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Members of the bone morphogenetic protein (BMP) and T-box gene families play several critical roles in the early embryonic development and tissue homeostasis. Although BMP proteins are the upstream regulators of T-box genes, few studies have investigated the molecular mechanisms between these two protein families. Here, we report that Tbx6 interacts directly with Smad6, an inhibitory Smad that antagonizes the BMP signal. This interaction is mediated through the Mad homology 2 (MH2) domain of Smad6 and residues 90-180 of Tbx6. We demonstrate that Smad6 facilitates the degradation of Tbx6 protein through recruitment of Smurf1, a ubiquitin E3 ligase. Consequently, Smad6 reduces Tbx6-mediated Myf-5 gene activation. Furthermore, specific knockdown of endogenous Smad6 and Smurf1 by small interfering RNA increases the protein levels of Tbx6 and enhance the expression of Tbx6 target genes. Collectively, these findings reveal that Smad6 serves as a critical mediator of BMP signal via a functional interaction with Tbx6, thus regulating the activation of Tbx6 downstream genes during cell differentiation. [ABSTRACT FROM AUTHOR]

1-(N,N-Diisopropylcarbamoyloxy)-1-tosyl-alkenes have been developed as an a²d¹ synthon via tandem umpolung. Upon addition of Grignard reagents and further quench by carbonyl compounds, this synthon produces α,α'-branched-α'-oxygenated ketones. Strategically, this widely applicable method installs respectively a carbanion unit and a carbonyl unit formally onto the α-carbon and the carbonyl center of an aldehyde in one-pot. [ABSTRACT FROM AUTHOR]

c-Met has emerged as an attractive target for targeted cancer therapy because of its abnormal activation in many cancer cells. To identify high potent and selective c-Met inhibitors, we started with profiling the potency and in vitro metabolic stability of a reported hit 7. By rational design, a novel sulfonylpyrazolo[4,3-b]pyridine 9 with improved DMPK properties was discovered. Further elaboration of p-p stacking interactions and solvent accessible polar moieties led to a series of highly potent and selective type I c-Met inhibitors. On the basis of in vitro and in vivo pharmacological and pharmacokinetics studies, compound 46 was selected as a preclinical candidate for further anticancer drug development. [ABSTRACT FROM AUTHOR]

A new strategy for diversity-oriented direct glycosylation of bioactive small molecules was developed. This reaction features (-)-β-pinene as acid scavenger and work with glycosyl iodides under mild conditions. With the aid of RP-HPLC and chiral SFC separation techniques, the new direct glycosylation proved effective at gram scale on bioactive small molecules including AZD6244, podophyllotoxin, paclitaxel, and docetaxel. Interesting glycoside derivatives were efficiently created with good yields and 1,2-cis selectivity. [ABSTRACT FROM AUTHOR]