While transition metals drive powerful bond-forming reactions in synthetic chemistry, their use for covalent modification of biomolecules has been largely underexplored and restricted to isolated proteins in vitro. Aryl-metal reagents for protein S-arylation have so far been dominated by palladium and gold complexes, but these systems require sterically bulky phosphine ligands that promote reductive elimination,…
The installation of alkyl substituents through C(sp³)-C(sp³) coupling is in high demand in synthetic and medicinal chemistry. While some strategies towards this goal employ Ni-catalysed cross couplings, this transformation remained challenging due to the difficulty of obtaining cross-selectivity between fleeting aliphatic radicals and alkyl electrophiles. Recently published research in JACS followed a two-stage evolution from…
We chemists love building molecular complexity efficiently and in as few steps as possible. This allows us to transform readily accessible compounds into compounds of high value and to explore and access the vast chemical space which is highly relevant to drug discovery, material science and other fields related to synthetic chemistry. One of the…
Until now, direct activation of the C─O bond was an unresolved problem, mainly due to high dissociation energy (approximately 96 kcal/mol) and the limited dissociation capacity of the hydroxyl group. A new photoredox methodology published in Angewandte Chemie tackled this challenge by developing a direct deoxygenative cross-coupling of non-activated primary and secondary alcohols with aryl…
KRAS has been in the focus of cancer research for quite some time as it has been recognized as a key driver of tumor growth in several human cancers. In recent years, scientists could target inactive KRAS forms (like G12C). However, targeting the active-state mutations (such as G12R, Q61K, Q61L, Q61 variants) remained elusive, partially…
Optimization of PROTACs for in vivo applications is non-trivial, thought not impossible. A nice example on this topic represents freshly published paper in J. Med. Chem., showcasing successful optimization of a RIPK1 PROTAC degrader. Previous RIPK1 degrader LD4172 suffered from metabolic degradation and fast clearance (I highlighted the metabolic soft spots in the figure below)….
Although Hetero-Diels-Alder will play a central role, I am not going to speak about gender. Not today. Instead, I would like to highlight another major advancement in organic chemistry that enables synthesis of alkenes from alkynes. Alkynes serve as versatile building blocks in organic synthesis, drug discovery, and materials science. We chemists use them for…
About 85% of disease-related proteins lack suitable binding pockets for conventional drug discovery. While RNA-targeting approaches like siRNAs have shown promise (with several FDA approvals), they struggle with poor cellular uptake, limited tissue specificity, and complex, costly synthesis. Researchers from Peking University Shenzhen Graduate School introduce a novel modality for targeting “undruggable” proteins through RNA…
The field of PROTACs continues to evolve. A recent Nature Communications paper describes another self-assembling nano-PROTAC that co-degrades androgen receptor (AR) and HSP90 and shows promise for treatment of castration-resistant prostate cancer (CRPC). To save your precious time, here is my summary and highlights: Design and mechanismPsa-AR (nano-PROTAC) is a modular peptide comprising:– A PSMA-targeting…
Researchers often steer the design of CRBN-based PROTACs to achieve selective degradation of a single target while suppressing degradation of CRBN neo-substrates. Two different research groups published independently two publications where they approached this differently. By intentional design they developed dual degraders by combining the principles of PROTACs and molecular glue degraders. The first work…