Overexpression and somatic heterozygous mutations of EZH2, the catalytic subunit of polycomb repressive complex 2 (PRC2), are associated with several tumor types. EZH2 inhibitor, EPZ-6438 (tazemetostat), demonstrated clinical efficacy in patients with acceptable safety profile as monotherapy. EED, another subunit of PRC2 complex, is essential for its histone methyltransferase activity through direct binding to trimethylated lysine 27 on histone 3 (H3K27Me3). Herein we disclose the discovery of a first-in-class potent, selective, and orally bioavailable EED inhibitor compound 43 (EED226). Guided by X-ray crystallography, compound 43 was discovered by fragmentation and regrowth of compound 7, a PRC2 HTS hit that directly binds EED. The ensuing scaffold hopping followed by multiparameter optimization led to the discovery of 43. Compound 43 induces robust and sustained tumor regression in EZH2 preclinical DLBCL model. For the first time we demonstrate that specific and direct inhibition of EED can be effective as an anticancer strategy.

The therapeutic potential of cisplatin in ovarian cancer treatment is restricted by the occurrence of cellular resistance. We aimed to explore the role of SRPK1 in cisplatin resistance related to the long non-coding RNA UCA1 in ovarian cancer cell.Totally, 24 ovarian cancer tissues and 16 normal tissues were used to assess the expression of UCA1 RNA. UCA1 stable transfected SKOV3 cells were established and the ability of cell migration, invasion and cisplatin resistance was assessed. The expression of SRPK1 and apoptosis pathway proteins was then assessed to explore the mechanism. In addition, SRPK1 knockdown cell line was also established and the effects of SRPK1 on cell migration, invasion and cisplatin resistance was evaluated.Elevated expression of UCA1 RNA was identified in ovarian cancer tissues compared with normal tissues. Expression of UCA1 RNA in SKOV3 cells enhanced the cell migration, invasion and cisplatin resistance. Increased expression of SRPK1 and anti-apoptosis proteins were found in SKOV3/pcDNA-UCA1 cells. Knocking-down SRPK1 could partly rescue the effect of UCA1 expression on cell migration, invasion and cisplatin resistance in SKOV3 cells.Elevated expression of UCA1 RNA was found in ovarian cancer tissues. UCA1 can improve the cell migration, invasion and induce cisplatin resistance. SRPK1 and apoptosis pathway proteins may be involved in the effect of UCA1.

Chromium catalysts derived from chiral sulfonamides represented by A effect the couplings of aldehydes with vinyl, allyl, or alkyl halides. With three distinct sites for structural modification, A affords access to a structurally diverse pool of chiral sulfonamides. The Cr catalysts derived from these sulfonamides exhibit a broad range of catalyst-substrate matching profiles. A strategy is presented to search for a satisfactory chiral sulfonamide for a given substrate. In order to demonstrate the generality and effectiveness of this approach, five diverse C-C bond-forming cases have been selected from the halichondrin synthesis. For each of the cases, two ligands have been deliberately searched for, to induce the formation of (R)- and (S)-alcohols, respectively, at the arbitrarily chosen efficiency level of ">or=80% yield with >or=20:1 stereoselectivity in the presence of

A de novo asymmetric approach to the natural product anthrax tetrasaccharide 1 and an analogue 2 with an anomeric hexyl azide group has been developed from acetylfuran. The construction of the tetrasaccharide was achieved by a traditional [3 + 1] glycosylation strategy. An iterative diastereoselective palladium-catalyzed glycosylation, Luche reduction, diastereoselective dihydroxylation, and regioselective acylation were employed for the assembly of the L-rhamno-trisaccharide building block. The anthrose building block also required a palladium-catalyzed azide allylation and a triflate inversion to set the gluco-stereochemistry in addition to Luche reduction and dihydroxylation.

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