Five science items today: de novo MYC binders, a bivalent BPTF inhibitor, a macrocyclic RAB27A binder, pairwise QSAR for potency extrapolation and benzodiazepine antimalarials. Business: Lakefront sells its shelved CAR-T programs to Paul Stoffels' new Armed Cell.
2026-10-16 · ⚗️Plasmodium falciparum (PfSET3 hypothesis) / 1,5-benzodiazepines · chemRxiv
- Eighteen new 3H-1,5-benzodiazepines were made and tested against chloroquine-sensitive and resistant P. falciparum strains, with HepG2 cytotoxicity as a first selectivity check.
- Several compounds were active in the low micromolar range, with different members showing the best potency and the best selectivity.
- The two leads were only weak inhibitors of human G9a; docking, MM-GBSA and MD were used to propose binding to parasite PfSET3.
💡 PointsLow-micromolar whole-cell activity with a thin selectivity window is a start, not a lead; the target claim rests on docking, which I'd treat as a hypothesis only. What I like is the unusual chemotype against a parasite epigenetic enzyme. Next I'd want a biochemical PfSET3 assay and some SAR around the best-selectivity compound.
3H-1,5-Benzodiazepine Derivatives as Novel Antimalarial Agents: Synthesis, Biological Evaluation and Computational Target Exploration ↗
2026-10-16 · ⚗️BPTF (PHD finger + bromodomain) · bioRxiv
- The BPTF PHD–bromodomain cassette reads H3K4me3 together with K14 acetylation, a pairing confirmed by crystallography and shown to work cooperatively, including in cis.
- The authors report first experimental evidence of a ligand-induced conformational change between the two reader domains.
- A peptide–small-molecule conjugate, MJ-1, was built from these insights and inhibits both domains, addressing the usual ligandability problem of PHD fingers.
💡 PointsEveryone has chased BPTF bromodomain binders with limited payoff; the PHD finger is the hard half, and a bivalent design is a pragmatic way to borrow affinity from a peptide. The catch is that a peptide conjugate is far from a cell-permeable lead. I'd want to see which half carries the potency and whether a fully small-molecule version holds up.
Bivalent Inhibitor Development for a Dynamic Epigenetic Tandem Reader Protein Using a Combinatorial Histone Code ↗
2026-10-15 · ⚗️MYC (disordered transcription factor) / de novo designed proteins · bioRxiv
- Designed proteins target conserved epitopes in MYC, including intrinsically disordered motifs needed for its oncogenic activity.
- They bind MYC tightly in vitro; in cells they engage MYC, disrupt MAX pairing and reshape MYC-associated complexes.
- Expressing the binders curbed proliferation across several MYC-dependent hematopoietic, liver, pancreatic and patient-derived models, and depleted tumor cells in an orthotopic pancreatic model.
💡 PointsMYC has no pocket for a small molecule to sit in, so going after disordered epitopes with designed binders is a sensible way around that. For us it's a target-validation tool first: expression inside the cell says nothing about delivery, and a protein binder won't become a drug without a delivery story. Still, it shows where a small-molecule PPI or degrader program should aim.
MYC targeted de novo binders impair tumor growth ↗
2026-10-15 · ⚗️RAB27A (small GTPase) / macrocyclic peptide · bioRxiv
- mRNA display against the RAB27A effector-binding interface produced macrocyclic peptide hits, which were optimized into IMP2660.
- IMP2660 binds RAB27A tightly and disrupts RAB27A–effector interactions.
- Its co-crystal structure with active-state RAB27A, solved without any effector, maps the effector-binding surface for structure-guided design.
💡 PointsThe crystallography chaperone angle is the underrated payoff: wild-type RAB27A only crystallized with its effector, so a clean macrocycle-bound structure unlocks soak-in and fragment work. Whether IMP2660 itself is more than a tool is another matter, since permeability for a nonapeptide-sized macrocycle against an intracellular GTPase is the obvious hurdle.
A potent macrocyclic peptide binder enables effector-free crystallization of the GTPase RAB27A ↗