Ruboxistaurin, also known as LY-333531, is a PKC beta inhibitor potentially for the treatment of diabetic nephropathy and diabetic macular edema. Ruboxistaurin attenuates diabetic nephropathy via modulation of TGF-β1/Smad and GRAP pathways. Ruboxistaurin reduces oxidative stress and attenuates left ventricular hypertrophy and dysfunction in rats with streptozotocin-induced diabetes. Ruboxistaurin inhibits retinal neovascularization via suppression of phosphorylation of ERK1/2 and Akt.
Chemical Formula: C28H29ClN4O3
Molecular Weight: 505.015
Elemental Analysis: C, 66.59; H, 5.79; Cl, 7.02; N, 11.09; O, 9.50
Related CAS #:
169939-94-0 (free base)
202260-21-7 (mesylate hydrate)
Appearance: Orange to red solid powder
Purity: >98% (or refer to the Certificate of Analysis)
Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility: Soluble in DMSO
Shelf Life: >2 years if stored properly
Drug Formulation: This drug may be formulated in DMSO
Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code: 2934.99.9001
Ruboxistaurin hydrochloride is a selective and ATP-competitive PKCβ inhibitor, with IC50s of 4.7 and 5.9 nM for PKCβI and PKCβII, shows less potent inhibition on PKCη (IC50, 52 nM), PKCα (IC50, 360 nM), PKCγ (IC50, 300 nM), PKCδ (IC50, 250 nM), and has no effect on PKCζ (IC50, >100 μM). Ruboxistaurin (10 and 400 nM) dramatically inhibits glucose-induced monocyte adherence to levels that are not different from baseline adherence of monocytes to endothelial cells under NG conditions. Ruboxistaurin (10 and 400 nM) dose not alter the endothelial expression of adhesion molecules or modify endothelial cell growth. Ruboxistaurin (LY333531; 10 nM) reduces high-glucose (HG)-induced human renal glomerular endothelial cells (HRGECs) viability, and inhibits the increases in swiprosin-1 in HRGECs incubated with HG.
Ruboxistaurin (LY333531; 1 mg/kg/d for 8 weeks) markedly reduces GEC apoptosis as well as swiprosin-1 upregulation, and ameliorates renal glomerular injury in the diabetic mice. Ruboxistaurin also potently attenuates the expression of PARP, cleaved-caspase9, cleaved-caspase3, and the Bax/Bcl-2 ratio, in diabetic mice. Ruboxistaurin (LY333531; 0.1, 1.0, or 10.0 mg/kg/d, po.o.) dramatically reduces the number of leukocytes trapped in the retinal microcirculation of diabetic rats.
- Pang C, Wen L, Lu X, Luo S, Qin H, Zhang X, Zhu B, Luo S. Ruboxistaurin maintains the bone mass of subchondral bone for blunting osteoarthritis progression by inhibition of osteoclastogenesis and bone resorption activity. Biomed Pharmacother. 2020 Sep 1;131:110650. doi: 10.1016/j.biopha.2020.110650. Epub ahead of print. PMID: 32882584.
- Zestos AG, Carpenter C, Kim Y, Low MJ, Kennedy RT, Gnegy ME. Ruboxistaurin Reduces Cocaine-Stimulated Increases in Extracellular Dopamine by Modifying Dopamine-Autoreceptor Activity. ACS Chem Neurosci. 2019 Apr 17;10(4):1960-1969. doi: 10.1021/acschemneuro.8b00259. Epub 2018 Nov 8. PMID: 30384585; PMCID: PMC6470047.
- Lewin AH, Brieaddy L, Deschamps JR, Imler GH, Mascarella SW, Reddy PA, Carroll FI. Synthesis and Characterization of the Selective, Reversible PKCβ Inhibitor (9 S)-9-[(Dimethylamino)methyl]-6,7,10,11-tetrahydro-9 H,18 H-5,21:12,17-dimethenodibenzo[ e,k]pyrrolo[3,4- h][1,4,13]oxadiazacyclohexadecine-18,20(19 H)-dione, Ruboxistaurin (LY333531). ACS Chem Neurosci. 2019 Jan 16;10(1):246-251. doi: 10.1021/acschemneuro.8b00196. Epub 2018 Sep 11. PMID: 30156829.
- Sharp TE 3rd, Kubo H, Berretta RM, Starosta T, Wallner M, Schena GJ, Hobby AR, Yu D, Trappanese DM, George JC, Molkentin JD, Houser SR. Protein Kinase C Inhibition With Ruboxistaurin Increases Contractility and Reduces Heart Size in a Swine Model of Heart Failure With Reduced Ejection Fraction. JACC Basic Transl Sci. 2017 Dec 25;2(6):669-683. doi: 10.1016/j.jacbts.2017.06.007. PMID: 30062182; PMCID: PMC6058945.
- Al-Onazi AS, Al-Rasheed NM, Attia HA, Al-Rasheed NM, Ahmed RM, Al-Amin MA, Poizat C. Ruboxistaurin attenuates diabetic nephropathy via modulation of TGF-β1/Smad and GRAP pathways. J Pharm Pharmacol. 2016 Feb;68(2):219-32. doi: 10.1111/jphp.12504. Epub 2016 Jan 28. PMID: 26817709.
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