SUMOylation is a reversible post-translational modification that regulates protein function through covalent attachment of small ubiquitin-like modifier (SUMO) proteins. The process of SUMOylating proteins involves an enzymatic cascade, the first step of which entails the activation of a SUMO protein through an ATP-dependent process catalyzed by SUMO-activating enzyme (SAE). Here, we describe the identification of TAK-981, a mechanism-based inhibitor of SAE which forms a SUMO−TAK-981 adduct as the inhibitory species within the enzyme catalytic site. Optimization of selectivity against related enzymes as well as enhancement of mean residence time of the adduct were critical to the identification of compounds with potent cellular pathway inhibition and ultimately a prolonged pharmacodynamic effect and efficacy in preclinical tumor models, culminating in the identification of the clinical molecule TAK-981.

[see reaction]. A catalytic amount of [(cod)IrCl]2 and indane-pybox converts diethylmethylsilane, methyl acrylate, and certain aldehydes to the derived reductive aldol adduct with good enantio- and diastereocontrol.

The first total synthesis of the natural product borrelidin is described. The propionate fragment of the molecule was concisely synthesized through catalytic enantioselective reductive aldol reactions, a catalytic Negishi coupling, and a catalytic directed hydrogenation. The propionate segment was then fused to the vinyl iodide fragment through a catalytic Sonogashira coupling. Subsequent catalytic hydrostannylation and catalytic cyanation allowed access to the target structure.

This article describes the discovery of a series of potent inhibitors of Polo-like kinase 1 (PLK1). Optimization of this benzolactam-derived chemical series produced an orally bioavailable inhibitor of PLK1 (12c, MLN0905). In vivo pharmacokinetic−pharmacodynamic experiments demonstrated prolonged mitotic arrest after oral administration of 12c to tumor bearing nude mice. A subsequent efficacy study in nude mice achieved tumor growth inhibition or regression in a human colon tumor (HT29) xenograft model.

The lituarines A-C comprise an architecturally novel, biologically active family of marine natural products (1-3; Figure 1) reported by Vidal and co-workers in 1992. 1a Isolated from the sea pen Lituaria australasaie, endemic to the western region of the New Caledonian Lagoon near the Baie de St. Vincent, their structures, including the connectivities and relative stereochemistries, were assigned on the basis of multidimensional NMR techniques; 1b the absolute stereochemistry remains undefined. From the biomedical perspective, the lituarines display significant cytotoxicities toward KB cells [(1): IC 50 ) 5.5-7.5 nM; (2): IC 50 ) 1-3 nM; (3): IC 50 ) 7-9 nM]. Intrigued both by the architecture and the biological activities of the lituarines, we initiated a research program directed toward the total synthesis of the lituarines. 2,3 The Robertson laboratory has also reported progress in this area. 4

Inhibition of mutant B-Raf signaling, through either direct inhibition of the enzyme or inhibition of MEK, the direct substrate of Raf, has been demonstrated preclinically to inhibit tumor growth. Very recently, treatment of B-Raf mutant melanoma patients with a selective B-Raf inhibitor has resulted in promising preliminary evidence of antitumor activity. This article describes the design and optimization of tetrahydronaphthalene-derived compounds as potent inhibitors of the Raf pathway in vitro and in vivo. These compounds possess good pharmacokinetic properties in rodents and inhibit B-Raf mutant tumor growth in mouse xenograft models.

This paper reports the utility of simple metal alkoxides for the catalytic, stereoselective hetero-aldol−Tishchenko reaction (eq 1). Choice of metal alkoxide is crucial to achieving high efficiency and stereoselectivity. Whereas NaO-t-Bu is an effective catalyst, delivering one product in 68% yield and 99:1 stereoselection, Sm(O-i-Pr)3 is less effective and delivers the same product in 42% yield with 4:1 stereoselection.

A new three-component coupling protocol, exploiting 2-bromoallyltrimethylsilane as a bifunctional linchpin, has been developed. The reaction sequence entails the following steps: lithiation of the vinyl bromide, addition of an aromatic or aliphatic aldehyde, execution of a solvent controlled 1,4-Brook rearrangement induced by HMPA to generate an allyl anion, and addition of a reactive second electrophile. Yields are moderate to good.