Casein kinase 1δ-dependent Wee1 protein degradation.

Eukaryotic mitotic entry is controlled by Cdk1, which is activated by the Cdc25 phosphatase and inhibited by Wee1 tyrosine kinase, a target of the ubiquitin proteasome pathway. Here we use a reporter of Wee1 degradation, K328M-Wee1-luciferase, to screen a kinase-directed chemical library. Hit profiling identified CK1δ-dependent Wee1 degradation. Small-molecule CK1δ inhibitors specifically disrupted Wee1 destruction and arrested HeLa cell proliferation. Pharmacological inhibition, siRNA knockdown, or conditional deletion of CK1δ also reduced Wee1 turnover. Thus, these studies define a previously unappreciated role for CK1δ in controlling the cell cycle.

Regioselective synthesis of enones via a titanium-promoted coupling of unsymmetrical alkynes with weinreb amides.

A modular titanium-promoted coupling of unsymmetrical internal alkynes with Weinreb amides is described. The coupling reaction takes place at room temperature and affords E-trisubstituted enones in moderate to good yields with high levels of regioselectivity. The system shows moderate chemoselectivity.

Development of highly selective casein kinase 1δ/1ε (CK1δ/ε) inhibitors with potent antiproliferative properties.

The development of a series of potent and highly selective casein kinase 1δ/ε (CK1δ/ε) inhibitors is described. Starting from a purine scaffold inhibitor (SR-653234) identified by high throughput screening, we developed a series of potent and highly kinase selective inhibitors, including SR-2890 and SR-3029, which have IC50 ≤ 50 nM versus CK1δ. The two lead compounds have ≤100 nM EC50 values in MTT assays against the human A375 melanoma cell line and have physical, in vitro and in vivo PK properties suitable for use in proof of principle animal xenograft studies against human cancer cell lines.

Titanium-Promoted Cross-Coupling for the Selective Synthesis of Polysubstituted, Conjugated Amides.

α,ß-Unsaturated amides are important building blocks and are key structural elements in a number of biologically active natural products. Despite their importance and prevalence, few methods exist to prepare conjugated amides directly and modularly. To address this gap, a titanium-promoted coupling of alkynes and isocyanates has been developed. The method is highly stereoselective, producing only the E isomer with good chemoselectivity and regioselectivity (>95/5), for unsymmetrical internal alkynes that contain a steric bias. The reactive titanacyclopentene intermediate formed from the coupling of the alkyne and isocyanate was additionally reacted with various electrophiles to access tetrasubstituted enamides.

Pd-catalyzed silicon hydride reductions of aromatic and aliphatic nitro groups.

[reaction: see text] Room-temperature reduction of aromatic nitro groups to amines can be accomplished in high yield, with wide functional group tolerance and short reaction times (30 min) using a combination of palladium(II) acetate, aqueous potassium fluoride, and polymethylhydrosiloxane (PMHS). Replacing PMHS/KF with triethylsilane allows aliphatic nitro groups to be reduced to their hydroxylamines.

Casein kinase 1δ is an APC/C(Cdh1) substrate that regulates cerebellar granule cell neurogenesis.

Although casein kinase 1δ (CK1δ) is at the center of multiple signaling pathways, its role in the expansion of CNS progenitor cells is unknown. Using mouse cerebellar granule cell progenitors (GCPs) as a model for brain neurogenesis, we demonstrate that the loss of CK1δ or treatment of GCPs with a highly selective small molecule inhibits GCP expansion. In contrast, CK1δ overexpression increases GCP proliferation. Thus, CK1δ appears to regulate GCP neurogenesis. CK1δ is targeted for proteolysis via the anaphase-promoting complex/cyclosome (APC/C(Cdh1)) ubiquitin ligase, and conditional deletion of the APC/C(Cdh1) activator Cdh1 in cerebellar GCPs results in higher levels of CK1δ. APC/C(Cdh1) also downregulates CK1δ during cell-cycle exit. Therefore, we conclude that APC/C(Cdh1) controls CK1δ levels to balance proliferation and cell-cycle exit in the developing CNS. Similar studies in medulloblastoma cells showed that CK1δ holds promise as a therapeutic target.

Sterically directed iridium-catalyzed hydrosilylation of alkenes in the presence of alkynes.

A selective iridium catalyzed hydrosilylation of alkenes in the presence of more reactive alkynes is described. By utilizing [IrCl(COD)]2 in the presence of excess COD, hydrosilylation of alkenes and alkynes with ethynylsilanes is achieved with good chemo- and regioselectivity. This approach goes against the traditional reactivity trends of platinum and rhodium catalysts and allows access to highly substituted silicon alkyne tethers.

C-O hydrogenolysis catalyzed by Pd-PMHS nanoparticles in the company of chloroarenes.

Catalytic Pd(OAc)(2) and polymethylhydrosiloxane (PMHS), in conjunction with aqueous KF, and a catalytic amount of an aromatic chloride, effects the chemo-, regio-, and stereoselective deoxygenation of benzylic oxygenated substrates at room temperature in THF. Preliminary mechanistic experiments suggest the process to involve palladium-nanoparticle-catalyzed hydrosilylation followed by C-O reduction. The chloroarene additive appears to facilitate the hydrogenolysis process through the slow controlled release of HCl.

Zinc-catalyzed silylation of terminal alkynes.

A rapid and high-yielding silylation of terminal alkynes employing TMSOTf and catalytic quantities of Zn(OTf)2 has been developed. The reaction works well for a variety of substrates including reactive esters. Fifteen examples with yields of >90% are reported.