Tarloxotinib bromide 1636180-98-7_EGFR_Protein Tyrosine Kinase_Signaling Pathways_Products

Tarloxotinib bromide (formerly TH-4000; PR-610) is a novel quarternary amine-based and irreversible EGFR/HER2 inhibitor designed as a prodrug to selectively release a covalent (irreversible (covalent)) EGFR tyrosine kinase inhibitor under severe hypoxia, a feature of many solid tumors. Tarloxotinib may be able to reduce or eliminate the systemic side effects of EGFR tyrosine kinase inhibitors that are currently on the market by effectively blocking aberrant EGFR signaling in a tumor-specific manner.

Physicochemical Properties

Molecular Formula	C24H24BR2CLN9O3
Molecular Weight	681.766860961914
Exact Mass	679.005
Elemental Analysis	C, 42.28; H, 3.55; Br, 23.44; Cl, 5.20; N, 18.49; O, 7.04
CAS #	1636180-98-7
Related CAS #	1636938-13-0 (cation);1636180-98-7 (bromide);
PubChem CID	51038315
Appearance	Light yellow to yellow solid powder
Hydrogen Bond Donor Count	2
Hydrogen Bond Acceptor Count	9
Rotatable Bond Count	8
Heavy Atom Count	39
Complexity	863
Defined Atom Stereocenter Count	0
SMILES	BrC1=C(C=CC(=C1)NC1C2C(=CN=C(C=2)NC(/C=C/C[N+](C)(C)CC2=C([N+](=O)[O-])N=CN2C)=O)N=CN=1)Cl.[Br-]
InChi Key	WAKIMVYUBWMMHJ-FXRZFVDSSA-N
InChi Code	InChI=1S/C24H23BrClN9O3.BrH/c1-33-14-30-24(34(37)38)20(33)12-35(2,3)8-4-5-22(36)32-21-10-16-19(11-27-21)28-13-29-23(16)31-15-6-7-18(26)17(25)9-15;/h4-7,9-11,13-14H,8,12H2,1-3H3,(H-,27,28,29,31,32,36);1H/b5-4+;
Chemical Name	[(E)-4-[[4-(3-bromo-4-chloroanilino)pyrido[3,4-d]pyrimidin-6-yl]amino]-4-oxobut-2-enyl]-dimethyl-[(3-methyl-5-nitroimidazol-4-yl)methyl]azanium;bromide
Synonyms	TH-4000; TH 4000; TH4000; PR-610; PR610; PR 610; Tarloxotinib bromide; Hypoxin; Tarloxotinib
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 Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.
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

EGFR/HER2

ln Vitro

Tarloxotinib bromide is demonstrated to be metabolized efficiently under hypoxia using a panel of human NSCLC cell lines (rate of TKI release 0.4-2.1 nM/hr/10⁶ cells), a process that is inhibited by oxygen (TKI release <0.002 nM/hr/10⁶ cells), in order to confirm the mechanism of action. Tarloxotinib bromide activity is reduced 14–80 fold compared to TKI in cellular anti-proliferative and receptor phosphorylation assays. Hyperbaric oxygen breathing, as opposed to air breathing controls, suppresses the release of TKI from tarloxotinib bromide by >80% (538 vs. 99 nM/kg; p<0.01) using PC9 tumors. The combined information confirms that tarloxotinib bromide is an irreversible EGFR-TKI that is activated by hypoxia and indicates that it is more active than erlotinib[2].

ln Vivo

Tarloxotinib bromide activity against each EGFR-TKI is benchmarked using a prototypic WT EGFR driven xenograft model (A431), which is created by "retrotranslation" of reported plasma exposure for each agent in human subjects back to the xenograft model. Tumor regression and long-lasting suppression of WT EGFR tumor phosphorylation are only linked to treatment with clinically relevant doses and schedules of tarloxotinib bromide. In agreement with these results, treatment with taroxotinib bromide has also been shown to regress the WT EGFR NSCLC tumor models H125 and H1648, indicating that taloxotinib bromide offers the required therapeutic index to inhibit WT EGFR in vivo[1].

References

[1]. Abstract A67: Preclinical efficacy of tarloxotinib bromide (TH-4000), a hypoxia-activated EGFR/HER2 inhibitor: rationale for clinical evaluation in EGFR mutant, T790M-negative NSCLC following progression on EGFR-TKI therapy. Abstracts: AACR-

[2]. Abstract 5358: The hypoxia-activated EGFR-TKI TH-4000 overcomes erlotinib-resistance in preclinical NSCLC models at plasma levels achieved in a Phase 1 clinical trial. AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA.

Solubility Data

Solubility (In Vitro)

DMSO: ≥ 33 mg/mL (~48.4 mM)

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 2.5 mg/mL (3.67 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 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.

Solubility in Formulation 2: ≥ 2.5 mg/mL (3.67 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 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.

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

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	1.4668 mL	7.3339 mL	14.6677 mL
	5 mM	0.2934 mL	1.4668 mL	2.9335 mL
	10 mM	0.1467 mL	0.7334 mL	1.4668 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.

PeptideDB

Tarloxotinib bromide 1636180-98-7

CAS No.: 1636180-98-7

Physicochemical Properties

Biological Activity

Solubility Data