Zeteletinib (BOS-172738; DS-5010) is an orally bioactive, selective RET kinase inhibitor (antagonist) with nanomolar potency for RET and >300-fold selectivity for VEGFR2. Zeteletinib showed high potency against wild-type RET, the RETV804M/L gatekeeper mutant, and the most common oncogenic RET mutant, M918T. Zeteletinib has potent anticancer effect.

Physicochemical Properties

Molecular Formula	C25H23F3N4O4
Molecular Weight	500.469736337662
Exact Mass	500.167
CAS #	2216753-97-6
Related CAS #	Zeteletinib hemiadipate;2375837-06-0
PubChem CID	134391533
Appearance	White to light yellow solid powder
LogP	4.6
Hydrogen Bond Donor Count	1
Hydrogen Bond Acceptor Count	10
Rotatable Bond Count	7
Heavy Atom Count	36
Complexity	755
Defined Atom Stereocenter Count	0
SMILES	FC(C(C)(C)C1C=C(NC(CC2=CN=C(C=C2)C2=CN=C3C=C(C(=CC3=C2)OC)OC)=O)ON=1)(F)F
InChi Key	KOLQINCWMXQEOF-UHFFFAOYSA-N
InChi Code	InChI=1S/C25H23F3N4O4/c1-24(2,25(26,27)28)21-11-23(36-32-21)31-22(33)7-14-5-6-17(29-12-14)16-8-15-9-19(34-3)20(35-4)10-18(15)30-13-16/h5-6,8-13H,7H2,1-4H3,(H,31,33)
Chemical Name	2-[6-(6,7-dimethoxyquinolin-3-yl)pyridin-3-yl]-N-[3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1,2-oxazol-5-yl]acetamide
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	PDGFR2
ln Vitro	193 nM Zeteletinib (BOS-172738; DS-5010) inhibited RET and platelet-derived growth factor receptor (PDGFR) alpha/beta by more than 80% in biochemical assays of 106 kinases. Even in the presence of high ATP concentrations, Zeteletinib's IC50 values against RET and RET -GKm (V804L) were single digit nano-molar; in addition, it was more than 1000 nM against KDR[1].
ln Vivo	Zeteletinib (BOS-172738; DS-5010) dosed at 10 mg/kg twice daily (bid) causes tumor shrinkage in a Ba/F3-RET subcutaneous tumor model[1]. Tumor regression was observed in an LC2/ad NSCLC xenograft model with the RET-CCDC6 fusion gene when zeteletinib was dosed at 1 mg/kg three times a day (tid)[1].
References	[1]. Abstract B173: Preclinical characterization and antitumor efficacy of DS-5010, a highly potent and selective RET inhibitor. MOLECULAR CANCERTHERAPEUTICS. January 2018, Volume 17, Issue 1. [2]. BOS172738, a highly potent and selective RET inhibitor, for the treatment of RET-altered tumors including RET-fusion+ NSCLC and RET-mutant MTC: Phase 1 study results. Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021) 3. [3]. Precision therapy for RET-altered cancers with RET inhibitors. Trends Cancer. 2021 Dec;7(12):1074-1088.
Additional Infomation	Zeteletinib is an orally bioavailable selective inhibitor of wild-type, fusion products and mutated forms, including gatekeeper mutations, of the proto-oncogene receptor tyrosine kinase rearranged during transfection (RET), with potential antineoplastic activity. Upon oral administration, zeteletinib selectively binds to and inhibits the activity of RET. This results in an inhibition of cell growth of tumors cells that exhibit increased RET activity. RET overexpression, activating mutations, and fusions result in the upregulation and/or overactivation of RET tyrosine kinase activity in various cancer cell types; dysregulation of RET activity plays a key role in the development and progression of these cancers.

Solubility Data

Solubility (In Vitro)

DMSO: 100 mg/mL (199.81 mM)

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.00 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 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. Solubility in Formulation 2: ≥ 2.5 mg/mL (5.00 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 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. Solubility in Formulation 3: ≥ 2.5 mg/mL (5.00 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.  (Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	1.9981 mL	9.9906 mL	19.9812 mL
	5 mM	0.3996 mL	1.9981 mL	3.9962 mL
	10 mM	0.1998 mL	0.9991 mL	1.9981 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.