GSK2578215A (GSK-2578215A; GSK 2578215A; GSK-2578215 A) is a novel, highly potent and selective LRRK2 kinase inhibitor with anti-PD (Parkinson's disease) activity. It inhibits LRRK2 (G2019S) and LRRK2 (WT) with an IC50 of 8.9 nM and 10.9 nM, respectively.

Physicochemical Properties

Molecular Formula	C24H18FN3O2
Molecular Weight	399.42
Exact Mass	399.138
CAS #	1285515-21-0
Related CAS #	1285515-21-0
PubChem CID	68107965
Appearance	Light yellow to yellow solid powder
Density	1.3±0.1 g/cm3
Boiling Point	556.1±50.0 °C at 760 mmHg
Flash Point	290.1±30.1 °C
Vapour Pressure	0.0±1.5 mmHg at 25°C
Index of Refraction	1.651
LogP	3.4
Hydrogen Bond Donor Count	1
Hydrogen Bond Acceptor Count	5
Rotatable Bond Count	6
Heavy Atom Count	30
Complexity	543
Defined Atom Stereocenter Count	0
InChi Key	WCIGMFCFPXZRMQ-UHFFFAOYSA-N
InChi Code	InChI=1S/C24H18FN3O2/c25-23-14-19(10-12-27-23)18-8-9-22(30-16-17-5-2-1-3-6-17)21(13-18)24(29)28-20-7-4-11-26-15-20/h1-15H,16H2,(H,28,29)
Chemical Name	5-(2-fluoropyridin-4-yl)-2-phenylmethoxy-N-pyridin-3-ylbenzamide
Synonyms	GSK-2578215A; GSK 2578215A; GSK2578215A; 2-(benzyloxy)-5-(2-fluoropyridin-4-yl)-N-(pyridin-3-yl)benzamide
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	GSK2578215A (0-1 μM, 90 minutes) inhibits the phosphorylation of Ser910 and Ser935 in mouse Swiss 3T3 cells [1] and HEK293 cells that have been stably transfected with wild-type LRRK2 and LRRK2[G2019S]. In SH-SY5Y cells, GSK2578215A (1 nM, 12 hours) induces autophagy (increased levels of LC3 and p62 protein) [2]. In SH-SY5Y cells, GSK2578215A (1 nM, 12 hours) causes Drp1-mediated mitochondrial fission as well as mitophagy (12 and 24 hours) [2]. In SH-SY5Y cells, GSK2578215A (1 nM, 24 hours) causes oxidative stress, which is reflected in the accumulation of 4-HNE, and causes apoptosis [2]. In OVCAR8 cells, GSK2578215A (1 μM, 24 hours) inhibits homologous recombination [3].
ln Vivo	In mice with OVCAR8 xenografts, GSK2578215A (5 mg/kg, i.p.) and olaparib (50 mg/kg, i.p., TIW for 3 weeks) can both efficiently reduce tumor growth [3]. With a brain exposure (brain/plasma exposure ratio) of 1.4 (IV) and 2.4 (PO) and a low oral bioavailability (IV, 12.2%), half-life of 1.14 hours (IV), and plasma exposure (PO, 635.3 h·ng/mL, AUClast), GSK2578215A (IV, 1 mg/kg or PO, 10 mg/kg) exhibits these characteristics [1].
Animal Protocol	Animal/Disease Models: mice bearing OVCAR8 xenografts[3] Doses: 5 mg/kg, with Olaparib (50 mg/kg) Route of Administration: ip, for 3 weeks Experimental Results: Inhibited the tumor growth and increased DNA damage in tumors more potently than Olaparib or GSK2578215A alone.
References	[1]. GSK2578215A; a potent and highly selective 2-arylmethyloxy-5-substitutent-N-arylbenzamide LRRK2 kinase inhibitor. Bioorg Med Chem Lett. 2012 Sep 1;22(17):5625-9. [2]. The LRRK2 inhibitor GSK2578215A induces protective autophagy in SH-SY5Y cells: involvement of Drp-1-mediated mitochondrial fission and mitochondrial-derived ROS signaling. Cell Death Dis. 2014 Aug 14;5(8):e1368. [3]. LRRK2 inhibition potentiates PARP inhibitor cytotoxicity through inhibiting homologous recombination-mediated DNA double strand break repair. Clin Transl Med. 2021 Mar;11(3):e341.

Solubility Data

Solubility (In Vitro)

DMSO: 79 mg/mL (197.8 mM) Water:<1 mg/mL Ethanol:<1 mg/mL

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 2.5 mg/mL (6.26 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	2.5036 mL	12.5182 mL	25.0363 mL
	5 mM	0.5007 mL	2.5036 mL	5.0073 mL
	10 mM	0.2504 mL	1.2518 mL	2.5036 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.