Defactinib HCl

Defactinib, also known as VS-6063 and PF-04554878, is an orally bioavailable, small-molecule focal adhesion kinase (FAK) inhibitor with potential antiangiogenic and antineoplastic activities. FAK inhibitor PF-04554878 inhibits FAK, which may prevent the integrin-mediated activation of several downstream signal transduction pathways, including ERK, JNK/MAPK and PI3K/Akt, thus inhibiting tumor cell migration, proliferation and survival.

Product information

CAS Number: 1073160-26-5

Molecular Weight: 546.95

Formula: C20H22ClF3N8O3S

Synonym:

Defactinib hydrochloride

VS-6063

PF-04554878

PF-4554878

Defactinib HCl

PF4554878

Chemical Name: N-Methyl-4-((4-(((3-(methyl(methylsulfonyl)amino)pyrazin-2-yl)methyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzamide monohydrochloride

Smiles: Cl.CNC(=O)C1C=CC(=CC=1)NC1=NC(NCC2=NC=CN=C2N(C)S(C)(=O)=O)=C(C=N1)C(F)(F)F

InChiKey: RCHQNUQAHJNRBY-UHFFFAOYSA-N

InChi: InChI=1S/C20H21F3N8O3S.ClH/c1-24-18(32)12-4-6-13(7-5-12)29-19-28-10-14(20(21,22)23)16(30-19)27-11-15-17(26-9-8-25-15)31(2)35(3,33)34;/h4-10H,11H2,1-3H3,(H,24,32)(H2,27,28,29,30);1H

Technical Data

Appearance: Solid Power.

Purity: ≥98% (or refer to the Certificate of Analysis)

Solubility: Soluble in DMSO

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical or refer to Certificate of Analysis

Storage Condition: Dry, dark and -20 ^oC for 1 year or refer to the Certificate of Analysis.

Shelf Life: ≥360 days if stored properly.

Stock Solution Storage: 0 - 4 ^oC for 1 month or refer to the Certificate of Analysis.

Drug Formulation: To be determined.

HS Tariff Code: 382200

How to use

In Vitro:

Defactinib (VS-6063) inhibits FAK phosphorylation at the Tyr397 site in a time- and dose-dependent manner. RPPA data shows that Defactinib reduces levels of AKT and YB-1 in taxane-resistant cell lines. The expression of pFAK (Tyr397) is statistically significantly inhibited by Defactinib in a dose-dependent manner in all cell lines. Defactinib inhibits pFAK (Tyr397) expression within 3 hours, with a gradual return of expression by 48 hours.

In Vivo:

Defactinib (VS-6063) doses of 25 mg/kg twice a day or greater statistically significantly inhibits pFAK (Tyr397) at 3 hours, with return of expression noted by 24 hours. Therefore, administration of Defactinib at 25 mg/kg twice a day is selected as the dosing schedule for subsequent therapy experiments. For therapy experiments, female nude mice bearing HeyA8 tumors in the peritoneal cavity are randomly divided into 4 groups (n=10 per group): 1) vehicle orally twice daily and phosphate-buffered saline intraperitoneally weekly (control); 2) Defactinib 25 mg/kg orally twice daily; 3) PTX intraperitoneally weekly; and 4) both VDefactinib 25 mg/kg orally twice daily and PTX intraperitoneally weekly. There is an 87.4% reduction in tumor weight by PTX monotherapy in the HeyA8 model, and combination therapy resulted in the greatest tumor weight reduction, with a 97.9% reduction (P=0.05 compared with PTX). In the SKOV3ip1 model, a 92.7% tumor weight reduction is observed in the combination group compared with PTX (P<0.001).

References:

1. Roy-Luzarraga M, Hodivala-Dilke K. Molecular Pathways: Endothelial Cell FAK-A Target for Cancer Treatment. Clin Cancer Res. 2016 Aug 1;22(15):3718-24. doi: 10.1158/1078-0432.CCR-14-2021. PubMed PMID: 27262114.
2. Shimizu T, Fukuoka K, Takeda M, Iwasa T, Yoshida T, Horobin J, Keegan M, Vaickus L, Chavan A, Padval M, Nakagawa K. A first-in-Asian phase 1 study to evaluate safety, pharmacokinetics and clinical activity of VS-6063, a focal adhesion kinase (FAK) inhibitor in Japanese patients with advanced solid tumors. Cancer Chemother Pharmacol. 2016 May;77(5):997-1003. doi: 10.1007/s00280-016-3010-1. PubMed PMID: 27025608; PubMed Central PMCID: PMC4844649.
3. Lee BY, Timpson P, Horvath LG, Daly RJ. FAK signaling in human cancer as a target for therapeutics. Pharmacol Ther. 2015 Feb;146:132-49. doi: 10.1016/j.pharmthera.2014.10.001. Review. PubMed PMID: 25316657.

Products are for research use only. Not for human use.