Tesevatinib (XL-647) potently inhibits the VEGF, ephrin RTK, and EGF/ErbB2 families. One reversible ATP competitive inhibitor is tesevatinib (XL-647). Ten tyrosine kinases, such as insulin and insulin-like growth factor-1 receptors, and fifty-five serine-threonine kinases, such as cyclin-dependent kinases, stress-activated proteins kinase, and protein kinase C isoform, are the targets of tesevatinib (XL-647). Tesevatinib (XL-647) inactivates the EGFR pathway and prevents cell division de the erlotinib-resistant H1975 cell line that carries two EGFR double mutations (L858R and T790M). Tesevatinib (XL-647) has an IC50 value of 13 nM, which lowers cell viability in A431 cells [1].

In vivo, tesevatinib (XL-647) exhibits a strong and sustained suppression of WT EGFR. Tesevatinib (XL-647) decreases tumor EGFR signaling, tumor vascular density, and H1975 xenograft tumor development considerably [1].

Biological Half-Life
50-70 hours

[1]. Inhibition of the T790M gatekeeper mutant of the epidermal growth factor receptor by EXEL-7647. Clin Cancer Res. 2007 Jun 15;13(12):3713-23.

Tesevatinib is a member of the class of quinazolines that is quinazoline substituted by (3,4-dichloro-2-fluorophenyl)amino, methoxy, and [(3aR,5r,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl]methoxy groups at positions 4, 6 and 7, respectively. It is a multi-target tyrosine kinase inhibitor of EGFR, ErbB2, KDR, Flt4 and EphB4 and exhibits anti-cancer properties. It has a role as an antineoplastic agent, an EC 2.7.10.1 (receptor protein-tyrosine kinase) inhibitor and an epidermal growth factor receptor antagonist. It is a member of quinazolines, an aromatic ether, a member of monofluorobenzenes, a dichlorobenzene, a secondary amino compound, a diether and a tertiary amino compound.
Tesevatinib has been used in trials studying the treatment of Cancer, Stomach Cancer, Brain Metastases, Esophageal Cancer, and Leptomeningeal Metastases, among others. Tesevatinib is a potent inhibitor of multiple RTKs implicated in driving tumor cell proliferation and tumor vascularization (blood vessel formation). Tesevatinib inhibits the EGF, HER2, and VEGF RTKs, each of which is a target of currently approved cancer therapies. In addition, tesevatinib inhibits EphB4, an RTK that is highly expressed in many human tumors and plays a role in promoting angiogenesis. In a broad array of preclinical tumor models including breast, lung, colon and prostate cancer, XL647 demonstrated potent inhibition of tumor growth and causes tumor regression. In cell culture models, tesevatinib retains significant potency against mutant EGFRs that are resistant to current EGFR inhibitors.
Tesevatinib is an orally bioavailable small-molecule receptor tyrosine kinase (RTK) inhibitor with potential antineoplastic activity. Tesevatinib binds to and inhibits several tyrosine receptor kinases that play major roles in tumor cell proliferation and tumor vascularization, including epidermal growth factor receptor (EGFR; ERBB1), epidermal growth factor receptor 2 (HER2; ERBB2), vascular endothelial growth factor receptor (VEGFR), and ephrin B4 (EphB4). This may result in the inhibition of tumor growth and angiogenesis, and tumor regression.

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Mechanism of Action
Tesevatinib inhibits the EGF, HER2, and VEGF RTKs, each of which is a target of currently approved cancer therapies. In addition, tesevatinib inhibits EphB4, an RTK that is highly expressed in many human tumors and plays a role in promoting angiogenesis. In a broad array of preclinical tumor models including breast, lung, colon and prostate cancer, XL647 demonstrated potent inhibition of tumor growth and causes tumor regression. In cell culture models, tesevatinib retains significant potency against mutant EGFRs that are resistant to current EGFR inhibitors.

C24H25CL2FN4O2

491.3853

490.133

781613-23-8

781613-23-8; 874286-84-7;

10458325

White to off-white solid powder

1.4±0.1 g/cm3

567.9±50.0 °C at 760 mmHg

297.3±30.1 °C

0.0±1.6 mmHg at 25°C

1.633

5.98

1

7

6

33

652

2

CN1C[C@H]2CC(C[C@H]2C1)COC3=C(C=C4C(=C3)N=CN=C4NC5=C(C(=C(C=C5)Cl)Cl)F)OC

RTIZZWMBGKGLFO-YWQXDYITSA-N

InChI=1S/C39H38N4O5/c1-42-34(22-27-8-5-4-6-9-27)38(45)41-33(39(42)46)21-28-10-7-11-30(20-28)37(44)40-32-14-12-26(13-15-32)16-18-43-19-17-29-23-35(47-2)36(48-3)24-31(29)25-43/h4-15,20-24H,16-19,25H2,1-3H3,(H,40,44)(H,41,45)/b33-21-,34-22-

N-(3,4-dichloro-2-fluorophenyl)-6-methoxy-7-(((3aR,6aS)-2-methyloctahydrocyclopenta[c]pyrrol-5-yl)methoxy)quinazolin-4-amine.

XL-647 EXEL7647 KD-019XL 647 EXEL-7647 KD019XL647 EXEL7647 KD 019.

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~100 mg/mL (~203.50 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.09 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (5.09 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)