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Purity: ≥98%
Falnidamol (formerly known as BIBX 1382) is a potent and selective inhibitor EGFR inhibitor with IC50 of 3 nM and potential anticancer activities; it displays > 1000-fold lower potency against ErbB2 (IC50 = 3.4 μM) and a range of other related tyrosine kinases (IC50 > 10 μM). BIBX1382 and BIBU1361 are both potent and selective submicromolar inhibitors of the EGFR kinase activity. An IC50 value of 3 nM was determined for both compounds. The potency of these two compounds compares with the one obtained with Iressa, which is a leading EGFR inhibitor in the field. Inhibition of the closest family member, HER2, was 100- to 1000-fold less potent. Furthermore, BIBX1382 and BIBU1361 did not inhibit a number of other related tyrosine kinases.
| Targets |
BIBX 1382 targets the intracellular tyrosine kinase domain of epidermal growth factor receptor (EGFR); [1]
BIBX 1382 is a selective EGFR kinase inhibitor that does not block the activity of other tyrosine kinases; inhibits EGFR with half-maximally effective doses in the nanomolar range in EGFR-expressing KB cells (exact value not specified) [2] |
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| ln Vitro |
Falnidamol (BIBX 1382) exhibits antiproliferative activity in KB cell mitogenic assays[2].
BIBX 1382 inhibits the intracellular tyrosine kinase domain of EGFR, reverting aberrant enzymatic activity from overexpressed and constitutively activated EGFR [1] BIBX 1382 potently and selectively inhibits thymidine incorporation into EGFR-expressing KB cells with half-maximally effective doses in the nanomolar range; it is a selective EGFR kinase inhibitor that does not block the activity of other tyrosine kinases [2] |
| ln Vivo |
After two weeks of treatment, falnidamol (BIBX 1382; po; 10 mg/kg/day; 16 days) totally inhibited the growth of tumors in human A431 xenografts, with a corresponding T/C value of 15%[2]. In mice bearing A431 xenografts, falnidamol (50 mg/kg/day) causes the EGF receptor to become dephosphorylated[2]. The C4h and C24h of falnidamol (po; 10 mg/kg/day; 16 days) are 2222 and 244 nM, respectively [2].
Oral administration of BIBX 1382 inhibits the growth of established human xenografts (vulval and head and neck squamous cell carcinomas) in athymic mice; tumor growth inhibition coincides with reduced pEGFR and Ki-67 levels in vivo [2] |
| Cell Assay |
For evaluating the effect of BIBX 1382 on EGFR-expressing KB cells, thymidine incorporation assay was conducted to assess cell proliferation; the assay measured the incorporation of thymidine into cellular DNA to reflect the anti-proliferative effect of the drug, and BIBX 1382 was found to selectively and potently inhibit thymidine incorporation in KB cells with half-maximally effective doses in the nanomolar range. Additionally, experiments were performed to detect epidermal growth factor-induced phosphorylation of EGFR and downstream signaling molecules (mitogen-activated protein kinase kinase (MAPK/extracellular signal-regulated kinase kinase) and MAPK) in cells, to verify the inhibitory effect of BIBX 1382 on EGFR activity and its downstream signaling pathways [2]
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| Animal Protocol |
Animal/Disease Models: Five- to sixweeks old athymic NMRI-nu/nu female mice (21-31 g) with A431, FaDu, or HN5 cells[2]
Doses: 10 mg/kg Route of Administration: po; daily; 16 days Experimental Results: Completely suppressed tumor growth of human A431 xenografts with respective T/C values of 15 and 6% after 2 weeks of treatment. Animal/Disease Models: Five- to sixweeks old athymic NMRI-nu/nu female mice (21–31 g) with A431 cells[2] Doses: 10 mg/kg (pharmacokinetic/PK Analysis) Route of Administration: po; daily; 16 days Experimental Results: The C4h is 2222 nM and the C24h is 244 nM. Athymic mice were used to establish human xenograft models (vulval and head and neck squamous cell carcinomas). BIBX 1382 was administered to the mice via oral route (specific dosage, dissolution formula/dosage form not specified). The growth of xenograft tumors was monitored to evaluate the in vivo anti-tumor efficacy of BIBX 1382; after the experiment, tumor tissues were collected to detect the levels of pEGFR and Ki-67 by relevant methods to explore the mechanism of tumor growth inhibition [2] |
| ADME/Pharmacokinetics |
After oral administration of BIBX 1382 in humans, the plasma drug concentration was far below the expected effective concentration; a preclinically unknown, pharmacologically inactive metabolite was identified in the urine of one patient, and this metabolite was found to be abundant in the patient's plasma [1].
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| Toxicity/Toxicokinetics |
In humans receiving daily oral administration of BIBX 1382, reversible, dose-dependent elevations of liver enzymes were observed (maximum common toxicity criteria (CTC) grade: gamma-glutamyl transferase (GGT): 4, aspartate aminotransferase (GOT): 3, alanine aminotransferase (GPT): 3, alkaline phosphatase (AP): 3, bilirubin: 3); this elevation of liver enzymes was a dose-limiting factor [1]
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| References |
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| Additional Infomation |
N4-(3-chloro-4-fluorophenyl)-N6-(1-methyl-4-piperidinyl)pyrimido[5,4-d]pyrimidin-4,6-diamine is a substituted aniline. Fanidamol has been used in clinical trials to investigate the treatment of undetermined types of adult solid tumors; details are available in the trial instructions. Fanidamol is a pyrimidopyrimidine compound with antitumor activity. BIBX 1382 inhibits the intracellular tyrosine kinase domain of epidermal growth factor receptor (EGFR), thereby specifically reversing the abnormal enzymatic activity of overexpressed and constitutively activated EGFR, thus inhibiting cell proliferation and inducing cell differentiation.
BIBX 1382 is a pyrimidine derivative; a Phase I pharmacokinetic study of BIBX 1382 was conducted in 11 patients with various solid tumors (7 women, 4 men, median age 63 years, WHO PS 0:5 patients, 1:6 patients). An accelerated titration design was used, starting from the first appearance of toxicity, followed by dose escalation using a modified Fibonacci protocol (dose: 25 mg, 50 mg, 100 mg, 200 mg, 150 mg; treatment period defined as 28 days, median number of treatment periods per patient: 2, range 1–7). The trial was terminated due to dose-limiting liver enzyme elevation, low bioavailability, and detection of pharmacologically inactive metabolites [1] BIBX 1382 (N8-(3-chloro-4-fluorophenyl)-N2-(1-methylpiperidin-4-yl)-pyrimidino[5,4-d]pyrimidin-2,8-diamine) is a pyrimidinopyrimidine derivative; it belongs to a new class of selective EGFR kinase inhibitors, and the pyrimidinopyrimidine structure class is an ideal scaffold for designing EGFR inhibitors [2] |
| Molecular Formula |
C18H19CLFN7
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| Molecular Weight |
387.84
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| Exact Mass |
387.137
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| CAS # |
196612-93-8
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| Related CAS # |
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| PubChem CID |
6918508
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| Appearance |
Light yellow to khaki solid powder
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| Boiling Point |
594ºC at 760mmHg
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| Flash Point |
313.1ºC
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| Vapour Pressure |
3.15E-12mmHg at 25°C
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| Index of Refraction |
1.7
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| LogP |
5.149
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
27
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| Complexity |
479
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
FTFRZXFNZVCRSK-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C18H19ClFN7/c1-27-6-4-11(5-7-27)25-18-21-9-15-16(26-18)17(23-10-22-15)24-12-2-3-14(20)13(19)8-12/h2-3,8-11H,4-7H2,1H3,(H,21,25,26)(H,22,23,24)
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| Chemical Name |
4-N-(3-chloro-4-fluorophenyl)-6-N-(1-methylpiperidin-4-yl)pyrimido[5,4-d]pyrimidine-4,6-diamine
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 1.67 mg/mL (4.31 mM) (saturation unknown) in 10% DMSO + 40% PEG300 +5% Tween-80 + 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 16.7 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.5784 mL | 12.8919 mL | 25.7838 mL | |
| 5 mM | 0.5157 mL | 2.5784 mL | 5.1568 mL | |
| 10 mM | 0.2578 mL | 1.2892 mL | 2.5784 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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