HER1 (IC50 = 7 nM); HER2 (IC50 = 2 nM); HER4 (IC50 = 4 nM)

Varlitinib (ARRY-334543) treatment significantly slows the growth of tumors; full tumor regression is seen at dosages of 100 mg/kg twice daily. The phosphorylation of HER1-3, RAS/RAF/MEK/MAPK, p70S6K, S6 ribosomal, 4EBP1, Cdk-2, Cdc-2, and retinoblastoma is significantly inhibited after five days of Varlitinib treatment. Treatment with varlitinib causes survivin to significantly decrease while Caspase 3 cleavage products increase simultaneously[1]. Varlitinib (ARRY-334543), when taken orally twice a day for 21 days, significantly inhibits the growth of A431-derived tumors in murine xenograft models at doses of 25, 50, and 100 mg/kg[2].

Varlitinib (ARRY-334543; ASLAN001) is a novel, potent, reversible, small molecule pan-EGFR inhibitor with IC50s of 7, 2, 4 nM for HER1, HER2 and HER4, respectively.

Varlitinib (ARRY-334543) potently inhibits substrate phosphorylation in cell-based assays with tumor cells that overexpress EGFR (A431) or ErbB-2 (BT474). When tested against a panel of 104 kinases, varlitinib is found to be highly selective for EGFR/ErbB-2 and to exhibit no discernible activity.

Mice: In SCID mice (HCC29-0909A) bearing patient-derived HCC xenografts co-expressing HER1, HER2, and HER3 receptors, the effects of varlitinib are examined. When the tumors in mice get to be as big as 100–150 mm³, they are treated with varlitinib. Twice a week, tumor volumes are computed and tumor sizes are measured[1].

[1]. Varlitinib to demonstrate anti-tumour efficacy in patient-derived hepatocellular carcinoma xenograft models. Journal of Clinical Oncology 34, no. 15_suppl

[2]. ARRY-334543, A potent, orally active small molecule inhibitor of EGFR and ErbB-2.Proc Amer Assoc Cancer Res (2005) 65 (9_Supplement): 801.

Varlitinib is a member of the class of quinazolines that is quinazoline substituted by {3-chloro-4-[(1,3-thiazol-2-yl)methoxy]phenyl}amino and [(4R)-4-methyl-4,5-dihydro-1,3-oxazol-2-yl]amino groups at positions 4 and 6, respectively. It is a tyrosine kinase inhibitor of both ErbB-2 (Her-2/neu) and EGFR and has shown significant anti-tumour activity in preclinical models of human breast, lung, and epidermal carcinoma tumours. It has a role as an EC 2.7.10.1 (receptor protein-tyrosine kinase) inhibitor, an antineoplastic agent, an apoptosis inducer and an epidermal growth factor receptor antagonist. It is a member of 1,3-thiazoles, a member of monochlorobenzenes, an aromatic ether, a substituted aniline, a quinazoline, a secondary amino compound and an oxazoline.
Varlitinib is an oral, selective, reversible, small molecule tyrosine kinase inhibitor of both ErbB-2 (Her-2/neu) and EGFR. Over-expression of ErbB-2 and EGFR receptors in tumors is predictive of poor prognosis in cancer patients. Varlitinib has shown significant anti-tumor activity in preclinical models of human breast, lung, and epidermal carcinoma tumors.
Varlitinib 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. Due to the dual inhibition of both EGFR and Her-2, this agent may be therapeutically more effective than agents that inhibit EGFR or Her-2 alone.

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Drug Indication
Investigated for use/treatment in cancer/tumors (unspecified).

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Mechanism of Action
Varlitinib is an orally active, reversible, enzymatic and cellular inhibitor, with nanomolar potency, of the key growth factor receptor tyrosine kinases ErbB-2 and EGFR. The compound possesses improved physiochemical properties relative to compounds directed at these targets currently in clinical development, and provides superior exposure and equivalent or greater efficacy in animal models of human cancer. Currently, there is no single drug on the market that selectively inhibits both ErbB-2 and EGFR. Varlitinib, which concurrently inhibits the molecular targets of the drugs Herceptin(R) (ErbB-2) and Erbitux(R) (EGFR), may provide enhanced efficacy in the treatment of cancer patients.

C22H19CLN6O2S

466.94

466.097

C, 56.59; H, 4.10; Cl, 7.59; N, 18.00; O, 6.85; S, 6.87

845272-21-1

Varlitinib tosylate;1146629-86-8

42642648

White solid powder

1.5±0.1 g/cm3

637.1±65.0 °C at 760 mmHg

339.1±34.3 °C

0.0±1.9 mmHg at 25°C

1.742

3.51

2

8

7

32

660

1

N(C1C=CC(OCC2SC=CN=2)=C(Cl)C=1)C1=NC=NC2=CC=C(C=C12)NC1OC[C@@H](C)N=1

UWXSAYUXVSFDBQ-CYBMUJFWSA-N

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

4-N-[3-chloro-4-(1,3-thiazol-2-ylmethoxy)phenyl]-6-N-[(4R)-4-methyl-4,5-dihydro-1,3-oxazol-2-yl]quinazoline-4,6-diamine

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)

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.35 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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Solubility in Formulation 2: ≥ 2.08 mg/mL (4.45 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.

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Solubility in Formulation 3: 2.08 mg/mL (4.45 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
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.

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