WARNING: This product is for research use only, not for human or veterinary use.
MedKoo CAT#: 205660
CAS#: 845272-21-1
Description: Varlitinib, also known as ARRY-543 and ASLAN001, is an orally bioavailable inhibitor of the epidermal growth factor receptor family with potential antineoplastic activity. Varlitinib selectively and reversibly binds to both EGFR (ErbB-1) and Her-2/neu (ErbB-2) and prevents their phosphorylation and activation, which may result in inhibition of the associated signal transduction pathways, inhibition of cellular proliferation and cell death. EGFR and Her-2 play important roles in cell proliferation and differentiation and are upregulated in various human tumor cell types.
MedKoo Cat#: 205660
Name: Varlitinib
CAS#: 845272-21-1
Chemical Formula: C22H19ClN6O2S
Exact Mass: 466.09787
Molecular Weight: 466.94
Elemental Analysis: C, 56.59; H, 4.10; Cl, 7.59; N, 18.00; O, 6.85; S, 6.87
Synonym: ASLAN001; ASLAN-001; ASLAN 001; AR 00334543; ARRY334543; ARRY-334543; ARRY543; ARRY-543; ARRY 543; Varlitinib.
IUPAC/Chemical Name: (R)-N4-(3-chloro-4-(thiazol-2-ylmethoxy)phenyl)-N6-(4-methyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine.
InChi Key: UWXSAYUXVSFDBQ-CYBMUJFWSA-N
InChi Code: InChI=1S/C22H19ClN6O2S/c1-13-10-31-22(27-13)29-14-2-4-18-16(8-14)21(26-12-25-18)28-15-3-5-19(17(23)9-15)30-11-20-24-6-7-32-20/h2-9,12-13H,10-11H2,1H3,(H,27,29)(H,25,26,28)/t13-/m1/s1
SMILES Code: C[C@H]1N=C(NC2=CC3=C(NC4=CC=C(OCC5=NC=CS5)C(Cl)=C4)N=CN=C3C=C2)OC1
Appearance: White solid powder
Purity: >98% (or refer to the Certificate of Analysis)
Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility: Soluble in DMSO, not in water
Shelf Life: >2 years if stored properly
Drug Formulation: This drug may be formulated in DMSO
Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code: 2934.99.9001
| Biological target: | Varlitinib (ASLAN001) is a potent, reversible, small molecule pan-EGFR inhibitor with IC50s of 7, 2, 4 nM for HER1, HER2 and HER4, respectively |
| In vitro activity: | In this study, the efficacy of varlitinib, a reversible small molecule pan-HER inhibitor in TNBC was evaluated. To explore varlitinib’s anti-tumor activity, cells were treated with varlitinib at various concentrations. Compared with MCF 10A cell lines, most of the cell lines exhibited lower IC50 except MDA-MB-231 cells (Figure 1B and Figure S1). Moreover, varlitinib significantly induced cell apoptosis in MDA-MB-453 and MDA-MB-468 cells but not in MDA-MB-231 cells (Figure 1B,C). Data showed varlitinib reduced pEGFR, pHER3 and pHER4 in MDA-MB-468 cells as well as reduced pHER2 in SK-BR-3 cells (Figure 2A,B). Activation of HER receptors leads to the activation of downstream pathways including RAS/RAF/MEK/ERK and PI3K/Akt signaling. The western blot results demonstrated that varlitinib treatment inhibited EGFR, AKT, MEK and ERK activation in MDA-MB-453 and MDA-MB-468 cells. In addition, varlitinib treatment also resulted in increased levels of cleaved PARP and cleaved Caspase-3 in these TNBC cell lines. Conversely, varlitinib did not inhibit MEK/ERK signaling in MDA-MB-231 cells (Figure 2C). Our results showed that varlitinib treatment inhibited cell migration, invasion and mammosphere formation of MDA-MB-231 and MDA-MB-468 cells (Figure 4A–C). Cancers (Basel). 2019 Jan; 11(1): 105. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6356324/ |
| In vivo activity: | Nude mice were subcutaneously implanted with MDA-MB-468 cells to evaluate anti-tumor activity of varlitinib. Once xenograft tumor sizes reached 200 mm3 varlitinib were orally administered. Varlitinib suppressed tumor growth in MDA-MB-468 xenograft mice with no effect on body weight (Figure 5A–C). In comparison to the control group, varlitinib treatment significantly suppressed EGFR and ERK activation with increased PARP cleavage (Figure 5D). Immunohistochemical staining was performed to further examine protein expression and localization within the xenograft tumors. The results showed that varlitinib treatment reduced EGFR and ERK phosphorylation and elicited cell apoptosis with M30 staining (Figure 5D,E). These results demonstrated varlitinib exerting anti-tumor activity in TNBC via the inhibition of HER receptor and downstream signaling. Cancers (Basel). 2019 Jan; 11(1): 105. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6356324/ |
| Solvent | Max Conc. mg/mL | Max Conc. mM | |
|---|---|---|---|
| Solubility | |||
| DMSO | 20.0 | 43.55 |
The following data is based on the product molecular weight 466.94 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.
| Concentration / Solvent Volume / Mass | 1 mg | 5 mg | 10 mg |
|---|---|---|---|
| 1 mM | 1.15 mL | 5.76 mL | 11.51 mL |
| 5 mM | 0.23 mL | 1.15 mL | 2.3 mL |
| 10 mM | 0.12 mL | 0.58 mL | 1.15 mL |
| 50 mM | 0.02 mL | 0.12 mL | 0.23 mL |
| Formulation protocol: | 1. Liu CY, Chu PY, Huang CT, Chen JL, Yang HP, Wang WL, Lau KY, Lee CH, Lan TY, Huang TT, Lin PH, Dai MS, Tseng LM. Varlitinib Downregulates HER/ERK Signaling and Induces Apoptosis in Triple Negative Breast Cancer Cells. Cancers (Basel). 2019 Jan 17;11(1):105. doi: 10.3390/cancers11010105. PMID: 30658422; PMCID: PMC6356324. 2. Dokduang H, Jamnongkarn W, Promraksa B, Suksawat M, Padthaisong S, Thanee M, Phetcharaburanin J, Namwat N, Sangkhamanon S, Titapun A, Khuntikeo N, Klanrit P, Loilome W. In vitro and in vivo Anti-Tumor Effects of Pan-HER Inhibitor Varlitinib on Cholangiocarcinoma Cell Lines. Drug Des Devel Ther. 2020 Jun 11;14:2319-2334. doi: 10.2147/DDDT.S250061. PMID: 32606601; PMCID: PMC7296552. 3. Liu CY, Chu PY, Huang CT, Chen JL, Yang HP, Wang WL, Lau KY, Lee CH, Lan TY, Huang TT, Lin PH, Dai MS, Tseng LM. Varlitinib Downregulates HER/ERK Signaling and Induces Apoptosis in Triple Negative Breast Cancer Cells. Cancers (Basel). 2019 Jan 17;11(1):105. doi: 10.3390/cancers11010105. PMID: 30658422; PMCID: PMC6356324. 4. Dokduang H, Jamnongkarn W, Promraksa B, Suksawat M, Padthaisong S, Thanee M, Phetcharaburanin J, Namwat N, Sangkhamanon S, Titapun A, Khuntikeo N, Klanrit P, Loilome W. In vitro and in vivo Anti-Tumor Effects of Pan-HER Inhibitor Varlitinib on Cholangiocarcinoma Cell Lines. Drug Des Devel Ther. 2020 Jun 11;14:2319-2334. doi: 10.2147/DDDT.S250061. PMID: 32606601; PMCID: PMC7296552. |
| In vitro protocol: | 1. Liu CY, Chu PY, Huang CT, Chen JL, Yang HP, Wang WL, Lau KY, Lee CH, Lan TY, Huang TT, Lin PH, Dai MS, Tseng LM. Varlitinib Downregulates HER/ERK Signaling and Induces Apoptosis in Triple Negative Breast Cancer Cells. Cancers (Basel). 2019 Jan 17;11(1):105. doi: 10.3390/cancers11010105. PMID: 30658422; PMCID: PMC6356324. 2. Dokduang H, Jamnongkarn W, Promraksa B, Suksawat M, Padthaisong S, Thanee M, Phetcharaburanin J, Namwat N, Sangkhamanon S, Titapun A, Khuntikeo N, Klanrit P, Loilome W. In vitro and in vivo Anti-Tumor Effects of Pan-HER Inhibitor Varlitinib on Cholangiocarcinoma Cell Lines. Drug Des Devel Ther. 2020 Jun 11;14:2319-2334. doi: 10.2147/DDDT.S250061. PMID: 32606601; PMCID: PMC7296552. |
| In vivo protocol: | 1. Liu CY, Chu PY, Huang CT, Chen JL, Yang HP, Wang WL, Lau KY, Lee CH, Lan TY, Huang TT, Lin PH, Dai MS, Tseng LM. Varlitinib Downregulates HER/ERK Signaling and Induces Apoptosis in Triple Negative Breast Cancer Cells. Cancers (Basel). 2019 Jan 17;11(1):105. doi: 10.3390/cancers11010105. PMID: 30658422; PMCID: PMC6356324. 2. Dokduang H, Jamnongkarn W, Promraksa B, Suksawat M, Padthaisong S, Thanee M, Phetcharaburanin J, Namwat N, Sangkhamanon S, Titapun A, Khuntikeo N, Klanrit P, Loilome W. In vitro and in vivo Anti-Tumor Effects of Pan-HER Inhibitor Varlitinib on Cholangiocarcinoma Cell Lines. Drug Des Devel Ther. 2020 Jun 11;14:2319-2334. doi: 10.2147/DDDT.S250061. PMID: 32606601; PMCID: PMC7296552. |
1. Wallace, Eli et al, Preparation of aminoquinazolines as receptor tyrosine kinase inhibitors, U.S. Pat. Appl. Publ., 20050043334, 24 Feb 2005.
ARRY-543 is a novel, oral ErbB family inhibitor that, unlike approved ErbB inhibitors, targets all members of the ErbB family, including ErbB3, either directly or indirectly, and has potential advantages in treating tumors that signal through multiple ErbB family members. ARRY-543 showed benefit in preclinical tumor models that signal through multiple ErbB family members, as well as its efficacy in preclinical models when compared to, and combined with, Herceptin (trastuzumab), Xeloda (capecitabine) and Taxotere (docetaxel) – widely used treatments for solid tumors.
