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p300 and its paralog CBP can acetylate histones and other proteins and have been implicated in a number of diseases characterized by aberrant gene activation, such as cancer. A novel, highly selective, orally bioavailable histone acetyltransferase (HAT) domain inhibitor has been identified through virtual ligand screening and subsequent optimization of a unique hydantoin screening hit. Conformational restraint in the form of a spirocyclization followed by substitution with a urea led to a significant improvement in potency. Replacement of the hydantoin moiety with an oxazolidinedione followed by fluoro substitution led to A-485, which exhibits potent cell activity, low clearance, and high oral bioavailability.

Abnormal pigmentation is related to a variety of cosmetic and clinical conditions including melasma, lentigo, age spots, inflammatory hypermelanosis and trauma-induced hyperpigmentation.1) A number of studies have been devoted to producing safe and efficient depigmenting agents. However, many popular depigmenting compounds either lack potency or produce undesirable side effects.Skin color depends on the type and quantity of melanin, a natural pigment produced by melanocytes. The major ratelimiting step in melanin biosynthesis involves the enzyme tyrosinase [EC 1.14.18.1]. Mutations that eliminate activity of the tyrosinase gene result in albinism.2) Tyrosinase, a coppercontaining binuclear enzyme catalyzes three steps of melanin biosynthesis: the hydroxylation of tyrosine to 3,4-dihydroxyphenylalanine (DOPA), oxidation of DOPA to DOPAquinone, and oxidation of 5,6-dihydroxyindole to indolequinone. Because of its key role in melanogenesis, tyrosinase is an attractive target in the search for various kinds of depigmenting agents. [3][4][5][6] This study is a report of the discovery and characterization of a novel tyrosinase inhibitor: 1-(2,4-dihydroxyphenyl)-3-(2,4-dimethoxy-3-methylphenyl)propane (coded as UP302), isolated from a medicinal plant. UP302 inhibited tyrosinase with nanomolar potency and exhibited strong skin-whitening effects. ResultsIdentification of UP302 A screening of 1144 plant extracts identified 20 extracts that inhibited DOPA oxidase activity of mushroom tyrosinase. Three compounds were isolated and identified from two different families of plants, Moraceae and Liliacea (Fig. 1). All three compounds shared a common diarylpropane structure, revealing the existence of a new class of tyrosinase inhibitors. Compound 3, isolated from Dianella ensifolia (Liliacea) exhibited the highest potency with IC 50 value equal to 0.24 mM. This compound, 1-(2,4-dihydroxyphenyl)-3-(2,4-dimethoxy-3-methylphenyl) propane (CAS# 869743-37-3) was coded as UP302, reflecting the molecular mass of this agent (302 Da).Enzyme Kinetics Studies As UP302 is not a very abundant compound in nature (0.01-0.05% of plant dry weight), an organic synthesis procedure was developed to produce enough of this compound for further studies. Figure 2 demonstrates that synthetic UP302 is equally capable of inhibiting mushroom tyrosinase as its plant-derived counterpart. Therefore, all the following studies were performed 1292 Vol. 56, No. 9 A series of diarylpropane compounds was isolated by screening a plant extract library for inhibitors of mushroom tyrosinase. The most potent compound, 1-(2,4-dihydroxyphenyl)-3-(2,4-dimethoxy-3-methylphenyl)propane (UP302: CAS# 869743-37-3), was found in the medicinal plant Dianella ensifolia. Synthetic and plantderived versions of UP302 inhibited mushroom tyrosinase with similar potencies. UP302 inhibited mushroom tyrosinase with K i ‫3.0؍‬ m mM, in a competitive and reversible fashion. UP302 was 22 times more potent than Kojic acid in inhibiting murine tyrosinase, with IC 50 values of 12 and 273 m m...

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Nutrigenomic studies were conducted to uncover the mechanism of action for the hypoglycemic and insulin sensitizing effects of UP780. From high fat diet-induced obesity mouse model for UP780, livers and white adipose tissues (WAT) from groups of lean control, high fat diet (HFD), and HFD treated with UP780 were collected for microarray study. Microarray generated gene expression changes were applied to Ingenuity Pathway Analysis for changes in canonical metabolic and signaling pathways. Microarray was validated by quantitative reverse transcriptase-polymerase chain reaction (QPCR), Western blots, liver triglyceride, liver cholesterol, liver steatosis, and insulin ELISA. UP780 treatment decreased liver gene expressions for multiple enzymes involved in fatty acid biosynthesis and triglyceride production. UP780 treatment increased gene expressions globally for the insulin receptor signaling pathway in WAT. Both liver triglyceride and liver cholesterol levels were significantly reduced by UP780 over HFD. The reduction of liver fat was confirmed by microscopic analysis of liver steatosis. Finally, UP780 significantly decreased fasting plasma insulin level over HFD. The mechanism of action for UP780 indicated a reduction of liver fat accumulation and an enhancement in adipose tissue insulin signaling pathway. This provided mechanistic explanation for the in vivo UP780 effects of enhanced insulin sensitiveity and decreased blood glucose in mouse diabetes and prediabetes models.