Scientific Updates

Curated highlights from medicinal chemistry, drug discovery, targeted protein degradation, screening technologies, and emerging therapeutic modalities.

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When Degradation Stops, BTK Inhibition Takes Over

Scientific illustration comparing two BTK degraders, NX-5948 and tacabrutideg (BGB-16673). Both promote CRBN-dependent BTK degradation, but when CRBN function is lost, BGB-16673 retains intrinsic BTK kinase inhibition while NX-5948 loses most of its inhibitory activity.

Targeted Protein DegradationNov 6, 20265 min read

Tacabrutideg (BGB-16673), NX-5948, and what resistance reveals about the design of BTK degraders. Removing a protein and inhibiting its enzymatic activity are not necessarily competing strategies. A recent preclinical study presented in the ASH 2026 abstract collection suggests that combining both mechanisms within a single degrader may provide an advantage when the ubiquitin–proteasome pathway becomes compromised. The study, conducted by researchers at BeOne Medicines, compares tacabrutideg (BGB-16673) with bexobrutideg (NX-5948), developed by Nurix Therapeutics and Roche. Both are cereblon (CRBN)-recruiting BTK degraders, but their intrinsic ability to inhibit BTK kinase activity differs substantially.

Scientific illustration showing a four-step PROTAC linker analysis workflow alongside PCA plots for USP7, IRAK4, and BRD4 degrader series. The plots compare linker descriptors with experimental degradation, permeability, solubility, lipophilicity, and other molecular properties.

Targeted Protein DegradationOct 28, 20265 min read

Linker optimization remains one of the most experimentally demanding steps in PROTAC development. A recent ChemMedChem study asks whether five simple molecular descriptors can help medicinal chemists make better decisions before synthesizing the next series. Apprato, G.; Traversa, S.; Caron, G.; Ermondi, G. Limiting Trial-and-Error: Linker-Based 2D Descriptor Analysis to Support Very Early Proteolysis-Targeting Chimeras Design. ChemMedChem, 2026, 21, e70532. https://doi.org/10.1002/cmdc.70532

Scientific illustration showing the structure-guided optimization of Fragment 4 into FORX-864, a covalent RAD52 inhibitor. Fragment growing and acrylamide-mediated engagement of Cys64 resulted in a more than 130,000-fold improvement in biochemical potency (IC₅₀: 664 µM to 5 nM). The figure highlights key molecular features, including salt-bridge formation, improved preorganization, and interactions with a lipophilic binding region.

ScreeningOct 26, 20264 min read

Protein–DNA interfaces remain challenging targets for small-molecule drug discovery. A recent JACS study offers an interesting perspective on how covalent chemistry can help overcome some of these limitations. Beyond conventional inhibition, this strategy could inspire new approaches to TPD, particularly for proteins with poorly defined binding pockets. However, molecular polarity, cellular permeability and the compatibility of irreversible target engagement with catalytic degradation remain important challenges. An interesting example of how covalent chemistry can expand the boundaries of druggable protein space. Read our scientific insight for a closer look at the chemistry, its potential applications and remaining questions. https://doi.org/10.1021/jacs.6c16278

FDA Q3 2026 drug approvals infographic showing 22 approved products: 12 small-molecule therapeutics (54.5%), 2 PET imaging agents (9.1%), and 8 other therapeutic modalities (36.4%). A red, brown, and yellow donut chart is accompanied by molecular structures of 12 approved small-molecule drugs, with their names and pharmaceutical companies.

Drug DiscoveryOct 22, 202610 min read

An analysis of 22 new FDA approvals, their underlying chemistry, emerging therapeutic strategies and commercial potential. The third quarter of 2026 delivered 22 novel drug approvals by the US FDA, compared with 13 in the preceding quarter. According to Evaluate Pharma estimates reported in Nature Reviews Drug Discovery, these products could collectively generate approximately $31 billion in annual global sales by 2032.

Diagram comparing pyrrolidine and azabicyclo[2.1.1]hexane (aza-BCH) bioisosteres, highlighting differences in lipophilicity and aqueous solubility, examples of bioactive aza-BCH derivatives, and asymmetric synthetic strategies using bicyclobutanes versus methylenecyclobutanes for electrochemical cyclization.

Medicinal ChemistryOct 19, 20265 min read

Replacing a pyrrolidine ring with a rigid bicyclic analogue can significantly change a molecule’s shape, conformational freedom, and physicochemical \[properties. Azabicyclo[2.1.1]hexanes (aza-BCHs) are particularly interesting in this context, but their use in medicinal chemistry has been limited by synthetic accessibility, especially when enantiomerically enriched compounds are required. A new study by Kasu, Singha, and Hari from the Indian Institute of Science, published in Nature Communications, introduces an electrochemical route to chiral aza-BCHs from methylenecyclobutanes. The chemistry is interesting for two reasons: it avoids the highly strained bicyclobutanes used in previous asymmetric approaches, and it produces halogenated bicyclic structures that can be further diversified. https://doi.org/10.1038/s41467-026-78484-y

Scientific figure comparing AI-predicted ligand binding sites with experimentally identified cysteine targets. Bar charts, distance plots, and protein structures show that Boltz-2 frequently places covalent tryptoline stereoprobes in known orthosteric pockets rather than at experimentally identified nonorthosteric cysteines, including IKBKB C464 and CRBN C219.

ScreeningOct 19, 20265 min read

A new Nature Chemical Biology study identifies covalent tryptoline stereoprobes that disrupt the mitochondrial GRPEL1–HSPA9 protein complex. Combining systematic chemical diversification, chemoproteomics and functional assays, the researchers demonstrate how substituents distant from an electrophilic warhead can redirect protein engagement. Their findings also expose important limitations of AI-based methods for predicting nonorthosteric ligand-binding sites.

Structural comparison of CRBN-based molecular glue ternary complexes with CK1α (a) and NEK7 (b), showing recognition through β-hairpin G-loop degrons in the kinase N-lobe, distinct from the ATP-binding site.

Targeted Protein DegradationOct 14, 20266 min read

Recent advances in molecular glue discovery are considerably expanding the range of protein kinases accessible to targeted protein degradation. A new review by Injeoung Hwang and Wooyoung Hur, published as an accepted manuscript in Bioorganic & Medicinal Chemistry, examines recent CRBN-binding molecular glue degraders, with particular emphasis on the structural mechanisms underlying kinase recruitment and selectivity.

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Scientific Updates

When Degradation Stops, BTK Inhibition Takes Over

The Linker Lottery May Have a Pattern

Can a DNA-binding interface become a starting point for covalent drug discovery?

FDA Drug Approvals in Q3 2026: When Molecular Glues, Macrocycles and Precision Medicine Meet Clinical Reality

Electrochemical Haloamination for Chiral Aza-BCH Synthesis

Covalent Tryptoline Stereoprobes Target GRPEL1–HSPA9: Molecular Recognition Beyond Conventional Binding Pockets

Beyond the G-Loop: Molecular Glues Are Expanding the Kinase Degradation Landscape

Start a conversation about your research