This week's drug-discovery toolkit: a light-activated protein label, new mitotic inhibitors, and a phototherapy for cancer and superbugs
Six preprints posted October 15 add working tools to the bench — photoactivated labeling chemistry, covalent mitotic inhibitors, an effector-free RAB27A structure, a computational amylase candidate, a dual-use photosensitizer, and a formal fix for silent mass-spec errors.
- AbzSH, an aminobenzamide-based photoactivated fluorescent probe, enables site-selective alkene labeling via thiol-ene ligation in aqueous media and complex cell lysates, and tolerates carbohydrates, amino acids, and steroids as substrates. Self-reported m:…7213
- A high-content screen of 3,520 cysteine-reactive molecules identified novel early mitotic spindle assembly inhibitors; two lead compounds induce mitotic arrest and reduce cancer cell viability at nanomolar concentrations. Self-reported m:…5728
- IMP2660, a nanomolar-affinity macrocyclic peptide discovered by mRNA display, binds the RAB27A effector-binding interface and enabled the first effector-free 2.1 Å structure of active-state RAB27A. Self-reported m:…0071
- Virtual screening of Enantia chlorantha stem bark compounds prioritized neoisolongifolene-8-ol against pancreatic alpha-amylase (docking score -6.201 kcal/mol; 10 ns MD with mean backbone RMSD 1.17 ± 0.13 Å; persistent hydrogen bond to His305). Computational only — no in vitro or in vivo validation. Self-reported m:…5629
- ZnPc-Me, a cationic amphiphilic ABAC zinc(II) phthalocyanine, is a multimodal phototherapy platform (PDT, vascular-targeted PDT, photodynamic inactivation, photochemical internalization) with nanomolar-range EC50 in cancer models, activity in 3D tumor spheroids, and efficacy against multidrug-resistant ESKAPE pathogens; negligible dark toxicity and no hemolysis in vitro, but no in vivo data yet. Self-reported m:…3531
- A formal gap-merge safety criterion for peptide alphabets eliminates silent residue-substitution errors in tandem MS sequencing simulations at fragment dropout rates up to 0.4. Simulation only — no wet-lab validation. Self-reported m:…1783
Labeling on light
A preprint posted to bioRxiv on October 15 describes AbzSH, an aminobenzamide-based fluorescent probe that activates under light to label alkene-containing biomolecules through thiol-ene ligation. Because the chemistry runs in aqueous media, it works in complex cell lysates rather than only in clean model systems. m:…7213
The probe tolerates a range of scaffolds, including carbohydrates, amino acids, and steroids, and can target proteins carrying genetically encoded alkene motifs, which positions it as a candidate tool for high-resolution proteomics and drug-discovery workflows. m:…7213
Covalent inhibitors of early mitosis
Another bioRxiv preprint posted October 15 reports a high-content screen of 3,520 cysteine-reactive molecules aimed at early mitotic spindle assembly. The screen produced multiple inhibitors that disrupt microtubule dynamics and chromosome alignment. m:…5728
Two lead compounds stood out, inducing mitotic arrest and reducing cancer cell viability at nanomolar concentrations. The preprint frames cysteine-reactive covalent inhibitors as a viable modality for targeting cell-cycle proteins involved in proliferation, and as chemical probes for studying early cell division. m:…5728
RAB27A, crystallized without an effector
RAB27A, a GTPase that regulates vesicle trafficking and has been linked to modulation of the tumor microenvironment, has been difficult to characterize structurally because crystallization has historically required an effector protein. A bioRxiv preprint posted October 15 reports a way around that problem. m:…0071
Using mRNA display, the authors identified IMP2660, a macrocyclic peptide that binds the effector-binding interface with nanomolar affinity. The resulting complex yielded the first effector-free structure of active-state RAB27A at 2.1 Å, which the preprint presents as a template for structure-guided ligand development. m:…0071
A computational candidate, and only that
A ChemRxiv preprint posted October 15 screened phytochemicals from Enantia chlorantha stem bark against human pancreatic alpha-amylase, a target relevant to type 2 diabetes management. Using Glide docking, induced-fit docking, and 10 ns molecular dynamics simulations, the authors prioritized neoisolongifolene-8-ol. m:…5629
The candidate docked with a score of -6.201 kcal/mol, and the complex held a mean backbone RMSD of 1.17 ± 0.13 Å over 10 ns, with a persistent hydrogen bond between the ligand hydroxyl group and the active-site residue His305. None of this has been tested in a dish or an animal: the preprint is computational throughout, with no in vitro kinetic or in vivo data. m:…5629
One photosensitizer, two fronts
A ChemRxiv preprint posted October 15 introduces ZnPc-Me, a cationic amphiphilic ABAC zinc(II) phthalocyanine that functions as a multimodal photodynamic platform. By adjusting administration and irradiation protocols, the compound can be switched between photodynamic therapy, vascular-targeted photodynamic therapy, photodynamic inactivation, and photochemical internalization. m:…3531
It showed nanomolar-range EC50 values in cancer models and retained activity in 3D tumor spheroids, while also inactivating multidrug-resistant ESKAPE pathogens. The in vitro safety readouts were favorable: negligible dark toxicity, no hemolysis, and no epidermal penetration. What is missing is any in vivo efficacy data, so the cancer-and-infection dual use remains preclinical. m:…3531
Fewer silent errors in peptide readout
Tandem mass spectrometry sequencing of peptides can fail silently: when fragment ions go missing, two adjacent residues can be misread as a single one. A ChemRxiv preprint posted October 15 argues that choosing a non-isobaric amino acid alphabet is not enough to prevent these gap-merge collisions. m:…1783
The author proposes a formal gap-merge safety criterion, requiring that no pair of residue masses sum to a third within a tolerance, and shows in simulation that alphabets satisfying it cut silent errors to zero at fragment dropout rates up to 0.4. The result matters for peptide-based diagnostics and peptide information-storage schemes, where a silent substitution is worse than a flagged failure. m:…1783
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