LLY-283 (LLY283) is the first-in-class and selective SAM-competitive inhibitor of PRMT5 (protein arginine methyltransferase 5) with antitumor activity. LLY-283 inhibited PRMT5 enzymatic activity in vitro and in cells with IC₅₀ values of 22 ± 3 and 25 ± 1 nM, respectively, while its diastereomer, LLY-284, was much less active. LLY-283 also showed antitumor activity in mouse xenografts when dosed orally and can serve as an excellent probe molecule for understanding the biological function of PRMT5 in normal and cancer cells. PRMT5 is ubiquitously expressed in most tissues and its expression has been shown to be elevated in several cancers including breast cancer, gastric cancer, glioblastoma, and lymphoma.

Physicochemical Properties

Molecular Formula	C17H18N4O4
Molecular Weight	342.3492
Exact Mass	342.132
CAS #	2040291-27-6
Related CAS #	LLY-284;2226515-75-7
PubChem CID	122669401
Appearance	White to off-white solid powder
LogP	0.2
Hydrogen Bond Donor Count	4
Hydrogen Bond Acceptor Count	7
Rotatable Bond Count	3
Heavy Atom Count	25
Complexity	464
Defined Atom Stereocenter Count	5
SMILES	[C@@H]1(O)[C@@]([H])([C@@H](C2=CC=CC=C2)O)O[C@H]([C@@H]1O)N1C=CC2C(N)=NC=NC=21
InChi Key	WWOOWAHTEXIWBO-QFRSUPTLSA-N
InChi Code	InChI=1S/C17H18N4O4/c18-15-10-6-7-21(16(10)20-8-19-15)17-13(24)12(23)14(25-17)11(22)9-4-2-1-3-5-9/h1-8,11-14,17,22-24H,(H2,18,19,20)/t11-,12+,13-,14-,17-/m1/s1
Chemical Name	(2R,3R,4S,5R)-2-(4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-5-[(R)-hydroxy(phenyl)methyl]oxolane-3,4-diol
Synonyms	LLY-283;LM5179; LLY283;LM-5179;LLY 283; LM 5179
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	LLY-283 is an oral, potent, and selective inhibitor of arginine methyltransferase 5 (PRMT5), with an IC50 of 22 nM in vitro and 25 nM in cells; in vitro, it has a Kd of 6 nM for the PRMT5:MEP50 complex. With an IC50 of 46 nM, LLY-283 also inhibits the proliferation of A375 cells[1].
ln Vivo	After 28 days of treatment, LLY-283 (20 mg/kg; po, QD; once daily)) significantly inhibits the growth of tumors in mice harboring A375 cells[1].
Animal Protocol	20 mg/kg; p.o. Mice bearing A375 tumor
References	[1]. LLY-283, a Potent and Selective Inhibitor of Arginine Methyltransferase 5, PRMT5, with Antitumor Activity. ACS Med. Chem. Lett., 2018, 9 (7), pp 612-617.

Solubility Data

Solubility (In Vitro)

DMSO:10 mM Water:N/A Ethanol: N/A

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 2.08 mg/mL (6.08 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 20.8 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: ≥ 2.08 mg/mL (6.08 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 20.8 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: ≥ 2.08 mg/mL (6.08 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 20.8 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	2.9210 mL	14.6049 mL	29.2099 mL
	5 mM	0.5842 mL	2.9210 mL	5.8420 mL
	10 mM	0.2921 mL	1.4605 mL	2.9210 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.