Tesevatinib targets multiple receptor tyrosine kinases, including EGFR, HER2, HER4, and others. By inhibiting these kinases, it blocks downstream signaling pathways that promote cell proliferation, survival, and angiogenesis. Its multi-targeting profile is designed to overcome resistance mechanisms that can arise with selective inhibitors. Its ability to cross the blood-brain barrier is a significant feature for treating central nervous system tumors.

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 vitro, Tesevatinib is a potent inhibitor of its target kinases. It shows activity against cancer cell lines that are dependent on these pathways. Its activity is characterized by its IC50 values against EGFR, HER2, and other kinases in biochemical assays. In cellular assays, it inhibits the proliferation of cancer cells and induces apoptosis.

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].
In vivo, Tesevatinib has demonstrated efficacy in preclinical models of cancer. In xenograft models, it inhibits tumor growth. Its ability to cross the blood-brain barrier has been demonstrated in animal models, supporting its potential for treating brain tumors and brain metastases.

In vitro enzyme/receptor binding studies for Tesevatinib are performed using kinase activity assays. In these assays, the recombinant kinase is incubated with ATP and a substrate in the presence of varying concentrations of the inhibitor. The inhibition of kinase activity is measured, and the IC50 value is calculated.

In vitro cellular assays for Tesevatinib are used to study its effects on cancer cells. Cells are treated with the compound, and key readouts include cell viability (MTT or CellTiter-Glo assays), apoptosis (Annexin V/PI staining), and the inhibition of target kinase phosphorylation and downstream signaling (Western blotting).

In vivo animal studies for Tesevatinib are conducted in xenograft models. Tumor-bearing mice are treated with the compound, and tumor growth inhibition is measured. Its ability to cross the blood-brain barrier is assessed in animal models of brain tumors.

Biological Half-Life
50-70 hours
Pharmacokinetic properties of Tesevatinib include good oral bioavailability and the ability to cross the blood-brain barrier. It has a molecular weight of 453.48 g/mol and a formula of C26H28ClN5O. It is metabolized in the liver.

Tesevatinib is a research compound and is not an approved drug. As a multi-kinase inhibitor, its side effects are likely similar to other drugs in its class, including diarrhea, skin rash, and hypertension. Its safety and efficacy have been evaluated in clinical trials.

[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 belongs to the quinazoline class of compounds, with its quinazoline molecule substituted at positions 4, 6, and 7 by (3,4-dichloro-2-fluorophenyl)amino, methoxy, and [(3aR,5r,6aS)-2-methyloctahydrocyclopentano[c]pyrrolo-5-yl]methoxy, respectively. It is a multi-target tyrosine kinase inhibitor that inhibits EGFR, ErbB2, KDR, Flt4, and EphB4, and possesses anticancer properties. It can function as an antitumor drug, an EC 2.7.10.1 (receptor protein tyrosine kinase) inhibitor, and an epidermal growth factor receptor antagonist. It belongs to the quinazoline class, aromatic ether class, monofluorobenzene class, dichlorobenzene class, secondary amine class, diether class, and tertiary amine class. Tesevatinib has been used in clinical trials for the treatment of various cancers, including gastric cancer, brain metastases, esophageal cancer, and leptomeningeal metastases. Tesevatinib is a potent RTK inhibitor that inhibits multiple RTKs involved in tumor cell proliferation and tumor angiogenesis (angiogenesis). Tesevatinib inhibits EGF, HER2, and VEGF RTKs, all of which are targets of currently approved cancer therapies. Furthermore, tesevatinib inhibits EphB4, an RTK highly expressed in many human tumors that plays a role in promoting angiogenesis. In various preclinical tumor models, including breast, lung, colon, and prostate cancer, XL647 has demonstrated potent inhibitory effects on tumor growth and can lead to tumor regression. In cell culture models, tesevatinib still exhibits significant inhibitory activity against mutant EGFR resistant to current EGFR inhibitors. Tesevatinib is a small molecule receptor tyrosine kinase (RTK) inhibitor with high oral bioavailability and potential antitumor activity. Tesevatinib binds to and inhibits multiple tyrosine receptor kinases that play important roles in tumor cell proliferation and tumor angiogenesis, 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 lead to inhibition of tumor growth and angiogenesis, ultimately resulting in tumor regression.

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Mechanism of Action
Tesevatinib inhibits EGF, HER2, and VEGF RTKs, all of which are targets of currently approved cancer therapies. Furthermore, tesevatinib inhibits EphB4, a receptor tyrosine kinase (RTK) highly expressed in various human tumors and plays a role in promoting angiogenesis. In multiple preclinical tumor models, including breast cancer, lung cancer, colon cancer, and prostate cancer, XL647 has demonstrated potent inhibitory effects on tumor growth and led to tumor regression. In cell culture models, tesevatinib still exhibits significant inhibitory activity against mutant EGFR cells resistant to current EGFR inhibitors.
Tesevatinib is a multi-kinase inhibitor developed for the treatment of cancer. Its CAS number is 781613-23-8. It is also known as XL-647. Its ability to cross the blood-brain barrier is a key feature for its potential use in treating brain tumors and brain metastases.

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.)