XL999, a Spectrum Selective Kinase Inhibitor(TM) (SSKIs), is a potent inhibitor of key RTKs implicated in the development and maintenance of tumor vasculature and in the proliferation of some tumor cells. It inhibits the FGFR, VEGFR and PDGFR RTKs and exhibited excellent activity in target-specific cellular functional assays. In addition, XL999 is a potent inhibitor of FLT3, an important driver of leukemia cell proliferation in some patients with acute myelogenous leukemia (AML). In several preclinical models of human tumors, including breast, lung, colon and prostate cancer, XL999 demonstrated potent inhibition of tumor growth, and also caused regression of large well-established tumors.
Physicochemical Properties
| Molecular Formula | C26H28FN5O |
| Molecular Weight | 445.5424 |
| Exact Mass | 445.227 |
| Elemental Analysis | C, 70.09; H, 6.33; F, 4.26; N, 15.72; O, 3.59 |
| CAS # | 705946-27-6 |
| Related CAS # | 705946-27-6 |
| PubChem CID | 10433653 |
| Appearance | Light brown to brown solid powder |
| Density | 1.3±0.1 g/cm3 |
| Index of Refraction | 1.652 |
| LogP | 2.59 |
| Hydrogen Bond Donor Count | 3 |
| Hydrogen Bond Acceptor Count | 5 |
| Rotatable Bond Count | 5 |
| Heavy Atom Count | 33 |
| Complexity | 736 |
| Defined Atom Stereocenter Count | 0 |
| SMILES | N1C2=C(C=C(NC3CCN(CC)CC3)C=C2)/C(=C(\C2=CC=CC(F)=C2)/C2NC(C)=CN=2)/C1=O |
| InChi Key | DMQYDVBIPXAAJA-VHXPQNKSSA-N |
| InChi Code | InChI=1S/C26H28FN5O/c1-3-32-11-9-19(10-12-32)30-20-7-8-22-21(14-20)24(26(33)31-22)23(25-28-15-16(2)29-25)17-5-4-6-18(27)13-17/h4-8,13-15,19,30H,3,9-12H2,1-2H3,(H,28,29)(H,31,33)/b24-23- |
| Chemical Name | (3Z)-5-[(1-ethylpiperidin-4-yl)amino]-3-[(3-fluorophenyl)-(5-methyl-1H-imidazol-2-yl)methylidene]-1H-indol-2-one |
| Synonyms | XL999; XL-999; XL 999 |
| HS Tariff Code | 2934.99.9001 |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets | Flt-1 (IC50 = 4 nM); KDR (IC50 = 20 nM); PDGFRα (IC50 = 4 nM); FGFR1 (IC50 = 2 nM) |
| ln Vitro | The source of tyrosine kinase-IN-1 was compound 8K [1]. |
| ln Vivo | The PK profile of tyrosine kinase-IN-1 was reasonable (AUC(0–∞)=1.9, t1/2=4.6 h). In rats, it has a high oral bioavailability (F=63%) [1]. |
| References |
[1]. The design, synthesis, and biological evaluation of potent receptor tyrosine kinase inhibitors. Bioorganic & Medicinal Chemistry Letters 22 (2012) 4979–4985. |
| Additional Infomation |
XL999 has the potential to provide benefit to patients with lung cancer and acute myelogenous leukemia. XL999 is a new chemical entity that inhibits a spectrum of receptor tyrosine kinases (RTKs) with growth promoting and angiogenic properties, including FGFR 1/3, PDGFRα/β, VEGFR2/KDR, KIT, and FLT3. XL999 also inhibits FLT4 and SRC. XL999 has the potential to prevent tumor growth — both directly by a novel effect on tumor cell proliferation and indirectly through inhibition of the host angiogenic response. XL999 induces a cell-cycle block by a mechanism distinct from those previously identified and exhibits broad antitumor activity in xenograft models. FGFR/VEGFR/PDGFR/FLT3/SRC Inhibitor XL999 is a small molecule inhibitor of numerous tyrosine kinases (TKs) including fibroblast growth factor receptor (FGFR), vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), FMS-related tyrosine kinase 3 (FLT3), and SRC, with potential antineoplastic activity. Upon administration, XL999 binds to and inhibits the activity of these TKs, thereby preventing both the activation of downstream signaling pathways and the proliferation of tumor cells overexpressing these TKs. FGFR, VEGFR, PDGFR, FLT-3, and SRC are upregulated in a variety of cancer cell types and play key roles in tumor cell proliferation, angiogenesis, and metastasis. Drug Indication Investigated for use/treatment in cancer/tumors (unspecified), lung cancer, and solid tumors. Mechanism of Action XL999 is a potent inhibitor of key receptor tyrosine kinases implicated in the development and maintenance of tumor vasculature and in the proliferation of some tumor cells. It inhibits FGFR1, FGFR3, RET, VEGFR2 and PDGFR, and is also a potent inhibitor of FLT3, an important driver of leukemia cell proliferation in some patients with acute myelogenous leukemia (AML). XL999 exhibited excellent activity in target-specific cellular functional assays. |
Solubility Data
| Solubility (In Vitro) | DMSO: ≥ 62.5 mg/mL (~140.3 mM) |
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.67 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 20.8 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. Solubility in Formulation 2: ≥ 2.08 mg/mL (4.67 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2445 mL | 11.2223 mL | 22.4447 mL | |
| 5 mM | 0.4489 mL | 2.2445 mL | 4.4889 mL | |
| 10 mM | 0.2244 mL | 1.1222 mL | 2.2445 mL |