Epigenetics
24 articles
Histone-code reading by BPTF guides a peptide–small-molecule bivalent inhibitor
- 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.
Everyone 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.
Adamantane-capped indole hydroxamate YP200 pushes HDAC11 selectivity into a lung cancer PDX model
- Starting from the earlier lead PB94, the authors optimized the core, linker and cap of an indole-based hydroxamic acid series against HDAC11.
- The best compound, YP200, combines a secondary-amine linker with an adamantane surface-recognition cap.
- It showed high potency for HDAC11 with strong selectivity over other HDAC isoforms, and suppressed tumor growth in a patient-derived NSCLC xenograft.
Hydroxamates are rarely clean across isoforms, so a bulky adamantane cap doing the selectivity work is the part I'd chase: it suggests HDAC11's narrow channel rewards cap size more than zinc-binder tweaks. Given the recent probe-validity debate around HDAC11 tools, I'd want kinetic isoform panels and cellular target engagement before trusting the efficacy story.
Elevenostat is a multi-HDAC inhibitor biased to HDAC6, not an HDAC11-selective probe
- Re-testing Elevenostat (JB3-22) against recombinant HDAC isoforms with two orthogonal HDAC11 assays showed only weak HDAC11 inhibition.
- Full HDAC1–11 profiling found much stronger inhibition of HDAC6 and HDAC10, plus class I enzymes, with HDAC11 the least sensitive isoform.
- Cellular readouts (tubulin and histone acetylation, reduced viability) matched HDAC6 and class I engagement, so past HDAC11 conclusions drawn from this compound need re-reading.
This is the unglamorous but valuable kind of paper: a compound used as an HDAC11 tool turns out to hit HDAC6 hardest. Any phenotype published with Elevenostat now has an attribution problem. Before I reuse an inhibitor as a probe, I want full-panel selectivity and a matched inactive control, which this case argues for.
GTA182: a brain-penetrant MTA-cooperative PRMT5 inhibitor for MTAP-deleted tumors
- Structure-based design and multiparameter optimization gave GTA182, a tricyclic amide with strong selectivity for MTAP-deleted over wild-type cells.
- Low efflux and tuned physicochemical properties delivered unbound brain exposure in the efficacious range.
- Orally dosed, it caused regression in MTAP-deleted xenografts and an orthotopic glioblastoma model, and early Phase I data reported good tolerability and intracranial tumor shrinkage.
MTA-cooperative PRMT5 inhibitors are crowded, and brain exposure is the clear differentiator: MTAP deletion is common in glioblastoma, where most competitors can't reach the tumor. A clinical readout appearing in a medicinal chemistry paper is rare. I'd now look at hematologic safety, the usual liability for this class, and at how much of the intracranial effect is truly unbound-drug driven.
Co-crystal-guided HDAC6 inhibitors that reach the L2 loop and trigger autophagy in lung cancer cells
- Second-generation HDAC6 inhibitors were designed from X-ray structures of earlier compounds bound to the zebrafish HDAC6 catalytic domain.
- Co-crystal structures of two leads showed engagement of S531 in the L2 loop; cells showed raised acetylated tubulin without a clear histone acetylation change.
- One lead cut A549 viability in 2D and 3D culture through pro-autophagic signalling and also affected phase-separation behaviour.
Grabbing the L2 loop is the obvious handle for isoform selectivity: the CD2 pocket is conserved, the loop is not. Acetylated tubulin up and histones flat is the readout I want before believing a selectivity claim. I'd still ask for a broad HDAC panel and some PK before getting excited about the autophagy story.
First thiazolamide PI4KIIIβ/HDAC dual inhibitors take a host-directed route against HCV
- Host-directed dual inhibition of PI4KIIIβ and HDACs had not previously been reported for hepatitis C, where resistance to direct-acting antivirals remains a concern.
- A series of thiazolamide-based dual inhibitors was designed, synthesised and evaluated.
- Lead compounds showed potent enzymatic inhibition of both targets together with anti-HCV activity.
With DAAs curing most patients, the case for a host-directed HCV drug is hard to make commercially, and a dual PI4KIIIβ/HDAC profile adds tox risk. I read this as a good exercise in multitarget design, but would want to see cytotoxicity and kinase selectivity before calling the window real.
Millepachine hybrid hits tubulin and HDAC8 together in ovarian cancer models
- The natural product millepachine was fused with a key HDAC-inhibitor pharmacophore to build dual tubulin/HDAC inhibitors.
- Lead compound 6 was broadly antiproliferative across 12 cancer lines, inhibited tubulin polymerisation and HDAC8, and was selective for HDAC8 over HDAC1, 4 and 6.
- It suppressed tumour growth in an ovarian cancer xenograft with a favourable safety profile.
HDAC8 is a less crowded choice than the usual HDAC6/class I pairing, and pairing it with a tubulin binder is mechanistically coherent. My worry is the classic one for dual hybrids: the two activities rarely scale together, so I'd want evidence that HDAC8 inhibition, not just the tubulin arm, contributes to the in vivo effect.
Longer semi-rigid linkers drive VHL-based HDAC6 degraders with antileukemic activity
- A solid-phase route enabled systematic variation of VHL ligand, exit vector and linker in vorinostat-derived HDAC6 PROTACs.
- Longer, semi-rigid linkers gave the best degradation; the lead compounds degraded HDAC6 preferentially in MM.1S and MV4-11 cells.
- A matched non-degrading control with similar HDAC inhibition was clearly less antiproliferative, pointing to degradation itself as the driver.
The non-degrading control with matched enzyme inhibition is the kind of experiment that separates degradation from plain inhibition, and it favors the PROTAC. Preferential, not exclusive, HDAC6 selectivity from a vorinostat-like warhead is the weak point; a more isoform-selective ligand might sharpen it.
Scaffold-hopping screen yields a 2-OG-noncompetitive KDM6B inhibitor active in cervical cancer xenografts
- Scaffold-hopping virtual screening produced a diaryl pyrimidine-guanidine series against the JmjC demethylase KDM6B, which is overexpressed in cervical cancer.
- The optimized lead matched GSK-J4 in enzyme potency but is non-competitive with 2-oxoglutarate, a different binding logic from most JmjC inhibitors.
- Despite pan-KDM activity in vitro, it selectively raised H3K27me3 in C33A cells and slowed xenograft growth.
Most JmjC inhibitors live or die on 2-OG-site chemistry and its polarity baggage, so a non-competitive series is a genuinely different starting point. I'd want to know why enzyme-level pan-KDM activity collapses to H3K27me3 selectivity in cells, and what the guanidine does to permeability.
Binding kinetics help isolate HDAC2-selective inhibitor KTT-1
- KTT-1 (compound 12) was identified as HDAC2-selective by evaluating both thermodynamics and kinetics of enzyme–inhibitor binding, rather than affinity alone.
- Crystallography of HDAC2 with the compound, plus quantum chemical calculations on model compounds, suggests its 2-furanyl group drives the selectivity.
- In cells it preferentially inhibited HDAC2 over the highly homologous HDAC1 and promoted neurite outgrowth; in stress-vulnerable mice it improved memory and depression-like behavior.
Screening on residence time rather than IC50 alone is how you get past the near-identical HDAC1/2 active sites, and a furanyl contact backed by both crystallography and QM is a clean, testable rationale. Cellular HDAC2-over-HDAC1 preference is rare, so I'd want it confirmed in neurons with real brain exposure.
Native MS Shows PROTAC Linker Length and Warhead Identity Shape Ternary Complexes Differently
- Ion mobility, surface-induced dissociation and variable-temperature ESI were combined to probe BRD4–PROTAC–VCB complexes built with two BET ligands (JQ1 and I-BET726) and PEG linkers of different lengths.
- Shorter linkers held complexes in more extended shapes; longer, flexible linkers allowed relaxed, native-like conformations.
- JQ1 complexes tended to eject the PROTAC under collision, while tighter-binding I-BET726 complexes retained it; the two also melted differently.
Linker optimization is still mostly empirical, so orthogonal readouts of how architecture shapes the complex interface are welcome. Gas-phase data are not solution cooperativity, and I'd not rank degraders by them alone, but pairing them with cellular degradation could help rationalize why two warheads behave so differently. A preprint, so treat the conclusions as provisional until peer review.
p300/CBP Drug Discovery: Do Bifunctional Degraders Now Beat Classical Inhibitors?
- A perspective reviewing small-molecule inhibitors of the p300/CBP bromodomain and catalytic (HAT) domain, with emphasis on how the leading clinical compounds were optimized.
- It then follows the field's shift toward bifunctional proximity-inducing molecules, including PROTAC degraders.
- The article compares what each modality offers for these large, multidomain coactivators.
p300/CBP is a good test of when degradation earns its molecular weight: scaffolding functions that inhibitors leave intact are exactly what a degrader removes. The HAT-domain and bromodomain optimization stories are useful reading for anyone with a stubborn chromatin target. I'd read the degrader sections skeptically on paralog selectivity, since p300 and CBP are nearly identical.
A '2-in-1' PROTAC Folds the Cereblon Ligand into the HDAC8 Cap to Shrink the Degrader
- Instead of tethering two ligands, the cereblon-binding motif is built into the capping group of an HDAC8 inhibitor, so one structural element engages both proteins.
- Versus the group's first-generation degrader, the compact analogs are smaller, more selective and more drug-like.
- They degrade HDAC8 potently in vivo.
Most of us accept PROTAC bulk as a tax; fusing the E3 ligand into the warhead's cap group attacks that directly and is a transferable idea for other zinc-enzyme targets. The question I'd press is whether the shared motif compromises either binding event or cereblon neosubstrate selectivity. If in vivo degradation holds with better properties, the 'linkerless' direction deserves more attention.
A 2-in-1 Strategy for the Discovery of Compact HDAC8 Protac Degraders ↗
LSD1 Inhibition May Modulate Response to Nucleoside Analogue Therapies
- Perspective-style article proposing that pharmacological inhibition of the epigenetic enzyme LSD1 (KDM1A) can modulate cellular sensitivity to nucleoside analogue therapeutics.
- Synthesizes evidence across myeloid malignancies and viral infections, two disease areas where nucleoside analogues are already established treatments.
- Argues LSD1-driven chromatin and transcriptional changes may underlie altered drug response, positioning LSD1 inhibitors as potential combination partners to enhance nucleoside analogue efficacy across both fields.
What grabs me is that clinical-stage LSD1 chemotypes already exist (bomedemstat, seclidemstat, and friends) — if the chromatin argument holds up, repurposing into combo trials is cheap and fast. But this is a Perspective stitching two literatures together, not new data; before I'd trust a DDI-manageable combo across both AML and antivirals, I want real mechanistic proof that LSD1 inhibition actually changes nucleoside analogue uptake/incorporation, not just correlation.
Imidazolium Amino Acids Proposed as Bioisosteres for Methylated Lysine and Arginine Residues
- Imidazolium amino acids are proposed as cationic bioisosteres mimicking the size and charge of trimethyllysine, dimethylarginine, and arginine side chains.
- Binding to methyl-lysine reader domains is evaluated to see how closely the surrogates reproduce native residue recognition and selectivity.
- Cell assays indicate the charged isosteres can still traverse membranes, and SAR trends tie ring substitution to the affinity-permeability tradeoff for reader ligands and CPPs.
A non-hydrolyzable Kme3/Rme2 mimic solves a genuine headache—native methylated peptides get erased by demethylases or clipped by proteases mid-assay, muddying SAR. If ring substitution tunes affinity without killing permeability, this is a genuine alternative scaffold for reader-domain PPI inhibitors and arginine-free CPPs, not just another quaternary-ammonium curiosity—worth testing against our own Kme3 reader panel.
TrmD as an Antibacterial Target: A Review of Small-Molecule Inhibitor Discovery Strategies
- TrmD, a SPOUT-family bacterial tRNA methyltransferase without a human counterpart, is highlighted as a validated antibacterial target amid rising antimicrobial resistance.
- The review catalogs strategies used to discover small-molecule TrmD inhibitors—fragment-based design, high-throughput and virtual screening, click-chemistry-enabled direct-to-biology methods, molecular hybridization, and prodrug approaches.
- It synthesizes structural features and structure-activity relationships across these diverse chemical scaffolds to inform future inhibitor optimization.
TrmD's lack of a human ortholog is the real selling point here — a wide therapeutic window without the usual off-target liability, which is rare enough in antibacterial discovery to justify the review's existence. The click-chemistry/direct-to-biology entries jump out as the underexploited lane: fast SAR turnaround without carrying every analog through full synthesis, exactly what a fragmented, scaffold-diverse target like this needs before someone finally nails spectrum and PK.
TrmD: A Promising Antibacterial Target and Its Small-Molecule Inhibitors ↗
Iron(II)-Activatable Conjugates Enable Tumor-Conditional Release of the HDAC Inhibitor Panobinostat
- Hydroxamic acid-based HDAC inhibitors are limited by poor selectivity among metalloenzymes and by genotoxicity risk linked to isocyanate metabolites.
- The study applies a previously reported iron(II)-activatable conjugate platform to cage the pan-HDAC inhibitor panobinostat, aiming for tumor-conditional payload release.
- In multiple myeloma cell line models, the conjugate successfully caged HDAC inhibitory activity, and a bioisosteric control conjugate showed reduced genotoxicity relative to the free hydroxamate.
- Follow-up investigation identified the carboxylesterase CES1 as responsible for unexpected proteolytic instability of the panobinostat conjugate observed both in vitro and in vivo.
- The finding is noted as a focus for future work toward mitigating hydroxamate-associated toxicity and mutagenicity through more robust tumor-conditional activation.
Caging panobinostat's hydroxamate behind an Fe(II) trigger is a sensible fix for the isocyanate-genotoxicity liability that's dogged this chemotype, and the bioisosteric control actually showing lower genotoxicity than free drug is the kind of data I'd want before calling any HDACi "safer." But what grabs me is the CES1 finding: an esterase chewing through the conjugate in vitro and in vivo is the failure mode a clean MM cell assay never warns you about. That's not a footnote — it's the design problem for the next iteration, whether you engineer around the CES1 recognition motif or add orthogonal masking. I'd rather see this reported now than discovered in an IND package; it's a useful cautionary data point for anyone building Fe(II)-activatable payloads beyond this one hydroxamate.
Hsc70-Recruiting Degraders Exploit Chaperone-Mediated Autophagy for Targeted Protein Degradation
- Researchers developed Hsc70-Mediated Targeting Chimeras (Hsc70TACs), bifunctional small molecules that link an Hsc70-binding ligand to a ligand for a protein of interest, directing target degradation through chaperone-mediated autophagy rather than the ubiquitin-proteasome pathway used by PROTACs.
- The approach is proposed to extend the range of degradable targets, including certain cytosolic and cell-membrane proteins, and to offer an alternative route that may help address resistance risks associated with proteasome-dependent degraders.
- Degradation activity was demonstrated across multiple protein classes, including the transcriptional regulator BRD4, the regulatory protein MDM2, and the cell-membrane immune checkpoint protein PD-L1, across diverse cellular contexts.
- A lead BRD4-directed compound, B-2, showed favorable pharmacokinetic behavior and produced robust BRD4 degradation in vivo, supporting continued development of the Hsc70TAC modality.
A degradation route that bypasses CRBN/VHL entirely is worth my attention regardless of target — CMA recruitment sidesteps the ubiquitin-proteasome toolbox, so it should be orthogonal to the resistance mechanisms (neosubstrate mutation, E3 downregulation) that kill PROTAC leads in the clinic. PD-L1 is the result I'd chase: pulling a membrane protein through chaperone-mediated autophagy via LAMP2A translocation is something UPS-based PROTACs structurally can't do. My skepticism sits with the Hsc70 arm — KFERQ-motif engagement is promiscuous by design, so selectivity and off-target chaperone-client disruption need real scrutiny before I trust the SAR. B-2's in vivo PK and clean BRD4 knockdown at least de-risks synthesis/linker chemistry enough to treat this as a platform, not just a proof of concept.
New Selective HDAC4/HDAC7 Inhibitors Offer Chemical Probes for Th17 Biology
- HDAC4 and HDAC7 — two class IIa histone deacetylases with tissue-restricted expression — were recently identified as distinct transcriptional drivers of Th17 cell differentiation.
- Using the class IIa scaffold TMP269 as a starting point, researchers designed and synthesized a new series of HDAC4/7-targeted inhibitors.
- Structure-guided optimization of the metal-proximal and hydrophobic-binding regions yielded analogs with improved potency and greater isoform selectivity.
- Luciferase transcriptional assays, protein-binding studies, and docking analyses revealed distinct SAR patterns that separately govern selectivity for HDAC4 versus HDAC7.
- The resulting compounds offer selective chemical probes for dissecting HDAC4 and HDAC7 function in Th17 biology and a foundation for future therapies targeting Th17-driven inflammatory disease, including IBD.
Class IIa HDACs are pseudo-catalytic with shallow, promiscuous pockets — TMP269 already buys you pan-IIa selectivity over class I/IIb almost for free, so the real fight here is splitting HDAC4 from HDAC7, and that's the part I'd actually flag. Their catalytic domains are near-identical; selectivity has to come from second-shell/rim contacts in the hydrophobic channel, not the zinc-binding group, so decoupling the metal-chelating SAR from the selectivity-driving SAR (as they describe) is the right strategy and not trivial to execute. As probes, these look solid — potency plus genuine paralog discrimination is exactly what's needed to deconvolute Th17 phenotypes cleanly, though I'd want permeability/off-target data before trusting cellular calls. Going after Th17/IBD instead of the usual oncology playground is the smarter long game too: pan-HDACi toxicity is a dealbreaker for chronic dosing, and isoform-restricted engagement is the only realistic path to a tolerable chronic immunomodulator.
Chemists Engineer Isoform-Selective HDAC4/HDAC7 Probes to Dissect Th17 Inflammation
- HDAC4 and HDAC7 are class IIa histone deacetylases with limited tissue expression, making them attractive, more selective epigenetic drug targets than broadly expressed HDAC family members.
- Both enzymes help drive the transcriptional program behind Th17 cell differentiation, a pathway linked to inflammatory bowel disease and other Th17-associated inflammatory conditions.
- Chemists reworked the metal-binding and hydrophobic contact regions of TMP269, a known class IIa scaffold, to build a new series of HDAC4/7-directed analogs.
- Reporter-gene, binding, and docking studies uncovered distinct structural features that separately steer potency toward HDAC4 versus HDAC7.
- The work delivered isoform-selective, potent compounds usable as chemical probes to separately study HDAC4 and HDAC7 function, and as starting points for Th17-targeted therapeutics.
Class IIa HDACs are the pseudo-catalytic oddballs of the family — barely any intrinsic deacetylase activity, so their biology runs largely through protein contacts rather than a clean catalytic pocket, which is why generic HDAC pharmacophores rarely discriminate them well. Building off TMP269 instead of starting de novo is the pragmatic call: it's a validated class IIa binder, so tuning the metal-binding warhead plus the adjacent hydrophobic contacts is a much more tractable SAR exercise than blind discovery. Pulling HDAC4 vs HDAC7 selectivity out of that is the real win — these two are highly homologous, and clean separation is notoriously hard. Most clinical HDAC drugs are pan- or Class I-selective, so isoform-pure IIa probes are genuinely useful tool compounds for picking apart Th17 biology, well before anyone's thinking about a lead.
Photocrosslinking Probes Uncover New Nonhistone Partners of the TRIM24 Bromodomain
- TRIM24 is a dual-module epigenetic "reader" whose bromodomain binds acetylated histones and is an established cancer drug-discovery target, though its nonhistone binding partners have been poorly defined.
- Researchers installed genetically encoded photocrosslinkers, AzF and BzF, at residue L922 within the bromodomain's acetyllysine pocket, preserving histone binding while enabling UV-triggered covalent capture of interacting proteins.
- Quantitative proteomics identified the nonhistone proteins NPM1 (AzF-enriched) and CDK9 (BzF-enriched), plus candidates MAP4, RAN, and SND1.
- ChIP-seq showed TRIM24, CDK9, and NPM1 co-localize near transcription start sites of cancer-associated genes; KEGG analysis tied the hits to several signaling pathways.
- The approach shows photocrosslinking can extend reader-domain interactome mapping beyond histones, yielding new candidate leads for chemical-probe and target-discovery work on TRIM24.
"Selective bromodomain inhibitor" just got a harder definition. NPM1 and CDK9 turned up riding along at L922 — the acetyllysine pocket where any TRIM24 bromodomain probe or degrader warhead would sit — so selectivity now has to mean selective against displacing these too, not just against other BRD family members. Most bromodomain campaigns are still built structure-first off that pocket alone, chasing histone-mimetic potency; this says the pocket's biology extends past histones, so cellular phenotype from a TRIM24 chemical probe could be confounded by NPM1/CDK9 disruption rather than histone reading per se. No compound here, just a crosslinker — useful, but MAP4, RAN and SND1 are "candidates" in a proteomics list, not validated partners; I'd want co-IP/FP confirmation and dose-response competition before building any SAR narrative around them.
Covalent Metal-Complex Platform Maps Proteome-Wide Cysteines, Nets a PRMT1 Inhibitor
- Introduces reactive metallo-scaffolds (r-mS), a new class of covalent metal complexes bearing a chloroacetamide electrophile designed to engage ligandable cysteines across the proteome.
- Chemoproteomic profiling of a focused r-mS series in HEK293T cell lysate mapped novel cysteine engagement proteome-wide.
- Metal identity, arene substituents, and overall scaffold topography together tune cysteine reactivity and targeting selectivity.
- Lead compound r-mS-2 engages a cysteine within the functionally relevant SAM-binding domain of the methyltransferase PRMT1, confirmed by intact-protein LC-MS.
- That engagement functionally inhibits PRMT1 activity, tying a covalent hit directly to modulation of a validated target.
- Positions the platform as a generalizable route to target discovery for rational, next-generation metallodrug design.
The SAM-pocket cysteine hit on PRMT1 is the part I trust most here — that's a genuinely druggable site, and confirming occupancy by intact-protein LC-MS rather than an activity readout alone is the right bar. Where I'd slow down is selectivity: tuning reactivity through metal identity and arene substituents is a real lever, but it's one more variable than iodoacetamide/chloroacetamide fragment libraries already juggle, and a lysate screen doesn't tell me the off-target cysteine load in cells. Chemically, this is genuinely unfamiliar ground for most of us — ligand exchange, redox lability, and batch-to-batch reproducibility are liabilities organic warheads simply don't have. Against established cysteine-directed chemoproteomic platforms, r-mS adds an interesting third tuning axis, not yet a clear win. Metallodrugs as a class still carry that same tractability tax relative to organic small molecules — worth watching, not yet worth reaching for.
Photocrosslinking Probes Reveal Nonhistone Partners of the TRIM24 Bromodomain
- Genetic code expansion installed site-specific photocrosslinkers (AzF and BzF) at residue L922, within the acetyllysine-binding pocket of the TRIM24 bromodomain.
- Both crosslinker variants retained recognition of acetylated histones and crosslinked efficiently under UV, enabling interaction-based protein profiling (IBPP) in a native context.
- Quantitative proteomics of the two complementary probes gave differing capture profiles: AzF enriched for NPM1, BzF enriched for CDK9, with MAP4, RAN, and SND1 as additional candidates.
- ChIP-seq showed TRIM24, CDK9, and NPM1 co-occupying regions near transcription start sites of cancer-associated genes.
- Together the results suggest the TRIM24 bromodomain reads acetylation on nonhistone proteins as well as histones, broadening its reader function and informing chemical-probe design against this pocket.
The crosslinker sits inside the acetyllysine pocket itself, at L922 — that's not a fortuitous surface hit, it's evidence TRIM24 reads acetylated lysine on NPM1 and CDK9 through the same pocket it uses on histones, not a peripheral contact. That reframes TRIM24 as an acetyl-lysine reader with a broader substrate scope, and it means any inhibitor competing for that pocket is also competing off a nonhistone binding event, not just a histone mark. Practically, TRIM24 probe programs need NPM1/CDK9 engagement counter-screens now, and the TSS co-occupancy by ChIP-seq suggests that off-target isn't background noise but transcriptionally active. Worth flagging: this is GCE-based interactome mapping, not medicinal chemistry — no chemotype, no SAR, just a map of what a pocket-directed probe will also touch. BET programs learned this same lesson with nonhistone acetyl-lysine substrates years ago; TRIM24 is only now catching up to that complexity.
One Molecule, Two Jobs: A Compact PROTAC Strategy for Degrading HDAC8
- Researchers describe a "2-in-1" PROTAC design that merges the CRBN-recruiting ligand into the capping group of an HDAC8 warhead, rather than linking two separate ligands.
- This lets one structural motif engage both HDAC8 and the CRBN E3 ligase, unlike conventional heterobifunctional PROTACs, whose separate POI- and E3-binding units plus linker often yield large, poorly drug-like molecules.
- Relative to the team's earlier HDAC8 degrader YX862, the new compact degraders show improved selectivity, lower molecular weight, and better overall drug-like properties.
- The compounds also achieved effective HDAC8 degradation in vivo, indicating therapeutic potential beyond cell-based activity.
- The study proposes a broader design framework for building smaller, more efficient PROTACs by integrating target engagement and E3 ligase recruitment into a single motif.
The move that catches my eye: folding the CRBN ligand into the HDAC8 warhead's capping group instead of bolting on a full separate E3 unit plus linker. That's a direct attack on the MW/logP bloat that tanks oral exposure in most heterobifunctional degraders — not incremental linker trimming, a structural collapse of the whole ternary-complex scaffold. Going from YX862 to these analogs with better selectivity AND lower MW (rarely a package deal) says the capping vector is actively shaping the HDAC8–CRBN interface, not just shedding atoms. In vivo degradation data is the sanity check I always want before trusting a compact-PROTAC claim. I'd want SAR around that fused cap next — how much substituent tolerance before CRBN engagement drops off. Feels like a real template for smaller, more drug-like degraders, not just this target.
A 2-in-1 Strategy for the Discovery of Compact HDAC8 Protac Degraders ↗