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

A trans-Pt(ii) hedgehog pathway inhibitor complex with cytotoxicity towards breast cancer stem cells and triple negative breast cancer cells

The first example of a Pt complex of GANT61, a hedgehog (Hh) pathway inhibitor is reported. Reaction of cis-[Pt(ii)Cl2(dmso)2] with one equivalent of 4-pyridine carboxaldehyde (4-PCA, control ligand) or one equivalent of GANT61 (Hh pathway inhibitor) in acetone at rt for 30 minutes afforded trans-[Pt(ii)Cl2(dmso)(4-PCA)] (1) and trans-[Pt(ii)Cl2(dmso)(GANT61)] (2) respectively, where 4-PCA and GANT61 are N-donor ligands. The structures of 1 and 2 were fully characterised by elemental analysis, 1H NMR, 13C NMR and IR spectroscopy and X-ray crystallography. 1 and 2 undergo isomerisation from trans- to cis-in solution and therefore the biological activity of 2 is also associated with the cis-configuration. The in vitro cytotoxicity data show that 2 is a potent inhibitor of the growth of breast CSC-depleted HMLER and breast CSC-enriched HMLER-shEcad cells. Furthermore 2 markedly reduced the size and viability and significantly reduced the number of CSC-enriched HMLER-shEcad mammospheres formed. 2 also induced apoptosis with low micromolar IC50 values against two triple negative breast cancer lines, MDA-MB-231 (MDA231) and BT549. 2, which possesses the Hh pathway inhibitor GANT61 as an N donor ligand exhibits far superior anti-CSC activity including in the CSC-enriched mammosphere model and activity against TNBC cells as compared to its control analogue, the trans-Pt(ii) 4-PCA complex 1. The trans-Pt GANT61 complex 2 has also been shown to cause DNA damage and inhibit the Hh pathway at the level of GLI