DS1205 (DS-1205b) is a potent AXL kinase inhibitor with anti-lung cancer activity. It inhibits AXL with an IC50 of 1.3 nM. Also inhibits MER, MET, and TRKA, with IC50s of 63, 104, and 407 nM, respectively. DS-1205b monotherapy exerted significant antitumor activity in an NIH3T3-AXL allograft model. In an HCC827 xenograft model, combination treatment with DS-1205b and osimertinib significantly delayed on the onset of tumor resistance compared to osimertinib alone in a manner proportional to DS-1205b does. DS-1205b also showed a similar resistance delay effect with erlotinib combination in the same xenograft model.

Physicochemical Properties

Molecular Formula	C41H42FN5O7
Molecular Weight	735.799893856049
Exact Mass	735.306
CAS #	1855860-24-0
Related CAS #	1855860-24-0;1855861-49-2 (mesylate);1855861-62-9 (phosphate);1855861-63-0 (2 sulfate); 1855861-64-1 (1.5 sulfate); 2407835-63-4 (X sulfate);
PubChem CID	129110632
Appearance	Off-white to yellow solid powder
LogP	4.3
Hydrogen Bond Donor Count	2
Hydrogen Bond Acceptor Count	12
Rotatable Bond Count	11
Heavy Atom Count	54
Complexity	1330
Defined Atom Stereocenter Count	1
SMILES	FC1=C(C2C(N)=NC=C(C=2)C2C=CC(=C(C=2)OC)OC[C@H]2COCCO2)C=CC(=C1)NC(C1C(C(C2C=CC(C)=CN=2)=CN(C=1)CC1CCOCC1)=O)=O
InChi Key	ZOEILZXFYPPMTR-SSEXGKCCSA-N
InChi Code	InChI=1S/C41H42FN5O7/c1-25-3-7-36(44-18-25)33-21-47(20-26-9-11-51-12-10-26)22-34(39(33)48)41(49)46-29-5-6-31(35(42)17-29)32-15-28(19-45-40(32)43)27-4-8-37(38(16-27)50-2)54-24-30-23-52-13-14-53-30/h3-8,15-19,21-22,26,30H,9-14,20,23-24H2,1-2H3,(H2,43,45)(H,46,49)/t30-/m1/s1
Chemical Name	(R)-N-(4-(5-(4-((1,4-dioxan-2-yl)methoxy)-3-methoxyphenyl)-2-aminopyridin-3-yl)-3-fluorophenyl)-5-methyl-4'-oxo-1'-((tetrahydro-2H-pyran-4-yl)methyl)-1',4'-dihydro-[2,3'-bipyridine]-5'-carboxamide
Synonyms	DS-1205bDS-1205 DS 1205b DS1205bDS 1205 DS1205 DS-1206b
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

ln Vitro	NIH3T3-AXL cells' hGAS6-induced migration is inhibited by DS-1205b (0.3-33 μM; 2-24 hours) (EC50=2.7 nM) [1]. In NIH3T3-AXL cells, DS-1205b (1-10000 μM; 2-24 hours) strongly reduces AXL phosphorylation. While DS-1205b decreases NIH3T3 cell proliferation, growth (GI50>10,000 nM) is not substantially inhibited[1].
ln Vivo	DS-1205b (3.1-50 mg/kg; orally given for 5 days) displays pAXL inhibition-mediated anti-tumor actions in mice [1].
Cell Assay	Western Blot analysis [1] Cell Types: NIH3T3-AXL cells Tested Concentrations: 1, 10, 100, 1000, 10000 μM Incubation Duration: 2, 24 hrs (hours) Experimental Results: The phosphorylation of AXL is completely inhibited when the concentration is higher than 10 nM. Slightly inhibits phosphorylation of AKT serine/threonine kinase in a dose-dependent manner.
Animal Protocol	Animal/Disease Models: Female NOD/Shi-scid IL-2Rγ KO Jic mice implanted with NIH3T3-AXL tumor mass [1] Doses: 3.1, 6.3, 13, 25, 50 mg/kg Route of Administration: Po, twice a day, Result lasted for 5 days: inhibited tumor growth by 39-94%. Reduces AXL and AKT phosphorylation in tumors.
References	[1]. DS-1205b, a novel selective inhibitor of AXL kinase, blocks resistance to EGFR-tyrosine kinase inhibitors in a non-small cell lung cancer xenograft model. Oncotarget. 2019 Aug 27;10(50):5152-5167.

Solubility Data

Solubility (In Vitro)

DMSO : ~50 mg/mL (~67.95 mM)

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 2.5 mg/mL (3.40 mM) (saturation unknown) in 10% DMSO + 40% PEG300 +5% Tween-80 + 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	1.3591 mL	6.7953 mL	13.5906 mL
	5 mM	0.2718 mL	1.3591 mL	2.7181 mL
	10 mM	0.1359 mL	0.6795 mL	1.3591 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.