Auto-RapTAC: A Versatile and Sustainable Platform for the Automated Rapid Synthesis and Evaluation of PROTAC.

The tedious synthesis and limited throughput biological evaluation remain a great challenge for discovering new proteolysis targeting chimera (PROTAC). To rapidly identify potential PROTAC lead compounds, we report a platform named Auto-RapTAC. Based on the modular characteristic of the PROTAC molecule, a streamlined workflow that integrates lab automation with "click chemistry" joint building-block libraries was constructed.

Discovery of an Exceptionally Orally Bioavailable and Potent HPK1 PROTAC with Enhancement of Antitumor Efficacy of Anti-PD-L1 Therapy.

HPK1, a well-known negative regulator of T cell receptors, can cause T cell dysfunction when abnormally activated. In this study, a PROTAC was designed and synthesized by optimizing the physicochemical properties of the warhead, linker, and CRBN ligand. demonstrated significant HPK1 degradation with a DC of 21.

Discovery of a potent CDKs/FLT3 PROTAC with enhanced differentiation and proliferation inhibition for AML.

AML is an aggressive malignancy of immature myeloid progenitor cells. Discovering effective treatments for AML through cell differentiation and anti-proliferation remains a significant challenge. Building on previous studies on CDK2 PROTACs with differentiation-inducing properties, this research aims to enhance CDKs degradation through structural optimization to facilitate the differentiation and inhibit the proliferation of AML cells.

Discovery of a potent and selective PARP1 degrader promoting cell cycle arrest via intercepting CDC25C-CDK1 axis for treating triple-negative breast cancer.

PARP1 is a multifaceted component of DNA repair and chromatin remodeling, making it an effective therapeutic target for cancer therapy. The recently reported proteolytic targeting chimera (PROTAC) could effectively degrade PARP1 through the ubiquitin-proteasome pathway, expanding the therapeutic application of PARP1 blocking. In this study, a series of nitrogen heterocyclic PROTACs were designed and synthesized through ternary complex simulation analysis based on our previous work.

Syntheses of 4-allyl-/4-allenyl-4-(arylthio)-1,4-dihydroisoquinolin-3-ones the photochemical Doyle-Kirmse reaction.

Facile synthesis of 4-allyl-/4-allenyl-4-(arylthio)-1,4-dihydroisoquinolin-3-ones via the visible-light-induced Doyle-Kirmse reaction of 4-diazo-1,4-dihydroisoquinolin-3-ones with allyl-/propargyl sulfides is reported. The reaction proceeds via the generation of free carbenes from cyclic diazo compounds followed by in situ formation of sulfonium ylide intermediates, which subsequently undergo [2,3-sigmatropic rearrangement] to give highly functionalized dihydroisoquinolinones in moderate to good yields. Broad substrate scope, and catalyst-free and mild conditions are the merits of this reaction.