Targeting subunits of BAF/PBAF chromatin remodeling complexes has been proposed as an approach to exploit cancer vulnerabilities. Here we develop PROTAC degraders of the BAF ATPase subunits SMARCA2 and SMARCA4 using a bromodomain ligand and recruitment of the E3 ubiquitin ligase VHL. High-resolution ternary complex crystal structures and biophysical investigation guided rational and efficient optimization towards ACBI1, a potent and cooperative degrader of SMARCA2, SMARCA4 and PBRM1. ACBI1 induced antiproliferative effects and cell death caused by SMARCA2 depletion in SMARCA4 mutant cancer cells, and in acute myeloid leukemia cells dependent on SMARCA4 ATPase activity. These findings exemplify a successful biophysics- and structure-based PROTAC design approach to degrade high profile drug targets and pave the way towards new therapeutics for the treatment of tumors sensitive to the loss of BAF complex ATPases.

The transcription factor BCL6 is a known driver of oncogenesis in lymphoid malignancies, including diffuse large B cell lymphoma (DLBCL). Disruption of its interaction with transcriptional repressors interferes with the oncogenic effects of BCL6. We used a structure-based drug design to develop highly potent compounds that block this interaction. A subset of these inhibitors also causes rapid ubiquitylation and degradation of BCL6 in cells. These compounds display significantly stronger induction of expression of BCL6-repressed genes and anti-proliferative effects than compounds that merely inhibit co-repressor interactions. This work establishes the BTB domain as a highly druggable structure, paving the way for the use of other members of this protein family as drug targets. The magnitude of effects elicited by this class of BCL6-degrading compounds exceeds that of our equipotent non-degrading inhibitors, suggesting opportunities for the development of BCL6-based lymphoma therapeutics.

The focal adhesion tyrosine kinase (PTK2) is often over-expressed in human hepatocellular carcinoma (HCC) and several reports have linked PTK2 depletion and/or pharmacological inhibition to reduced tumorigenicity. However, the clinical relevance of targeting PTK2 still remains to be proven. Here we present two highly selective and functional PTK2 PROTACs utilizing VHL and cereblon ligands to hijack E3 ligases for PTK2 degradation. BI-3663 (cereblon-based) degrades PTK2 with a median DC 50 of 30 nM to > 80 % across a panel of eleven HCC cell lines. Despite effective PTK2 degradation, these compounds did not phenocopy the reported anti-proliferative effects of PTK2 depletion in any of the cell lines tested. By disclosing these compounds, we hope to provide valuable tools for the study of PTK2 degradation across different biological systems.

In the version of this article originally published, several lines of text in the last paragraph of the right column on page 1 of the PDF were transposed into the bottom paragraph of the left column. The affected text of the left column should read "The ATP-dependent activities of the BAF (SWI/SNF) chromatin remodeling complexes affect the positioning of nucleosomes on DNA and thereby many cellular processes related to chromatin structure, including transcription, DNA repair and decatenation of chromosomes during mitosis 12,13. " The affected text of the right column should read "SMARCA2/4 BD inhibitors are thus precluded from use for the treatment of SMARCA4 mutant cancers but could provide attractive ligands for PROTAC conjugation. Small molecules binding to other bromodomains have been successfully converted into PROTACs by conjugating them with structures capable of binding to the E3 ligases von Hippel−Lindau (VHL) or cereblon 5,6,10,11,25,26,27. " The errors have been corrected in the PDF version of the paper.

No abstract

The diterpenoid alkaloids serve as a rich source of synthetic targets for organic chemists, due to the intriguing structure of the overlapping ring systems, along with biological activities commonly associated with compounds of this group. Fifteen total syntheses and numerous synthetic studies towards construction of ring fragments have been reported since 2010. This review article gives a brief overview of diterpenoid alkaloids and summarizes the recent synthetic efforts.1 Introduction1.1 Structural Classification and Biosynthetic Origin1.2 Structure Elucidation of the Aconitum Alkaloids2 Total Syntheses2.1 C18-Diterpenoid Alkaloids2.2 C19-Diterpenoid Alkaloids2.3 C20-Diterpenoid Alkaloids3 Strategies To Synthesize Ring Systems3.1 Radical-Based Cyclizations3.2 Ruthenium-Mediated Enyne Cycloisomerization3.3 Reductive Coupling3.4 Diels–Alder Reactions3.5 Oxidative Dearomatization/Diels–Alder Sequence3.6 Transannular Aziridation3.7 Intramolecular [5+2] Cycloaddition3.8 Miscellaneous4 Conclusion

Compounds featuring aziridine moieties are widely known and extensively used in literature. Due to their great potential from a synthetic and pharmacological point of view, many researchers focus their efforts...

3-Aminomethylation of salicylalkylamides afforded hybrids with a Mannich base. In addition, it triggered the rotation of the amide bond. The observed conformational switch is driven by strong intramolecular hydrogen bonding between the Mannich base and phenolic group. Crystal structure analysis reveals the stabilization of the hybrid molecules by double hydrogen bonding of the phenolic OH, which acts as an acceptor and donor simultaneously. The molecules contain an amide site and a Mannich base site in an orthogonal spatial arrangement. The intramolecular hydrogen bonds are persistent in a nonpolar solvent (e.g., chloroform). The conformational change can be reversed upon protection or protonation of the Mannich base nitrogen.