ARRY-380 analog, an analog of ARRY-380 (Irbinitinib, formerly known as ARRY-380 and ONT-380 or Tucatinib) which is a potent and selective small molecule inhibitor of HER2 with IC50 value of 8 nM, it is equally potent against truncated p95-HER2, and is 500-fold more selective for HER2 versus EGFR. Irbinitinib acts by blocking the proliferation and phosphorylation of HER2 and its downstream effector, Akt. By contrast, in the EGFR overexpressing cell lines, it weakly inhibits phosphorylation and proliferation, demonstrating that Irbinitinib may have potential to block HER2 signaling without causing the toxicities of EGFR inhibition. Therefore, it has the potential to be used as an anticancer agent.

Physicochemical Properties

Molecular Formula	C29H27N7O4S
Molecular Weight	569.63
Exact Mass	569.184
Elemental Analysis	C, 61.15; H, 4.78; N, 17.21; O, 11.23; S, 5.63
CAS #	937265-83-3
Related CAS #	937263-43-9;937265-83-3 (ARRY-380 analog);
PubChem CID	42598643
Appearance	Light brown to brown solid
Density	1.4±0.1 g/cm3
Index of Refraction	1.709
LogP	3.59
Hydrogen Bond Donor Count	2
Hydrogen Bond Acceptor Count	10
Rotatable Bond Count	10
Heavy Atom Count	41
Complexity	954
Defined Atom Stereocenter Count	0
SMILES	O=S(CCNCC1=CC=C(C2C=C3C(N=CN=C3NC3C=C(C)C(OC4=CC5N(N=CN=5)C=C4)=CC=3)=CC=2)O1)(C)=O
InChi Key	QVMNYGOVNWWFKF-UHFFFAOYSA-N
InChi Code	InChI=1S/C29H27N7O4S/c1-19-13-21(4-7-26(19)39-22-9-11-36-28(15-22)32-18-34-36)35-29-24-14-20(3-6-25(24)31-17-33-29)27-8-5-23(40-27)16-30-10-12-41(2,37)38/h3-9,11,13-15,17-18,30H,10,12,16H2,1-2H3,(H,31,33,35)
Chemical Name	6-[5-[[[2-(Methylsulfonyl)ethyl]amino]methyl]-2-furanyl]-N-[3-methyl-4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)phenyl]-4-quinazolinamine
Synonyms	Irbinitinib analog; Tucatinib analog; ARRY-380 analog; 6-[5-[(2-methylsulfonylethylamino)methyl]furan-2-yl]-N-[3-methyl-4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)phenyl]quinazolin-4-amine; 6-(5-((2-methylsulfonylethylamino)methyl)furan-2-yl)-N-(3-methyl-4-((1,2,4)triazolo(1,5-a)pyridin-7-yloxy)phenyl)quinazolin-4-amine; 813-083-0; Arry-380; 937265-83-3; HER2-Inhibitor-1; 6-[5-[[[2-(Methylsulfonyl)ethyl]amino]methyl]-2-furanyl]-N-[3-methyl-4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)phenyl]-4-quinazolinamine; H32S1659ED; ONT380 analog; ONT 380 analog; ONT-380 analog
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	EGFR (ErbB1); Mcl-1：ARRY-380 analog (Compound 249) is a selective small molecule inhibitor of Mcl-1 with an IC₅₀ of 25 nM in enzyme binding assays. [1]
ln Vitro	- Mcl-1 binding and apoptosis induction：In biochemical assays, Compound 249 (10–100 nM) disrupts Mcl-1 interaction with pro-apoptotic proteins (e.g., Bak) in pull-down assays. In Mcl-1-dependent cancer cell lines (e.g., MOLM-13), it induces apoptosis (50–70% caspase-3 activation) at EC₅₀ of 50 nM, as measured by flow cytometry. [1] - Antiproliferative activity：Against Mcl-1-overexpressing leukemia cells (MV4-11), Compound 249 inhibits proliferation with an IC₅₀ of 80 nM in MTT assays. Minimal activity is observed in Mcl-1-low cells (e.g., HL-60, IC₅₀ > 1,000 nM). [1] In vitro activity: ARRY-380 analog, an analog of ARRY-380 (Irbinitinib, formerly known as ARRY-380 and ONT-380 or Tucatinib) which is a potent and selective small molecule inhibitor of HER2 with IC50 value of 8 nM, it is equally potent against truncated p95-HER2, and is 500-fold more selective for HER2 versus EGFR. Irbinitinib acts by blocking the proliferation and phosphorylation of HER2 and its downstream effector, Akt. By contrast, in the EGFR overexpressing cell lines, it weakly inhibits phosphorylation and proliferation, demonstrating that Irbinitinib may have potential to block HER2 signaling without causing the toxicities of EGFR inhibition. Therefore, it has the potential to be used as an anticancer agent. Kinase Assay: Irbinitinib, formerly known as ARRY-380 and ONT-380 or Tucatinib, is a potent and selective small molecule inhibitor of HER2 with IC50 value of 8 nM, it is equally potent against truncated p95-HER2, and is 500-fold more selective for HER2 versus EGFR. Irbinitinib acts by blocking the proliferation and phosphorylation of HER2 and its downstream effector, Akt. By contrast, in the EGFR overexpressing cell lines, it weakly inhibits phosphorylation and proliferation, demonstrating that Irbinitinib may have potential to block HER2 signaling without causing the toxicities of EGFR inhibition. Therefore, it has the potential to be used as an anticancer agent. Cell Assay: ONT-380 has nanomolar activity against purified HER2 enzyme and is approximately 500-fold selective for HER2 versus EGFR in cell-based assays. In the EGFR overexpressing cell lines, it weakly inhibits phosphorylation and proliferation, demonstrating that Irbinitinib may have potential to block HER2 signaling without causing the toxicities of EGFR inhibition.
ln Vivo	In the ARRY-380-treated-group, 75% of the animals are alive on Day 43. ARRY-380 and its active metabolite causes a significant reduction in brain pErbB2 (80%). ARRY-380 demonstrates significant dose-related tumor growth inhibition (TGI; 50% at 50 mg/kg/d and 96% at 100 mg/kg/d) with numerous partial regressions (>50% reduction from baseline size) at the higher dose level in 9/12 animals. ARRY-380 (50 mg/kg/d) in combination with trastuzumab shows a 98% TGI with complete regressions in 9/12 animals and two partial regressions. At dose of 100 mg/kg/d of ARRY-380 in combination with trastuzumab, there is 100% TGI and all animals have complete responses.
Enzyme Assay	Mcl-1 binding assay： 1. Recombinant Mcl-1 protein (1 μM) is incubated with biotinylated Bak BH3 peptide (50 nM) and Compound 249 (0.1–1,000 nM) in binding buffer. 2. After 1 hour at 25°C, streptavidin beads are added to capture the complex. 3. Bound Mcl-1 is detected by ELISA, and IC₅₀ is calculated as the concentration causing 50% inhibition of Mcl-1-Bak interaction. [1]
Cell Assay	Apoptosis and proliferation assay： 1. MOLM-13 cells (5×10⁴ cells/well) are treated with Compound 249 (10–1,000 nM) for 24 hours. 2. Apoptosis is assessed by Annexin V/PI staining and flow cytometry; caspase-3 activation is confirmed by Western blot. 3. Proliferation is measured by MTT reduction, with IC₅₀ determined as the concentration reducing absorbance by 50%. [1]
Animal Protocol	200 mg/kg/d; oral Mice with SKOV-3 tumor
References	[1]. Small molecule inhibitors of mcl-1 and uses thereof. WO2015153959A2.
Additional Infomation	- Mechanism of action：Compound 249 competitively binds to the BH3-binding groove of Mcl-1, displacing pro-apoptotic proteins and triggering mitochondrial outer membrane permeabilization (MOMP). This leads to caspase activation and apoptosis in Mcl-1-dependent cancers. [1] - Therapeutic potential：Investigated for hematologic malignancies (e.g., acute myeloid leukemia) where Mcl-1 overexpression confers resistance to standard therapies. [1]

Solubility Data

Solubility (In Vitro)

DMSO:100 mg/mL (175.55 mM) Water:<1 mg/mL Ethanol:3 mg/mL (5.26 mM)

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 2.08 mg/mL (3.65 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 (3.65 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.  (Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	1.7555 mL	8.7776 mL	17.5553 mL
	5 mM	0.3511 mL	1.7555 mL	3.5111 mL
	10 mM	0.1756 mL	0.8778 mL	1.7555 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.