What do FDA approved drugs propranolol, naproxen and terbinafine have in common? They all contain a naphthalene moiety, which is a common structural motif in biologically active compounds. The reasons are perhaps clear to most medicinal chemists. Naphthalene fits well into many lipophilic pockets on proteins, many functionalized derivatives of naphthalene are commercially available and…
Enlicitide decanoate (MK-0616) is a beautifully complex macrocyclic (not so small) peptide (or rather pseudo-peptide). This 1720 Da heavy beauty with 10 stereocentres is an inhibitor that blocks interaction between PCSK9 and LDL receptor and is under development at Merck for atherosclerotic cardiovascular disease. Most macrocyclic peptide drugs have to be injected. Enlicitide, however, is orally…
Big molecules, big permeability issues. All medicinal chemists know that well. No wonder that many scientists in drug discovery were skeptical whether such large molecules (800+ Da) can make it through clinical trials. Yet they enter cells as well as systemic circulation sufficiently to drive potent target degradation and elicit a therapeutic effect. However, how…
For decades, ubiquitin has been considered almost exclusively as a protein tag. Its C-terminal Gly-Gly motif forms isopeptide (or occasionally thio-/oxy-ester) bonds with Lys, Cys, Ser or Thr residues, marking proteins for degradation, trafficking or regulation. While a handful of reports have suggested that ubiquitin can also be attached to sugars, lipids, nucleic acids or…
Although PROTACs hijacking cytosolic E3 ligases have been reported to degrade certain trans-membrane (TM) proteins (including EGFR, GPCRs, and PD-L1), It is plausible that this approach is for some TM targets sub-optimal as TM targets have restricted access to the cytosolic degradation machinery. Strategies specifically designed for membrane proteins, such as LYTACs, GlueTACs, and TransTACs,…
PROTACs and molecular glue degraders are the front runners in the area of targeted protein degradation (TPD), with several clinical candidates. While they demonstrated their usefulness and applicability on a wide range of proteins with diverse function and structure (many of them being disease relevant or hard-to-drug), probing the intricate mechanisms of biological processes and…
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…