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/20439741 | http://mct.aacrjournals.org/content/8/12_Supplement/PR-2https://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	Potency
Serine/threonine-protein kinase PAK 4 3 Target ID: CHEMBL4482 Sources: https://www.ncbi.nlm.nih.gov/pubmed/26191365 \| https://www.ncbi.nlm.nih.gov/pubmed/20439741	Inhibitor 8297	1.3 nM [IC50]
Serine/threonine-protein kinase PAK 4 3 Target ID: CHEMBL4482 Sources: https://www.ncbi.nlm.nih.gov/pubmed/24432870	Inhibitor 8297	36.0 nM [Ki]
Serine/threonine-protein kinase PAK 1 5 Target ID: CHEMBL4600 Sources: https://www.ncbi.nlm.nih.gov/pubmed/24432870	Inhibitor 8297	36.0 nM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Solid tumors 145 Sources: https://clinicaltrials.gov/ct2/show/NCT00932126	Primary	Phase I 428	Unknown Approved Use Unknown
Colon cancer 62 Sources: https://www.ncbi.nlm.nih.gov/pubmed/23543898	Primary	Basic research	Unknown Approved Use Unknown
Lung cancer 69 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 1461	P-gp 1537 BCRP 561

Drug as perpetrator

Target	Modality	Activity	Metabolite	Clinical evidence
P-gp 1650	inhibitor 3277 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1346987#sid=363677350	no

Drug as victim

Target	Modality	Activity	Metabolite	Clinical evidence
BCRP 561	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/23524533/	yes
P-gp 1537	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/23524533/	yes

PubMed

Title	Date	PubMed
Small-molecule p21-activated kinase inhibitor PF-3758309 is a potent inhibitor of oncogenic signaling and tumor growth.	2010 May 18	20439741
Back pocket flexibility provides group II p21-activated kinase (PAK) selectivity for type I 1/2 kinase inhibitors.	2014 Feb 13	24432870
Optimization of a Dibenzodiazepine Hit to a Potent and Selective Allosteric PAK1 Inhibitor.	2015 Jul 9	26191365
Chronic exposure to cigarette smoke leads to activation of p21 (RAC1)-activated kinase 6 (PAK6) in non-small cell lung cancer cells.	2016 Sep 20	27542207
p21-activated kinase 1 activity is required for histone H3 Ser(10) phosphorylation and chromatin condensation in mouse oocyte meiosis.	2017 Jul	27166635

Patents

Sample Use Guides

In Vivo Use Guide

Oral PF-03758309 will be administered in capsules (once or twice daily) until toxicity, progressive disease, or patient refusal to continue on therapy. The starting dose is 1 mg once daily.

Route of Administration: Oral

In Vitro Use Guide

PF-3758309 potently inhibits cellular proliferation (IC50 = 20 nM) and anchorage-independent growth (IC50 = 27 nM) of A549 cells.

Name

Type

Language

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

PF-3758309

Code

English

Code System Code Type Description

DRUG BANK

DB11775