Misconceptions among medicinal chemists regarding ADME and PK optimization
Yue Pan, Curie.Bio
https://doi.org/10.1007/s00044-026-03543-4
Optimisation of ADME and PK profiles is a core task for medicinal chemists when trying to produce a development candidate. To do this, chemists need to interpret this data correctly, which can often be counterintuitive. Yue used his LinkedIn presence to conduct a series of quizzes which focused on common misconceptions of ADME and PK data. This article discusses each misconception, why it arises, and a recommended best practice for interpreting this data.
From KRASG12D to Pan-KRAS Inhibitors- A Journey Enabled by Synthetic Innovation and Structure-Based Drug Design
Merck & Co, Astex Pharmaceutical, Taiho Pharmaceutical Co.
https://doi.org/10.1021/acs.jmedchem.5c03662
Early successes in KRAS inhibitors have targeted the G12C mutant, taking advantage of the reactive cysteine residue using covalent warheads. However, other clinically important mutations, including G12D and G12V are also common. This article details Merck’s work to develop G12D inhibitors and subsequently pan-KRAS inhibitors. This involved optimisation of the diamine group, which forms an ionic interaction with the mutated Asp residue. This was then replaced with neutral groups capable of inhibiting multiple forms of KRAS.
Discovery and Structural Optimization of BRD4-Selective Monovalent Direct Degraders
Monovalent degraders are molecules which bind directly to a protein of interest (POI) and induce degradation by facilitating interactions with an E3 ligase. They are distinct from PROTACs, which have a POI ligand and an E3 ligase warhead. They often have more drug-like properties, which is advantageous when trying to develop orally bioavailable compounds. In this article, Plexium describes its work to identify monovalent direct degraders of BRD4. They use one-bead one-compound DNA-encoded libraries coupled with their ultrahigh-throughput platform. This resulted in the development of PLX-4104, which showed complete tumour regression in the AML MV-4-11 xenograft model.
Massive barcode-free chemical screenings enable the discovery of bioactive macrocycles with passive membrane permeability
Leiden University, Oncode Institute, Kavli Institute of NanoScience, University of Torino
https://doi.org/10.1038/s41467-026-71641-3
Cyclic peptides are becoming increasingly important in drug discovery for targets which are difficult to drug with small molecules. Screening approaches typically rely on large genetically encoded libraries, such as mRNA and phage display. However, many of the hits that come out of these screens have poor permeability, a well-known problem for cyclic peptides and other beyond-rule-of-five (bRo5) molecules. In this work, the authors introduced Cyclic Self-Encoded Libraries (CycloSEL), a 16-million-member cyclic peptide library where most members fall into the “drug-like” bRo5 space. They used this platform to identify inhibitors of intracellular targets and show that these hits can be converted in to cell-active inhibitors.
Nicotine-Inspired, De Novo-Designed SARS-CoV-2 Main Protease Inhibitors Reveal Unique Chemistry for Covalently Conjugating Both Cysteine and Histidine Residues in the Catalytic Dyad
Texas A&M University
https://doi.org/10.1021/jacs.6c01119
Di- and Trihaloacetamides are covalent warheads that have both been used in the development of SARS-CoV-2 main protease inhibitors. These warheads (and others) target Cys145, the protease's catalytic cysteine residue. In this work, the authors describe a unique mechanism for some of their covalent inhibitors. They show that under certain binding modes, these warheads can engage both Cys145 and His41 in a novel dual covalent mechanism. This suggests that related haloacetamide warheads could potentially be used to cross-link Cys and His residues in other protein targets.
Discovery of molecular glues that bind FKBP12 and structurally distinct targets using DNA-encoded libraries
Novartis, Broad Institute of MIT and Harvard, Harvard University
https://doi.org/10.1038/s41467-026-71512-x
FK506 and rapamycin are immunosuppressant drugs that act as molecular glues. They bind to FKBP12 to form a binary complex, which then recruits and inhibits distinct protein targets. However, little is known about molecular glues which allow FKBP12 to target other proteins. In this work, the authors used an FKBP12-directed DNA-encoded library to screen 25 different proteins. This identified molecular glues that recruit BRD9 and QDPR to FKBP12.
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