Darovasertib (LXS-196; IDE-196) is a novel, potent, selective and orally bioactive inhibitor of protein kinase C (PKC) with IC50 values of 1.9 nM, 0.4 nM and 3.1 μM for PKCα, PKCθ and GSK3β, respectively. It can be used for the treatment of uveal melanoma. LXS-196 can be potentially used for the treatment of uveal melanoma. After oral administration, protein kinase C inhibitor LXS196 binds to and inhibits PKC, which prevents the activation of PKC-mediated signaling pathways. This may lead to the induction of cell cycle arrest and apoptosis in susceptible tumor cells. PKC, a serine/threonine protein kinase overexpressed in certain types of cancer cells, is involved in tumor cell differentiation, proliferation, invasion and survival.

Physicochemical Properties

Molecular Formula	C22H23F3N8O
Molecular Weight	472.47
Exact Mass	472.194
CAS #	1874276-76-2
Related CAS #	1874276-76-2;LXS-196 HCl;
PubChem CID	118873253
Appearance	Light yellow to yellow solid powder
Density	1.4±0.1 g/cm3
Boiling Point	592.7±50.0 °C at 760 mmHg
Flash Point	312.3±30.1 °C
Vapour Pressure	0.0±1.7 mmHg at 25°C
Index of Refraction	1.622
LogP	3.7
Hydrogen Bond Donor Count	3
Hydrogen Bond Acceptor Count	11
Rotatable Bond Count	4
Heavy Atom Count	34
Complexity	702
Defined Atom Stereocenter Count	0
InChi Key	XXJXHXJWQSCNPX-UHFFFAOYSA-N
InChi Code	InChI=1S/C22H23F3N8O/c1-21(27)6-10-33(11-7-21)15-5-3-9-29-19(15)32-20(34)17-18(26)30-12-14(31-17)16-13(22(23,24)25)4-2-8-28-16/h2-5,8-9,12H,6-7,10-11,27H2,1H3,(H2,26,30)(H,29,32,34)
Chemical Name	3-amino-N-[3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl]-6-[3-(trifluoromethyl)pyridin-2-yl]pyrazine-2-carboxamide
Synonyms	LXS196; NVP-LXS196; LXS-196; NVP-LXS-196
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	Following the toxin, PKC is bound by the protein product C-head Darovasertib (LXS196), which inhibits PKC and stops PKC-mediated signal amplifiers from activating. In tumor cells that are vulnerable, this could result in the production of cell cycle candles and HCC. PKC is a serine/threonine protein stall that is overexpressed in some cancer cell types and linked to ischemia, tumor cell sudden death, urogenital tract, and sudden death [1].
ln Vivo	In a dose-dependent manner, darovasertib (LXS196; Compound 9) inhibits tumor growth in the 92.1 GNAQ grape melanoma xenograft model [2]. Uveal melanoma cells with a 92.1 GNAQ mutation were implanted into mice [2].
Animal Protocol	Animal/Disease Models: Mice implanted with 92.1 GNAQ mutant uveal melanoma cells[2]. Doses: 15, 30, 75, 150 mg/kg Route of Administration: P.O. (bid) for 35 days Experimental Results:Dose-dependently suppressed the tumor growth.
References	[1]. Protein Kinase C Inhibitor LXS196. [2]. US20180179181.
Additional Infomation	IDE-196 is under investigation in clinical trial NCT03947385 (Study of IDE196 in Patients With Solid Tumors Harboring GNAQ/11 Mutations or PRKC Fusions). Darovasertib is an orally available protein kinase C (PKC) inhibitor with potential immunosuppressive and antineoplastic activities. Upon oral administration, darovasertib inds to and inhibits PKC, which prevents the activation of PKC-mediated signaling pathways. This may lead to the induction of cell cycle arrest and apoptosis in susceptible tumor cells. PKC, a serine/threonine protein kinase overexpressed in certain types of cancer cells, is involved in tumor cell differentiation, proliferation, invasion and survival.

Solubility Data

Solubility (In Vitro)

DMSO : ~25 mg/mL (~52.91 mM)

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.29 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 (5.29 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 (5.29 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. Solubility in Formulation 4: ≥ 1.67 mg/mL (3.53 mM) (saturation unknown) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 5: ≥ 1.67 mg/mL (3.53 mM) (saturation unknown) in 5% DMSO + 95% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. 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 6: 0.33 mg/mL (0.70 mM) in 1% DMSO 99% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. 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	2.1165 mL	10.5827 mL	21.1654 mL
	5 mM	0.4233 mL	2.1165 mL	4.2331 mL
	10 mM	0.2117 mL	1.0583 mL	2.1165 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.