Identification of triazolyl KAT6 inhibitors via a templated fragment approach.

KAT6, a histone acetyltransferase from the MYST family, has emerged as an attractive oncology target due to its role in regulating genes that control cell cycle progression and cellular senescence. Amplification of the KAT6A gene has been seen among patients with worse clinical outcome in ER+ breast cancers. Although multiple inhibitors have been reported, no KAT6 inhibitors have been approved to date. Here, we report the fragment-based discovery of a series of N-(1-phenyl-1H-1,2,3-triazol-4-yl)benzenesulfonamide KAT6 inhibitors and early hit-to-lead efforts to improve the KAT6 potency.

Development of a General Method for the Hiyama-Denmark Cross-Coupling of Tetrasubstituted Vinyl Silanes.

General conditions for the Hiyama-Denmark cross-coupling of tetrasubstituted vinyl silanes and aryl halides are reported. Prior reports of Hiyama-Denmark reactions of tetrasubstituted vinyl silanes have required the use of vinyl silanols or silanolates, which are challenging to handle, or internally activated vinyl silanes, which lack structural generality. Now, unactivated tetrasubstituted vinyl silanes, bearing bench-stable tetraorganosilicon centers, and aryl halides can be coupled. The key to this discovery is the identification of dimethyl(5-methylfuryl)vinylsilanes as bench stable and easily prepared cross-coupling partners that are readily activated under mild conditions in Hiyama-Denmark couplings. These palladium-catalyzed cross-couplings proceed well with aryl chlorides, though aryl bromides and iodides are also tolerated, and the reactions display high stereospecificity in the formation of tetrasubstituted alkenes. In addition, only a mild base (KOSiMe3) and common solvents (THF/DMA) are required, and importantly toxic additives (such as 18-crown-6) are not needed. We also show that these conditions are equally applicable to Hiyama-Denamrk coupling of trisubstituted vinyl silanes.

Stereoselective Synthesis of Cis- and Trans-Tetrasubstituted Vinyl Silanes Using a Silyl-Heck Strategy and Hiyama Conditions for Their Cross-Coupling.

We report a palladium-catalyzed, three-component carbosilylation reaction of internal symmetrical alkynes, silicon electrophiles, and primary alkyl zinc iodides. Depending on the choice of ligand, stereoselective synthesis of either cis- or trans-tetrasubstituted vinyl silanes is possible. We also demonstrate conditions for the Hiyama cross-coupling of these products to prepare geometrically defined tetrasubstituted alkenes.