Volume 16 Issue 11, November 2020

Targeted small-molecule inhibition of BRAF^V600E faces seemingly insurmountable obstacles in the clinic, such as rapid emergence of drug resistance. A recent study illustrates the potential of an alternative therapeutic strategy via PROTAC-mediated degradation of the oncogenic BRAF.

Molecular glues induce novel protein–protein interactions to modulate protein function and downstream biology. A recent study unveils manumycin polyketides with multiple electrophilic centers as covalent molecular glues between UBR7 and TP53.

Two recent studies identified CDK12 inhibitors that bind to CDK12–cyclin K complexes and act as molecular glues to stabilize an interaction with the ubiquitin ligase CUL4–DDB1, leading to cyclin K degradation.

Transfer of ubiquitin onto target proteins requires controlled interplay between E2 conjugating enzymes and E3 ligases. The structure of a trapped E2~Ub/RCR E3 transfer intermediate provides novel insight into the diversity of mechanisms used to fine tune this relay.

This Review summarizes the chemical and physical properties of methylated nucleobases in DNA and RNA, proposes a chemical classification of methylation types, and discusses recent advance in demethylation reactions mediated by dioxygenases.

A PROTAC termed P4B targeting BRAF V600E mutant has been developed, which displays enhanced inhibitory function in cell lines carrying BRAF mutations that impart resistance to conventional BRAF inhibitors.

A bifunctional AURORA-A degrader induces the fast and specific degradation of this kinase in cancer cell lines, which enables targeting of non-catalytic, oncogenic functions of AURORA-A resulting in S-phase arrest and rampant apoptosis.

Manumycin natural products were found to target the E3 ligase UBR7 and engage in molecular glue interactions with p53, leading to the activation of p53 and cell death.

Chemical profiling in hyponeddylated cells coupled with multi-omics target deconvolution led to the identification of molecular glue degraders of cyclin K that function by inducing proximity between the CRL adaptor DDB1 and a CDK12–cyclin K complex.

Immunomodulatory drugs are used for the treatment of multiple myeloma. ARID2, a component of the PBAF chromatin-remodeling complex, is a new pomalidomide-induced neosubstrate of CRL4^CRBN, which accounts for its superior efficacy over lenalidomide.

The interaction between E1 and E2 is targeted by a stapled peptide that mimics the alpha-1 helix of E2, resulting in blockade of ubiquitin transfer from E1 to E2.

The structural analysis of a covalent E2–E3 ubiquitin transfer intermediate reveals the ubiquitin relay mechanism via two Cys residues of E3 ligase MYCBP2, which is related to neurite growth and neurite protection phenotypes.

Structural and biochemical analysis of E. coli transketolase with 2′-methoxy-thiamine shows that this antivitamin selectively inhibits the bacterial enzyme via a steric clash with a critical glutamate residue, preventing cofactor activation.

Cryo-EM structural work defines binding of the insecticide CHL in the pseudo-voltage-sensor domain of ryanodine receptor RyR that triggers conformational changes leading to channel opening and explains the resistance to CHL by some insects.

Biocatalytic cascade reactions using engineered variants of ferulic acid decarboxylase coupled to carboxylic acid reductase utilize carbon dioxide fixation to enable the carboxylation and functionalization of styrene and other aromatic compounds.

Pyruvate-responsive circuits based on an orthologous transcription factor and adaptation of an antisense transcriptional circuit were developed to sense pyruvate in Bacillus subtilis and redirect metabolism for optimized glucaric acid production.

Structural and biophysical approaches suggest that structural preorganization is important for triggering endogenous CD8⁺ T cells and escape from immune tolerance, as demonstrated by a single nonsynonymous mutation in an ovarian cancer neoepitope