Alkenyl oxindole is a novel PROTAC moiety that recruits the CRL4DCAF11 E3 ubiquitin ligase complex for targeted protein degradation.

Alkenyl oxindoles have been characterized as autophagosome-tethering compounds (ATTECs), which can target mutant huntingtin protein (mHTT) for lysosomal degradation. In order to expand the application of alkenyl oxindoles for targeted protein degradation, we designed and synthesized a series of heterobifunctional compounds by conjugating different alkenyl oxindoles with bromodomain-containing protein 4 (BRD4) inhibitor JQ1. Through structure-activity relationship study, we successfully developed JQ1-alkenyl oxindole conjugates that potently degrade BRD4. Unexpectedly, we found that these molecules degrade BRD4 through the ubiquitin-proteasome system, rather than the autophagy-lysosomal pathway. Using pooled CRISPR interference (CRISPRi) screening, we revealed that JQ1-alkenyl oxindole conjugates recruit the E3 ubiquitin ligase complex CRL4DCAF11 for substrate degradation. Furthermore, we validated the most potent heterobifunctional molecule HL435 as a promising drug-like lead compound to exert antitumor activity both in vitro and in a mouse xenograft tumor model. Our research provides new employable proteolysis targeting chimera (PROTAC) moieties for targeted protein degradation, providing new possibilities for drug discovery.

Organocatalytic enantioselective construction of axially chiral (1H)-isochromen-1-imines.

Heterocycloalkenyl atropisomers, derived from biaryl atropisomers and axially chiral styrenes, have emerged as a new class of nonbiaryl C-C atropisomers due to the benefit in improving the pharmacological activity and structural diversity. This paper proposes an intramolecular annulation strategy for constructing the heterocycloalkenyl atropisomers (1H)-isochromen-1-imines by organocatalysis. Various heterocycloalkenyl atropisomers (1H)-isochromen-1-imines were prepared in good to excellent yields with excellent enantioselectivity (up to 98% ee), and could be easily converted to atropisomeric lactones isocoumarins.

Design and synthesis of dual BRD4/Src inhibitors for treatment of triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is an extremely aggressive tumor with limited treatment options and effectiveness. Dual-target inhibitors capable of simultaneously suppressing invasion may represent a promising therapeutic approach for TNBC. In this work, we developed a series of dual BRD4/Src inhibitors by connecting JQ1 and dasatinib using various linkers and evaluated their efficacy against TNBC both in vitro and in vivo. Among these compounds, HL403 demonstrated IC50 values of 133 nM for BRD4 inhibition and 4.5 nM for Src inhibition. Most importantly, HL403 not only exhibited potent anti-proliferative capabilities, but also effectively suppressed the invasion of MDA-MB-231 cells in vitro. Finally, the anti-tumor efficacy of HL403 was validated in a mouse MDA-MB-231 xenograft tumor model, achieving a tumor growth inhibition rate (TGI) of 70.7 %, which was superior to the combination of JQ1 and dasatinib (TGI = 54.0 %). Our research provides a promising and feasible new strategy for improving the treatment of TNBC.

Organocatalytic Enantioselective Construction of Spiroketal Lactones Bearing Axial and Central Chirality via an Asymmetric Domino Reaction.

The catalytic asymmetric synthesis of chiral compounds with multiple stereogenic elements via a single catalytic process is challenging. This paper proposes a domino asymmetric electrophilic halocyclization strategy for constructing heterocycloalkenyl atropisomeric spiroketal lactones. A single catalyst was utilized to realize two independent stereodetermining steps. Various spiroketal lactones containing both chiral axes and chiral centers were prepared in excellent yields with excellent enantioselectivity and diastereoselective (up to 99% ee and >20:1 dr).