Light-mediated multi-target protein degradation using arylazopyrazole photoswitchable PROTACs (AP-PROTACs).

Light-activable spatiotemporal control of PROTAC-induced protein degradation was achieved with novel arylazopyrazole photoswitchable PROTACs (AP-PROTACs). The use of a promiscuous kinase inhibitor in the design enables this unique photoswitchable PROTAC to selectively degrade four protein kinases together with on/off optical control using different wavelengths of light.

NITD-688, a pan-serotype inhibitor of the dengue virus NS4B protein, shows favorable pharmacokinetics and efficacy in preclinical animal models.

Dengue virus (DENV) is a mosquito-borne flavivirus that poses a threat to public health, yet no antiviral drug is available. We performed a high-throughput phenotypic screen using the Novartis compound library and identified candidate chemical inhibitors of DENV. This chemical series was optimized to improve properties such as anti-DENV potency and solubility.

Photoactive Bifunctional Degraders: Precision Tools To Regulate Protein Stability.

Targeted protein degradation with bifunctional degraders is positioned as a remarkable game-changing strategy to control cellular protein levels and promises a new therapeutic modality in drug discovery. Light activation of a degrader to achieve exquisite spatiotemporal control over protein stability in cells has attracted the interest of multiple research groups, with recent reports demonstrating optical control of proteolysis with chimeric molecules bearing photolabile or photoswitchable motifs. In this context of targeted proteolysis research spurring the emergence of innovative tools, we examine the design, synthesis, and properties of light-activated degraders.

Antibody-PROTAC Conjugates Enable HER2-Dependent Targeted Protein Degradation of BRD4.

Targeting protein degradation with Proteolysis-Targeting Chimeras (PROTACs) is an area of great current interest in drug discovery. Nevertheless, although the high effectiveness of PROTACs against a wide variety of targets has been established, most degraders reported to date display limited intrinsic tissue selectivity and do not discriminate between cells of different types. Here, we describe a strategy for selective protein degradation in a specific cell type.

A caged E3 ligase ligand for PROTAC-mediated protein degradation with light.

With the intent of achieving greater spatiotemporal control of PROTAC-induced protein degradation, a light-activated degrader was designed by photocaging an essential E3 ligase binding motif in a BRD4 targeting PROTAC. Proteolysis was triggered only after a short irradiation time, the kinetics of which could be monitored by live-cell video microscopy.

Discovery of 2-oxopiperazine dengue inhibitors by scaffold morphing of a phenotypic high-throughput screening hit.

A series of 2-oxopiperazine derivatives were designed from the pyrrolopiperazinone cell-based screening hit 4 as a dengue virus inhibitor. Systematic investigation of the structure-activity relationship (SAR) around the piperazinone ring led to the identification of compound (S)-29, which exhibited potent anti-dengue activity in the cell-based assay across all four dengue serotypes with EC<0.1μM.