Advances in the design and development of PROTAC-mediated HDAC degradation.

Due to developments in modern chemistry, previously undruggable targets are becoming druggable thanks to selective degradation using the ubiquitin-proteasomal degradation system. PROteolysis TArgeting Chimeras (PROTACs) are heterobifunctional molecules designed specifically to degrade target proteins (protein of interest, POI). They are of significant interest to industry and academia as they are highly specific and can target previously undruggable target proteins from transcription factors to enzymes. More than 15 degraders are expected to be evaluated in clinical trials by the end of 2021. Herein, we describe recent advances in the design and development of PROTAC-mediated degradation of histone deacetylases (HDACs). PROTAC-mediated degradation of HDACs can offer some significant advantages over direct inhibition, such as the use of substoichiometric doses and the potential to disrupt enzyme-independent HDAC function. Herein, we discuss the potential implications of the degradation of HDACs with HDAC knockout studies and the selection of HDAC inhibitors and E3 ligase ligands for the design of the PROTACs. The potential utility of HDAC PROTACs in various disease pathologies from cancer to inflammation to neurodegeneration is driving the interest in this field.</p

First-in-class metallo-PROTAC as an effective degrader of select Pt-binding proteins

The targeted degradation of proteins bound by metals represents a promising approach to treat diseases. We report the development of the first metallo-PROTAC, specifically a Pt-PROTAC, that can effectively degrade select Pt(II)-binding proteins. The reported Pt-PROTAC prototype successfully degraded thioredoxin-1 and thioredoxin reductase-1 though not glutathione-S-transferase in JJN3 and MM1.S multiple myeloma cancer cell lines. Deactivated Pt-PROTAC does not degrade thioredoxin-1 and thioredoxin reductase-1. Furthermore pretreatment of cells with the proteasome inhibitor bortezomib prevents Pt-PROTAC target degradation thereby implicating the ubiquitin proteasome system with its mode of degradation. Metallo-PROTACS will have important applications in the identification of metal binding proteins and as chemotherapeutic agents. </p

First-in-class metallo-PROTAC as an effective degrader of select Pt-binding proteins.

We report the development of the first metallo-PROTAC, specifically a Pt-PROTAC, that can effectively degrade select Pt(II)-binding proteins. The Pt-PROTAC prototype successfully degraded thioredoxin-1 and thioredoxin reductase-1 in multiple myeloma cancer cell lines. Metallo-PROTACs will have important applications in the identification of metal binding proteins and as chemotherapeutic agents

First-in-class metallo-PROTAC as an effective degrader of select Pt-binding proteins.

We report the development of the first metallo-PROTAC, specifically a Pt-PROTAC, that can effectively degrade select Pt(II)-binding proteins. The Pt-PROTAC prototype successfully degraded thioredoxin-1 and thioredoxin reductase-1 in multiple myeloma cancer cell lines. Metallo-PROTACs will have important applications in the identification of metal binding proteins and as chemotherapeutic agents

First-in-class metallo-PROTAC as an effective degrader of select Pt-binding proteins

The targeted degradation of proteins bound by metals represents a promising approach to treat diseases. We report the development of the first metallo-PROTAC, specifically a Pt-PROTAC, that can effectively degrade select Pt(II)-binding proteins. The reported Pt-PROTAC prototype successfully degraded thioredoxin-1 and thioredoxin reductase-1 though not glutathione-S-transferase in JJN3 and MM1.S multiple myeloma cancer cell lines. Deactivated Pt-PROTAC does not degrade thioredoxin-1 and thioredoxin reductase-1. Furthermore pretreatment of cells with the proteasome inhibitor bortezomib prevents Pt-PROTAC target degradation thereby implicating the ubiquitin proteasome system with its mode of degradation. Metallo-PROTACS will have important applications in the identification of metal binding proteins and as chemotherapeutic agents. </p

Exploring the conformational effects of <i>N</i>- and<i> C</i>-methylation of <i>N</i>-acylhydrazones

N-Acylhydrazones (NAH) are privileged structures in chemistry and medicinal chemistry. In this study, we describe the conformational effects of N- and C-methylated N-acylhydrazone derivatives, combining theoretical and experimental data analysis. Four N-acylhydrazone (NAH) derivatives (4–7) were synthesized and structurally characterized to investigate the impact of methylation on their conformational preferences and electronic properties. The structural characterization by NMR spectroscopy, including 2D techniques (HSQC, HMBC, and NOESY), confirmed the exclusive formation of (E)-diastereomers. Theoretical conformational analysis using density functional theory (DFT) calculations (CAM-B3LYP/6-31+G(d,p) with the C-PCM solvation model) revealed that N-methylation (6) significantly alters the preferred dihedral angle (O=C–N–X), inducing a shift from an antiperiplanar to a synperiplanar conformation. Notably, compound 7 showed two possible conformers in solution, anti and syn at the amide bond, and exhibited a greater deviation from planarity due to steric effects imposed by the two methyl groups, which disrupt conjugation within the NAH moiety. This was further supported by natural bond orbital (NBO) analysis, which demonstrated changes in electron density distribution, particularly at the carbonyl and imine carbons, correlating well with the calculated and experimental 13C NMR chemical shifts. Noncovalent interaction (NCI) analysis and powder X-ray diffraction provided additional evidence for these conformational trends, reinforcing the influence of methylation on NAH planarity. The findings highlight the steric and electronic consequences of methylation on NAH derivatives, which may have implications for their biological activity and molecular recognition properties.</p