL)-2-OXOETHYL)-2-(METHYLAMINO)-, (2S)-
Systematic Name English
LCL 161 [WHO-DD]
Common Name English
LCL161
Code English
Classification Tree Code System Code
FDA ORPHAN DRUG 582917
Created by admin on Sat Dec 16 08:34:45 GMT 2023 , Edited by admin on Sat Dec 16 08:34:45 GMT 2023
Code System Code Type Description
PUBCHEM
24737642
Created by admin on Sat Dec 16 08:34:45 GMT 2023 , Edited by admin on Sat Dec 16 08:34:45 GMT 2023
PRIMARY
FDA UNII
6TNS415Y3P
Created by admin on Sat Dec 16 08:34:45 GMT 2023 , Edited by admin on Sat Dec 16 08:34:45 GMT 2023
PRIMARY
DRUG BANK
DB12085
Created by admin on Sat Dec 16 08:34:45 GMT 2023 , Edited by admin on Sat Dec 16 08:34:45 GMT 2023
PRIMARY
NCI_THESAURUS
C91079
Created by admin on Sat Dec 16 08:34:45 GMT 2023 , Edited by admin on Sat Dec 16 08:34:45 GMT 2023
PRIMARY
EPA CompTox
DTXSID501025866
Created by admin on Sat Dec 16 08:34:45 GMT 2023 , Edited by admin on Sat Dec 16 08:34:45 GMT 2023
PRIMARY
CAS
1005342-46-0
Created by admin on Sat Dec 16 08:34:45 GMT 2023 , Edited by admin on Sat Dec 16 08:34:45 GMT 2023
PRIMARY
SMS_ID
300000041394
Created by admin on Sat Dec 16 08:34:45 GMT 2023 , Edited by admin on Sat Dec 16 08:34:45 GMT 2023
PRIMARY
Related Record Type Details
DIABLO HOMOLOG, MITOCHONDRIAL
TARGET->MIMETIC
Structure of LCL-161 HEMIHYDRATE
SALT/SOLVATE -> PARENT
BACULOVIRAL IAP REPEAT-CONTAINING PROTEIN 3
TARGET -> INHIBITOR
small molecule second mitochondrial activator of caspase (SMAC) mimetic, which both disengages IAPs from caspases and induces proteasomal degradation of cIAP-1 and -2, resulting in altered signaling through the NFκB pathway.
BINDING
Structure of LCL-161 HEMIHYDRATE
SOLVATE->ANHYDROUS
BACULOVIRAL IAP REPEAT-CONTAINING PROTEIN 2
TARGET -> INHIBITOR
Small molecule second mitochondrial activator of caspase (SMAC) mimetic, which both disengages IAPs from caspases and induces proteasomal degradation of cIAP-1 and -2, resulting in altered signaling through the NFκB pathway
BINDING
Related Record Type Details
Structure of LCL-161
ACTIVE MOIETY
NIH
NCATS
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