Defactinib hydrochloride | CAS#1073154-85-4 | FAK inhibitor

MedKoo Cat#: 206742 | Name: Defactinib HCl

Description:

WARNING: This product is for research use only, not for human or veterinary use.

Defactinib, also known as VS-6063 and PF04554878, is an orally bioavailable, small-molecule focal adhesion kinase (FAK) inhibitor with potential antiangiogenic and antineoplastic activities. Defactinib inhibits FAK, which may prevent the integrin-mediated activation of several downstream signal transduction pathways, including those involving RAS/MEK/ERK and PI3K/Akt, thus inhibiting tumor cell migration, proliferation, survival, and tumor angiogenesis.

Chemical Structure

Defactinib HCl

CAS#1073160-26-5 (HCl)

Theoretical Analysis

MedKoo Cat#: 206742

Name: Defactinib HCl

CAS#: 1073160-26-5 (HCl)

Chemical Formula: C20H22ClF3N8O3S

Exact Mass: 0.0000

Molecular Weight: 546.95

Elemental Analysis: C, 43.92; H, 4.05; Cl, 6.48; F, 10.42; N, 20.49; O, 8.78; S, 5.86

Price and Availability

Size	Price	Availability
10mg	USD 90.00	Ready to ship
25mg	USD 180.00	Ready to ship
50mg	USD 285.00	Ready to ship
100mg	USD 450.00	Ready to ship
200mg	USD 750.00	Ready to ship
500mg	USD 1,650.00	Ready to ship
1g	USD 2,950.00	Ready to ship
2g	USD 5,250.00	Ready to ship

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Related CAS #

1073160-26-5 (HCl) 1073154-85-4 (free base) 1345713-71-4 (free base)

Synonym

Defactinib hydrochloride; Defactinib HCl; VS6063; VS 6063; VS-6063; PF04554878; PF-04554878; PF 04554878; PF4554878; PF-4554878; PF4554878.

IUPAC/Chemical Name

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

InChi Key

RCHQNUQAHJNRBY-UHFFFAOYSA-N

InChi Code

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

SMILES Code

O=C(NC)C1=CC=C(NC2=NC=C(C(F)(F)F)C(NCC3=NC=CN=C3N(C)S(=O)(C)=O)=N2)C=C1.[H]Cl

Appearance

Solid powder

Purity

>98% (or refer to the Certificate of Analysis)

Shipping Condition

Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition

Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility

Soluble in DMSO

Shelf Life

>2 years if stored properly

Drug Formulation

This drug may be formulated in DMSO

Stock Solution Storage

0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code

2934.99.9001

More Info

Product Data

Product Data

Certificate of Analysis

View CoA: current batch, Lot#A8T08K02

QC Data

View QC data: current batch, Lot#A8T08K02

Safety Data Sheet (SDS)

View Safety Data Sheet (SDS)

Instruction

View handling instruction

Biological target:

Defactinib hydrochloride (VS-6063 hydrochloride; PF 04554878 hydrochloride) is a FAK inhibitor.

In vitro activity:

As shown in Figure 1A, defactinib treatment for 72 h dose-dependently decreased the viability of these indicated ESCC cell lines (Figure 1A). This study further observed the anti-invasive or migratory ability of defactinib in KYSE410 and KYSE510 using Transwell assay. As shown in Figure 1B,C, defactinib dose-dependently inhibited the migration and invasion of indicated ESCC cells. Taken together, these results indicate that defactinib exerts excellent antitumor effects in ESCC cells. Reference: Mol Carcinog. 2021 Feb;60(2):113-124. https://pubmed.ncbi.nlm.nih.gov/33283357/

In vivo activity:

In this study, FAK expression was elevated significantly in the subchondral bone of the vehicle-treated ACLT mice in comparison with the sham controls and defactinib (FAK inhibitor)-treated ACLT mice (Fig. 1A). Through CT-based microangiography, the vessel number (VN) and vessel volume/total tissue volume (VV/TV) increased significantly in the subchondral bone of the vehicle-treated ACLT mice (Fig. 1B–D), whereas defactinib treatment normalized them. These demonstrated that the vasculature in the subchondral bone was significantly elevated during the onset of OA. The increase in the vasculature was from H-type vessels. Double immunofluorescence staining of CD31 and endomucin revealed a significant increase in H-type vessels (CD31+ endomucin+) in the subchondral bone marrow of vehicle-treated ACLT mice, whereas defactinib treatment lowered H-type vessels with no significant difference relative to the sham controls (Fig. 1E and F). Taken together, these results demonstrate that an increase in FAK modulates H-type vessel formation during the onset of OA. Reference: J Orthop Translat. 2020 Sep; 24: 12–22. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7261948/

	Solvent	mg/mL	mM
Solubility
	DMSO	30.0	54.85

Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 546.95 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Concentration / Solvent Volume / Mass	1 mg	5 mg	10 mg
1 mM	1.15 mL	5.76 mL	11.51 mL
5 mM	0.23 mL	1.15 mL	2.3 mL
10 mM	0.12 mL	0.58 mL	1.15 mL
50 mM	0.02 mL	0.12 mL	0.23 mL

Formulation protocol:

1. Fu Y, Zhang Y, Lei Z, Liu T, Cai T, Wang A, Du W, Zeng Y, Zhu J, Liu Z, Huang JA. Abnormally activated OPN/integrin αVβ3/FAK signalling is responsible for EGFR-TKI resistance in EGFR mutant non-small-cell lung cancer. J Hematol Oncol. 2020 Dec 7;13(1):169. doi: 10.1186/s13045-020-01009-7. PMID: 33287873; PMCID: PMC7720454. 2. Zhang L, Zhao D, Wang Y, Zhang W, Zhang J, Fan J, Zhan Q, Chen J. Focal adhesion kinase (FAK) inhibitor-defactinib suppresses the malignant progression of human esophageal squamous cell carcinoma (ESCC) cells via effective blockade of PI3K/AKT axis and downstream molecular network. Mol Carcinog. 2021 Feb;60(2):113-124. doi: 10.1002/mc.23273. Epub 2020 Dec 6. PMID: 33283357. 3. Hu Y, Wu H, Xu T, Wang Y, Qin H, Yao Z, Chen P, Xie Y, Ji Z, Yang K, Chai Y, Zhang X, Yu B, Cui Z. Defactinib attenuates osteoarthritis by inhibiting positive feedback loop between H-type vessels and MSCs in subchondral bone. J Orthop Translat. 2020 May 19;24:12-22. doi: 10.1016/j.jot.2020.04.008. PMID: 32518750; PMCID: PMC7261948. 4. Kolev VN, Tam WF, Wright QG, McDermott SP, Vidal CM, Shapiro IM, Xu Q, Wicha MS, Pachter JA, Weaver DT. Inhibition of FAK kinase activity preferentially targets cancer stem cells. Oncotarget. 2017 Jun 16;8(31):51733-51747. doi: 10.18632/oncotarget.18517. PMID: 28881682; PMCID: PMC5584283.

In vitro protocol:

In vivo protocol:

1. Hu Y, Wu H, Xu T, Wang Y, Qin H, Yao Z, Chen P, Xie Y, Ji Z, Yang K, Chai Y, Zhang X, Yu B, Cui Z. Defactinib attenuates osteoarthritis by inhibiting positive feedback loop between H-type vessels and MSCs in subchondral bone. J Orthop Translat. 2020 May 19;24:12-22. doi: 10.1016/j.jot.2020.04.008. PMID: 32518750; PMCID: PMC7261948. 2. Kolev VN, Tam WF, Wright QG, McDermott SP, Vidal CM, Shapiro IM, Xu Q, Wicha MS, Pachter JA, Weaver DT. Inhibition of FAK kinase activity preferentially targets cancer stem cells. Oncotarget. 2017 Jun 16;8(31):51733-51747. doi: 10.18632/oncotarget.18517. PMID: 28881682; PMCID: PMC5584283.

1: Ryzhakov G, Almuttaqi H, Corbin AL, Berthold DL, Khoyratty T, Eames HL, Bullers S, Pearson C, Ai Z, Zec K, Bonham S, Fischer R, Jostins-Dean L, Travis SPL, Kessler BM, Udalova IA. Defactinib inhibits PYK2 phosphorylation of IRF5 and reduces intestinal inflammation. Nat Commun. 2021 Nov 18;12(1):6702. doi: 10.1038/s41467-021-27038-5. PMID: 34795257; PMCID: PMC8602323. 2: Wang-Gillam A, Lim KH, McWilliams R, Suresh R, Lockhart AC, Brown A, Breden M, Belle JI, Herndon J, Bogner SJ, Pedersen K, Tan B, Boice N, Acharya A, Abdiannia M, Gao F, Yoon HH, Zhu M, Trikalinos NA, Ratner L, Aranha O, Hawkins WG, Herzog BH, DeNardo DG. Defactinib, Pembrolizumab, and Gemcitabine in Patients with Advanced Treatment Refractory Pancreatic Cancer: A Phase I Dose Escalation and Expansion Study. Clin Cancer Res. 2022 Dec 15;28(24):5254-5262. doi: 10.1158/1078-0432.CCR-22-0308. PMID: 36228156; PMCID: PMC9772237. 3: Hosein AN, Brekken RA, Maitra A. Pancreatic cancer stroma: an update on therapeutic targeting strategies. Nat Rev Gastroenterol Hepatol. 2020 Aug;17(8):487-505. doi: 10.1038/s41575-020-0300-1. Epub 2020 May 11. PMID: 32393771; PMCID: PMC8284850. 4: Hu Y, Wu H, Xu T, Wang Y, Qin H, Yao Z, Chen P, Xie Y, Ji Z, Yang K, Chai Y, Zhang X, Yu B, Cui Z. Defactinib attenuates osteoarthritis by inhibiting positive feedback loop between H-type vessels and MSCs in subchondral bone. J Orthop Translat. 2020 May 19;24:12-22. doi: 10.1016/j.jot.2020.04.008. PMID: 32518750; PMCID: PMC7261948. 5: Lander VE, Belle JI, Kingston NL, Herndon JM, Hogg GD, Liu X, Kang LI, Knolhoff BL, Bogner SJ, Baer JM, Zuo C, Borcherding NC, Lander DP, Mpoy C, Scott J, Zahner M, Rogers BE, Schwarz JK, Kim H, DeNardo DG. Stromal Reprogramming by FAK Inhibition Overcomes Radiation Resistance to Allow for Immune Priming and Response to Checkpoint Blockade. Cancer Discov. 2022 Dec 2;12(12):2774-2799. doi: 10.1158/2159-8290.CD-22-0192. PMID: 36165893; PMCID: PMC9722639. 6: Fennell DA, Baas P, Taylor P, Nowak AK, Gilligan D, Nakano T, Pachter JA, Weaver DT, Scherpereel A, Pavlakis N, van Meerbeeck JP, Cedrés S, Nolan L, Kindler H, Aerts JGJV. Maintenance Defactinib Versus Placebo After First-Line Chemotherapy in Patients With Merlin-Stratified Pleural Mesothelioma: COMMAND-A Double-Blind, Randomized, Phase II Study. J Clin Oncol. 2019 Apr 1;37(10):790-798. doi: 10.1200/JCO.2018.79.0543. Epub 2019 Feb 20. PMID: 30785827. 7: Capelletto E, Bironzo P, Denis L, Koustenis A, Bungaro M, Novello S. Single agent VS-6766 or VS-6766 plus defactinib in KRAS-mutant non-small-cell lung cancer: the RAMP-202 phase II trial. Future Oncol. 2022 May;18(16):1907-1915. doi: 10.2217/fon-2021-1582. Epub 2022 Mar 14. PMID: 35285277. 8: Fu Y, Zhang Y, Lei Z, Liu T, Cai T, Wang A, Du W, Zeng Y, Zhu J, Liu Z, Huang JA. Abnormally activated OPN/integrin αVβ3/FAK signalling is responsible for EGFR-TKI resistance in EGFR mutant non-small-cell lung cancer. J Hematol Oncol. 2020 Dec 7;13(1):169. doi: 10.1186/s13045-020-01009-7. PMID: 33287873; PMCID: PMC7720454. 9: Zhang L, Zhao D, Wang Y, Zhang W, Zhang J, Fan J, Zhan Q, Chen J. Focal adhesion kinase (FAK) inhibitor-defactinib suppresses the malignant progression of human esophageal squamous cell carcinoma (ESCC) cells via effective blockade of PI3K/AKT axis and downstream molecular network. Mol Carcinog. 2021 Feb;60(2):113-124. doi: 10.1002/mc.23273. Epub 2020 Dec 6. PMID: 33283357. 10: Allert C, Waclawiczek A, Zimmermann SMN, Göllner S, Heid D, Janssen M, Renders S, Rohde C, Bauer M, Bruckmann M, Zinz R, Pauli C, Besenbeck B, Wickenhauser C, Trumpp A, Krijgsveld J, Müller-Tidow C, Blank MF. Protein tyrosine kinase 2b inhibition reverts niche-associated resistance to tyrosine kinase inhibitors in AML. Leukemia. 2022 Oct;36(10):2418-2429. doi: 10.1038/s41375-022-01687-x. Epub 2022 Sep 2. PMID: 36056084; PMCID: PMC9522596. 11: Guo C, Li Q, Xiao J, Ma F, Xia X, Shi M. Identification of defactinib derivatives targeting focal adhesion kinase using ensemble docking, molecular dynamics simulations and binding free energy calculations. J Biomol Struct Dyn. 2023 Oct-Nov;41(18):8654-8670. doi: 10.1080/07391102.2022.2135601. Epub 2022 Oct 25. PMID: 36281703. 12: Lopez-Mejia IC, Pijuan J, Navaridas R, Santacana M, Gatius S, Velasco A, Castellà G, Panosa A, Cabiscol E, Pinyol M, Coll L, Bonifaci N, Peña LP, Vidal A, Villanueva A, Gari E, Llobet-Navàs D, Fajas L, Matias-Guiu X, Yeramian A. Oxidative stress-induced FAK activation contributes to uterine serous carcinoma aggressiveness. Mol Oncol. 2023 Jan;17(1):98-118. doi: 10.1002/1878-0261.13346. Epub 2022 Dec 7. PMID: 36409196; PMCID: PMC9812840. 13: Hallur G, Tamizharasan N, Sulochana SP, Saini NK, Zainuddin M, Mullangi R. LC-ESI-MS/MS determination of defactinib, a novel FAK inhibitor in mice plasma and its application to a pharmacokinetic study in mice. J Pharm Biomed Anal. 2018 Feb 5;149:358-364. doi: 10.1016/j.jpba.2017.11.022. Epub 2017 Nov 10. PMID: 29145097. 14: Lin HM, Lee BY, Castillo L, Spielman C, Grogan J, Yeung NK, Kench JG, Stricker PD, Haynes AM, Centenera MM, Butler LM, Shreeve SM, Horvath LG, Daly RJ. Effect of FAK inhibitor VS-6063 (defactinib) on docetaxel efficacy in prostate cancer. Prostate. 2018 Mar;78(4):308-317. doi: 10.1002/pros.23476. Epub 2018 Jan 5. PMID: 29314097. 15: Xie M, Sun M, Ji X, Li D, Chen X, Zhang B, Huang W, Zhang T, Wang Y, Tian D, Xia L. Overexpression of BACH1 mediated by IGF2 facilitates hepatocellular carcinoma growth and metastasis via IGF1R and PTK2. Theranostics. 2022 Jan 1;12(3):1097-1116. doi: 10.7150/thno.65775. PMID: 35154476; PMCID: PMC8771560. 16: Masuda K, Ishiki H, Oyamada S, Shimizu M, Kiuchi D, Satomi E. Questions Regarding the Randomized Phase II Trial of Defactinib as Maintenance Therapy in Malignant Pleural Mesothelioma. J Clin Oncol. 2019 Sep 1;37(25):2293-2294. doi: 10.1200/JCO.19.00891. Epub 2019 Jul 22. PMID: 31329518. 17: Gerber DE, Camidge DR, Morgensztern D, Cetnar J, Kelly RJ, Ramalingam SS, Spigel DR, Jeong W, Scaglioni PP, Zhang S, Li M, Weaver DT, Vaikus L, Keegan M, Horobin JC, Burns TF. Phase 2 study of the focal adhesion kinase inhibitor defactinib (VS-6063) in previously treated advanced KRAS mutant non-small cell lung cancer. Lung Cancer. 2020 Jan;139:60-67. doi: 10.1016/j.lungcan.2019.10.033. Epub 2019 Nov 4. PMID: 31739184; PMCID: PMC6942685. 18: Zhang T, Wang Y, Xie M, Ji X, Luo X, Chen X, Zhang B, Liu D, Feng Y, Sun M, Huang W, Xia L. HGF-mediated elevation of ETV1 facilitates hepatocellular carcinoma metastasis through upregulating PTK2 and c-MET. J Exp Clin Cancer Res. 2022 Sep 16;41(1):275. doi: 10.1186/s13046-022-02475-2. PMID: 36109787; PMCID: PMC9479266. 19: Fennell DA, Baitei EY. Mesothelioma: Hippo pathway as a target, lessons from COMMAND. Oncotarget. 2019 Jun 18;10(40):3996-3997. doi: 10.18632/oncotarget.27018. PMID: 31976036; PMCID: PMC6956825. 20: Fennell DA, Taylor P, Gilligan D, Nakano T, Scherpereel A, Pavlakis N, van Meerbeeck JP, Aerts JGJV, Nowak AK, Kindler H, Baas P. Reply to K. Masuda et al. J Clin Oncol. 2019 Sep 1;37(25):2294-2295. doi: 10.1200/JCO.19.01208. Epub 2019 Jul 22. PMID: 31329517.