SH-1028 is an irreversible third-generation EGFR TKI that can overcome T790M-mediated drug resistance in non-small cell lung cancer. SH-1028 is a mutation-selective inhibitor of EGFR kinase activity, inhibiting EGFRWT, EGFRL858R, EGFRL861Q, EGFRL858R/T790M, EGFRd746-750 and EGFRd746-750/T790M kinases, with IC50s of 18, 0.7, 4, 0.1, 1.4 and 0.89 nM.

Physicochemical Properties

Molecular Formula	C31H37N7O2
Molecular Weight	539.67
Exact Mass	539.3
CAS #	2035089-28-0
Related CAS #	Oritinib mesylate;2180164-79-6
PubChem CID	122666966
Appearance	Off-white to light yellow solid powder
LogP	4.4
Hydrogen Bond Donor Count	2
Hydrogen Bond Acceptor Count	7
Rotatable Bond Count	10
Heavy Atom Count	40
Complexity	843
Defined Atom Stereocenter Count	0
SMILES	C1C=CC2N3CCCCC3=C(C3C=CN=C(NC4C=C(C(N(CCN(C)C)C)=CC=4OC)NC(=O)C=C)N=3)C=2C=1
InChi Key	PLUKVDOZEJBBIS-UHFFFAOYSA-N
InChi Code	InChI=1S/C31H37N7O2/c1-6-29(39)33-23-19-24(28(40-5)20-27(23)37(4)18-17-36(2)3)35-31-32-15-14-22(34-31)30-21-11-7-8-12-25(21)38-16-10-9-13-26(30)38/h6-8,11-12,14-15,19-20H,1,9-10,13,16-18H2,2-5H3,(H,33,39)(H,32,34,35)
Chemical Name	N-[2-[2-(dimethylamino)ethyl-methylamino]-4-methoxy-5-[[4-(6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl)pyrimidin-2-yl]amino]phenyl]prop-2-enamide
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 (WT) 18 nM (IC50) EGFRL858R 0.7 nM (IC50) EGFRL861Q 4 nM (IC50) EGFRL858R/T790M 0.1 nM (IC50) EGFRd746-750 1.4 nM (IC50) EGFRd746-750/T790M 0.89 nM (IC50)
ln Vitro	Oritinib (SH-1028) targets the cysteine-797 residue in the ATP binding site by covalent bond formation, forming an irreversible binding to EGFR kinase[1]. In vitro, oritinib (0.001-10 μM) displays strong and selective effects on mutant EGFR cell lines. At lower concentrations or even when the cells are drug-free for at least 6 hours, oritinib (0.1 μM) consistently suppresses the phosphorylation of EGFR in PC-9 and NCI-H1975 cells[1].
ln Vivo	In mice xenograft models, oral administration of Oritinib at a daily dose of 5 mg/kg substantially reduces the growth of tumor cells with EGFR sensitive mutation (exon 19 del) and resistant mutation (T790 M) for a consecutive 14 days, without causing TKI-induced weight loss[1]. Oritinib is widely dispersed from the plasma into the tissues and exhibits high bioavailability[1].
Cell Assay	Cell Proliferation Assay[1] Cell Types: A431 (EGFRWT ), H3255 (EGFRL858R), PC-9 (EGFRd746-750) and NCI-H1975 (EGFRL858R/T790M) cells Tested Concentrations: 0.001, 0.01, 0.1, 1, and 10 μM Incubation Duration: 72 hrs (hours) Experimental Results: Selectively inhibited EGFR-mutated NCI-H1975, H3255 and PC-9 cells, with IC50s of 3.93±1.12, 9.39±0.88 and 7.63±0.18 nmol/L, respectively, which were about 198-, 83- and 102-fold more sensitive than the inhibition of wild -type EGFR in A431 cells (IC50=778.89±134.74 nM).
Animal Protocol	Animal/Disease Models: 6-8 weeks old female mice bearing NCI-H1975 and A431 xenograft models[1] Doses: 2.5, 5 , and 15 mg/kg Route of Administration: Orally administered one time/day for consecutive 14 days Experimental Results: Led to a significant inhibition of tumor cell growth in both PC-9 (exon 19 del) and NCI-H1975 (L858R/T790M) xenograft models. Animal/Disease Models: NCI-H1975 tumor-bearing mice[1] Doses: 2.5, 5, and 15 mg/kg (pharmacokinetic/PK Analysis) Route of Administration: Oral administration for 1 day or 14 days. Experimental Results: The Tmax is 1.5-2 h, indicating rapidly distributed into tissues, including lung tumor tissues. The AUC0–t values in plasma were 118, 300 and 931 ng×h/mL on Day 1, while 272, 308 and 993 ng×h/ml on Day 14, respectively.
References	[1]. SH-1028, An Irreversible Third-Generation EGFR TKI, Overcomes T790M-Mediated Resistance in Non-Small Cell Lung Cancer. Front Pharmacol. 2021 Apr 27;12:665253.

Solubility Data

Solubility (In Vitro)

DMSO: 125 mg/mL (231.62 mM)

Solubility (In Vivo)

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples. Injection Formulations (e.g. IP/IV/IM/SC) Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] *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. Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline) Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline) Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline) Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil) Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Oral Formulations Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). Oral Formulation 3: Dissolved in PEG400 Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose Oral Formulation 6: Mixing with food powders Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.  (Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	1.8530 mL	9.2649 mL	18.5298 mL
	5 mM	0.3706 mL	1.8530 mL	3.7060 mL
	10 mM	0.1853 mL	0.9265 mL	1.8530 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.