LY 333531 hydrochloride is an orally selective and ATP-competitive PKCβ inhibitor with IC50 values of 4.7nM and 5.9nM for PKCβI and PKCβII, respectively[1]. LY 333531 hydrochloride inhibits Ser180 phosphorylation of Bruton's tyrosine kinase (BTK), with an EC50 value of 0.21μM[2]. By targeting PKCβ, LY 333531 hydrochloride alleviates diastolic dysfunction, myocardial hypertrophy and collagen deposition, and maintains myocardial contractility[3]. LY 333531 hydrochloride has been widely used in diabetic rat models to restore the renal hemodynamic indicators and improve renal function[4].
In vitro, LY 333531 hydrochloride treatment for 24 hours significantly inhibited the proliferation of MOLM13 cells harboring FLT3-ITD mutation (IC50=0.7μM) and induced cell apoptosis (IC50=1.5μM)[5]. Incubation with 1μM of LY 333531 hydrochloride for 48 hours markedly suppressed VEGF (10ng/ml)-induced proliferation and migration of human umbilical vein endothelial cells (HUVECs), and decreased the phosphorylation of ERK1/2 and Akt[6]. Pretreatment with 10nM LY 333531 hydrochloride for 2 hours ameliorated reactive oxygen species (ROS) production, decreased cell permeability, and alleviated oxidative stress in stretch-treated human coronary artery endothelial cells (HCAECs)[7].
In vivo, LY 333531 hydrochloride treatment via oral administration at a dose of 10mg/kg/day for 8 weeks attenuated the increased urinary albumin excretion rate, glomerular volume, and tubulointerstitial injury index in diabetic rats[8]. Oral administration of LY 333531 hydrochloride at a dose of 10mg/kg/day for 4 weeks reduced the number of leukocytes trapped in the retinal microcirculation and ameliorated abnormal retinal blood flow in early diabetic rats[9].
References:[1] Jirousek M R, Gillig J R, Gonzalez C M, et al. (S)-13-[(Dimethylamino) methyl]-10, 11, 14, 15-tetrahydro-4, 9: 16, 21-dimetheno-1 H, 13 H-dibenzo [e, k] pyrrolo [3, 4-h][1, 4, 13] oxadiazacyclohexadecene-1, 3 (2 H)-dione (LY333531) and related analogues: isozyme selective inhibitors of protein kinase Cβ[J]. Journal of medicinal chemistry, 1996, 39(14): 2664-2671.
[2] Venkataraman C, Chen X C, Na S, et al. Selective role of PKCβ enzymatic function in regulating cell survival mediated by B cell antigen receptor cross-linking[J]. Immunology letters, 2006, 105(1): 83-89.
[3] Connelly K A, Kelly D J, Zhang Y, et al. Inhibition of protein kinase C–β by ruboxistaurin preserves cardiac function and reduces extracellular matrix production in diabetic cardiomyopathy[J]. Circulation: Heart Failure, 2009, 2(2): 129-137.
[4] Koya D, Jirousek M R, Lin Y W, et al. Characterization of protein kinase C beta isoform activation on the gene expression of transforming growth factor-beta, extracellular matrix components, and prostanoids in the glomeruli of diabetic rats[J]. The Journal of clinical investigation, 1997, 100(1): 115-126.
[5] Fedorov O, Marsden B, Pogacic V, et al. A systematic interaction map of validated kinase inhibitors with Ser/Thr kinases[J]. Proceedings of the National Academy of Sciences, 2007, 104(51): 20523-20528.
[6] Nakamura S, Chikaraishi Y, Tsuruma K, et al. Ruboxistaurin, a PKCβ inhibitor, inhibits retinal neovascularization via suppression of phosphorylation of ERK1/2 and Akt[J]. Experimental eye research, 2010, 90(1): 137-145.
[7] Li X, Wang M, Kalina J O, et al. Empagliflozin prevents oxidative stress in human coronary artery endothelial cells via the NHE/PKC/NOX axis[J]. Redox biology, 2024, 69: 102979.
[8] Wu Y, Wu G, Qi X, et al. Protein kinase C β inhibitor LY333531 attenuates intercellular adhesion molecule-1 and monocyte chemotactic protein-1 expression in the kidney in diabetic rats[J]. Journal of pharmacological sciences, 2006, 101(4): 335-343.
[9] Nonaka A, Kiryu J, Tsujikawa A, et al. PKC-β inhibitor (LY333531) attenuates leukocyte entrapment in retinal microcirculation of diabetic rats[J]. Investigative ophthalmology & visual science, 2000, 41(9): 2702-2706.