Miniaturized Traceless Staudinger Ligation Enables Direct-to-Biology Screening of Potent BRD4 PROTACs

Miniaturized base-free traceless Staudinger ligation enabled direct-to-biology screening of BRD4 PROTACs, achieving ~65% mean LC-MS conversion and identifying 23 hits at 250 nM.

• Why it matters: D2B PROTAC discovery is limited by which chemical steps tolerate crude mixtures, so expanding compatible linker-forming reactions is needed to broaden screening-ready libraries.
• What they did: Using phosphine-functionalized JQ1 derivatives with 72 selected azide building blocks, the team ran traceless Staudinger ligations in 384-well plates on a 5 L scale and then screened crude mixtures in cells.
• The result: Cellular assays found 23 hits at 250 nM, with BRD4 levels reduced below 40%, and two purified resynthesized PROTACs showed pDC50 values of 8.2 and 7.0 with Dmax of 90% and 96%.

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