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Details

Stereochemistry ACHIRAL
Molecular Formula C35H29F3N4O3
Molecular Weight 610.625
Optical Activity NONE
Defined Stereocenters 0 / 0
E/Z Centers 1
Charge 0

SHOW SMILES / InChI
Structure of PADNARSERTIB

SMILES

NC1=NC=C(\C=C\C(=O)NCC2=CC3=CC(=CC(=C3O2)C4=CC=C(F)C=C4)C5=CC=C(C=C5)C(=O)N6CCC(F)(F)CC6)C=C1

InChI

InChIKey=MRFOPLWJZULAQD-SWGQDTFXSA-N
InChI=1S/C35H29F3N4O3/c36-28-9-7-24(8-10-28)30-19-26(23-3-5-25(6-4-23)34(44)42-15-13-35(37,38)14-16-42)17-27-18-29(45-33(27)30)21-41-32(43)12-2-22-1-11-31(39)40-20-22/h1-12,17-20H,13-16,21H2,(H2,39,40)(H,41,43)/b12-2+

HIDE SMILES / InChI
PAK4-IN-1 (KPT-9274) is a first-in-class, orally bioavailable, small molecule immunometabolic modulator that works through non-competitive dual inhibition of p21-activated kinase 4 (PAK4) and nicotinamide phosphoribosyltransferase (NAMPT). Co-inhibition of these targets is believed to lead to synergistic anti-tumor effects through suppression of ß-catenin by blocking PAK4, leading to both immune cell activation and inhibition of tumor growth, energy depletion through NAMPT inhibition, blockade of DNA repair, cell cycle arrest and ultimately apoptosis. KPT-9274 may therefore have both immune-activating and direct antitumor effects. In contrast, normal cells are less sensitive to inhibition by KPT-9274 due in part to their relative genomic stability and lower metabolic demands. Mechanistic studies demonstrate that inhibition of the PAK4 pathway by KPT-9274 attenuates nuclear β-catenin as well as the Wnt/β-catenin targets cyclin D1 and c-Myc. KPT-9274 demonstrated the expected on-target effects in this mouse model. KPT-9274 can reduce the steady state level of PAK4 protein in triple negative breast cancer cells. Oral administration of KPT-9274 reduces tumorigenesis in mouse models of human triple negative breast cancer. KPT-9274 is a novel therapeutic option for triple negative breast cancer therapy. KPT-9274 is being evaluated in a phase I human clinical trial in solid tumors and lymphomas, which will allow this data to be rapidly translated into the clinic for the treatment of RCC.

Approval Year

Cmax

Cmax

ValueDoseCo-administeredAnalytePopulation
565 ng/mL
40 mg single, oral
dose: 40 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
PAK4-IN-1 plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
1550 ng/mL
40 mg 3 times / week multiple, oral
dose: 40 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
PAK4-IN-1 plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
AUC

AUC

ValueDoseCo-administeredAnalytePopulation
18709 ng × h/mL
40 mg single, oral
dose: 40 mg
route of administration: Oral
experiment type: SINGLE
co-administered:
PAK4-IN-1 plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
53430 ng × h/mL
40 mg 3 times / week multiple, oral
dose: 40 mg
route of administration: Oral
experiment type: MULTIPLE
co-administered:
PAK4-IN-1 plasma
Homo sapiens
population: UNHEALTHY
age: ADULT
sex: FEMALE / MALE
food status: UNKNOWN
Doses

Doses

DosePopulationAdverse events​
40 mg 3 times / week multiple, oral
Highest studied dose
Dose: 40 mg, 3 times / week
Route: oral
Route: multiple
Dose: 40 mg, 3 times / week
Sources:
unhealthy, ADULT
n = 7
Health Status: unhealthy
Condition: cancer
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 7
Sources:
DLT: Anemia...
AEs

AEs

AESignificanceDosePopulation
Anemia grade 4, 14.3%
DLT
40 mg 3 times / week multiple, oral
Highest studied dose
Dose: 40 mg, 3 times / week
Route: oral
Route: multiple
Dose: 40 mg, 3 times / week
Sources:
unhealthy, ADULT
n = 7
Health Status: unhealthy
Condition: cancer
Age Group: ADULT
Sex: M+F
Food Status: UNKNOWN
Population Size: 7
Sources:
Overview

Overview

CYP3A4CYP2C9CYP2D6hERG

OverviewOther

Other InhibitorOther SubstrateOther Inducer


Drug as perpetrator​

Drug as perpetrator​

TargetModalityActivityMetaboliteClinical evidence
no
yes [IC50 5.1735 uM]
PubMed

PubMed

TitleDatePubMed
Functional role and therapeutic targeting of p21-activated kinase 4 in multiple myeloma.
2017 Apr 20
A novel orally bioavailable compound KPT-9274 inhibits PAK4, and blocks triple negative breast cancer tumor growth.
2017 Feb 15
Patents

Patents

Sample Use Guides

PAK4-IN-1 (KPT-9274) is well tolerated in mice with the absence of any signs of toxicity when 200 mg/kg daily is administered either intravenously or orally.
Route of Administration: Other
MDA-MB-231 cell growth was almost completely inhibited in the presence of as little as 1 uM PAK4-IN-1 (KPT-9274). MDA-MB-468 and SUM159 cells proliferation was completely inhibited with 300 nM KPT-9274.
Name Type Language
PADNARSERTIB
INN  
Official Name English
padnarsertib [INN]
Common Name English
(E)-3-(6-AMINOPYRIDIN-3-YL)-N-((5-(4-(4,4-DIFLUOROPIPERIDINE-1-CARBONYL)PHENYL)-7-(4-FLUOROPHENYL)BENZOFURAN-2-YL)METHYL)ACRYLAMIDE
Systematic Name English
PAK4-IN-1
Common Name English
2-PROPENAMIDE, 3-(6-AMINO-3-PYRIDINYL)-N-((5-(4-((4,4-DIFLUORO-1-PIPERIDINYL)CARBONYL)PHENYL)-7-(4-FLUOROPHENYL)-2-BENZOFURANYL)METHYL)-, (2E)-
Systematic Name English
(2E)-3-(6-AMINO-3-PYRIDINYL)-N-((5-(4-((4,4-DIFLUORO-1-PIPERIDINYL)CARBONYL)PHENYL)-7-(4-FLUOROPHENYL)-2-BENZOFURANYL)METHYL)-2-PROPENAMIDE
Common Name English
KPT-9274
Code English
KPT 9274 [WHO-DD]
Common Name English
Code System Code Type Description
PUBCHEM
117779453
Created by admin on Sat Dec 16 18:07:20 GMT 2023 , Edited by admin on Sat Dec 16 18:07:20 GMT 2023
PRIMARY
INN
11749
Created by admin on Sat Dec 16 18:07:20 GMT 2023 , Edited by admin on Sat Dec 16 18:07:20 GMT 2023
PRIMARY
FDA UNII
9T56TV18X7
Created by admin on Sat Dec 16 18:07:20 GMT 2023 , Edited by admin on Sat Dec 16 18:07:20 GMT 2023
PRIMARY
SMS_ID
300000042033
Created by admin on Sat Dec 16 18:07:20 GMT 2023 , Edited by admin on Sat Dec 16 18:07:20 GMT 2023
PRIMARY
CAS
1643913-93-2
Created by admin on Sat Dec 16 18:07:20 GMT 2023 , Edited by admin on Sat Dec 16 18:07:20 GMT 2023
PRIMARY
NCI_THESAURUS
C126646
Created by admin on Sat Dec 16 18:07:20 GMT 2023 , Edited by admin on Sat Dec 16 18:07:20 GMT 2023
PRIMARY