PF-03758309

Investigational

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C25H30N8OS
Molecular Weight	490.624
Optical Activity	UNSPECIFIED
Defined Stereocenters	1 / 1
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CN(C)C[C@@H](NC(=O)N1CC2=C(NN=C2NC3=C4SC=CC4=NC(C)=N3)C1(C)C)C5=CC=CC=C5

InChI

InChIKey=AYCPARAPKDAOEN-LJQANCHMSA-N

InChI=1S/C25H30N8OS/c1-15-26-18-11-12-35-20(18)23(27-15)29-22-17-13-33(25(2,3)21(17)30-31-22)24(34)28-19(14-32(4)5)16-9-7-6-8-10-16/h6-12,19H,13-14H2,1-5H3,(H,28,34)(H2,26,27,29,30,31)/t19-/m1/s1

HIDE SMILES / InChI

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/24366569
Curator's Comment: description was created based on several sources, including https://www.ncbi.nlm.nih.gov/pubmed/20439741 | https://www.ncbi.nlm.nih.gov/pubmed/23543898 | https://www.ncbi.nlm.nih.gov/pubmed/24432870

PF-3758309 was developed as an ATP-competitive inhibitor of PAK4. In cells, PF-3758309 inhibits phosphorylation of the PAK4 substrate GEF-H1 (IC50 = 1.3 nM) and anchorage-independent growth of a panel of tumor cell lines (IC50 = 4.7 nM). PF-3758309 blocks the growth of multiple human tumor xenografts, with a plasma EC50 value of 0.4 nM in the most sensitive model. PF-3758309 is antiproliferative and induces apoptosis in an HCT116 tumor model.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Serine/threonine-protein kinase PAK 4 3 Target ID: CHEMBL4482 Sources: https://www.ncbi.nlm.nih.gov/pubmed/24432870	Inhibitor 8504		36.0 nM [Ki]
Serine/threonine-protein kinase PAK 1 5 Target ID: CHEMBL4600 Sources: https://www.ncbi.nlm.nih.gov/pubmed/24432870	Inhibitor 8504		36.0 nM [IC50]

Conditions

Condition	Modality	Targets	Highest Phase	Product
Colon cancer 66 Sources: https://www.ncbi.nlm.nih.gov/pubmed/23543898	Primary		Basic research	Unknown Approved Use Unknown
Lung cancer 70 Sources: https://www.ncbi.nlm.nih.gov/pubmed/24366569	Primary		Basic research	Unknown Approved Use Unknown

Overview

CYP3A4	CYP2C9	CYP2D6	hERG

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
P-gp 1741	P-gp 2052 BCRP 697

Drug as perpetrator

Target	Modality	Activity	Metabolite	Clinical evidence
P-gp 1932	inhibitor 4027 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1346987#sid=363677350	no

Drug as victim

Target	Modality	Activity	Metabolite	Clinical evidence
BCRP 697	substrate 4014 Sources: https://pubmed.ncbi.nlm.nih.gov/23524533/	yes
P-gp 2052	substrate 4014 Sources: https://pubmed.ncbi.nlm.nih.gov/23524533/	yes

PubMed

Title	Date	PubMed
p21-activated kinase 1 activity is required for histone H3 Ser10 phosphorylation and chromatin condensation in mouse oocyte meiosis.	2017-07	27166635
Chronic exposure to cigarette smoke leads to activation of p21 (RAC1)-activated kinase 6 (PAK6) in non-small cell lung cancer cells.	2016-09-20	27542207

Patents

Sample Use Guides

In Vivo Use Guide

Five- to six-week-old female athymic nude mice bearing colorectal cancer xenograft were treated for 14 days with either vehicle control (0.5% methylcellulose), or PF-3758309 (25 mg/kg) twice daily by oral gavage.

Route of Administration: Oral

In Vitro Use Guide

To evaluate the sensitivity of colorectal cancer (CRC) cell lines to PF-3758309, a panel of 27 CRC cell lines were exposed to increasing concentrations and assessed for proliferation using the SRB assay. Treatment of RKO, COLO205, HTC116, SW620, SW480, SW48, LS123, SW403, LOVO, LS180, SKC01, COLO201, LS513 and LS174T cell lines with PF-3758309 (0.1nM-1mkM) for 72 h leads to inhibition of cell proliferation (IC50< 0.0125mkM).

Name

Type

Language

PF-3758309

Preferred Name

English

PF-03758309

Common Name

English

N-((1S)-2-(DIMETHYLAMINO)-1-PHENYLETHYL)-6,6-DIMETHYL-3-((2-METHYLTHIENO(3,2-D)PYRIMIDIN-4-YL)AMINO)-4,6-DIHYDROPYRROLO(3,4-C)PYRAZOLE-5(1H)-CARBOXAMIDE

Systematic Name

English

Code System Code Type Description

DRUG BANK

DB11775