Immune checkpoints & innate immunity
16 articles
An oral STING inhibitor that blocks palmitoylation shows efficacy in inflammation models
- Researchers built a tetrahydropyrazolo[1,5-a]pyrazine series as inhibitors of STING, the innate-immune adaptor behind several interferonopathies and autoimmune conditions.
- The lead, compound 37, combined strong cellular STING inhibition with good oral exposure and a clean safety read.
- Mechanistically it prevents STING palmitoylation, which in turn shuts down downstream signaling.
- Oral dosing reduced inflammation in acute chemical-challenge and Trex1-deficient mouse models, among others.
STING inhibitors have mostly been tool compounds or covalent binders, so a non-covalent-looking, orally dosed chemotype that acts by blocking palmitoylation is a different handle on the target. I would want to know whether it truly binds the Cys91 pocket or acts upstream, because that decides selectivity versus other palmitoylated proteins. The Trex1 mouse data is the convincing part for an autoimmune indication.
Designing out a BRD4 liability from dual TLR7/8 antagonists for lupus
- Structure-based optimization of 2-(pyridin-2(1H)-one)indoles gave dual TLR7/8 antagonists with better permeability, less ion-channel activity and lower volume of distribution than the earlier series.
- Early pyridone leads unexpectedly suppressed immune-cell proliferation, which the team traced to a hypothesized BRD4 off-target.
- Optimizing away BRD4 binding removed the anti-proliferative effect while keeping potent inhibition of TLR7/8-driven IL-6 in human whole blood.
This is a tidy example of phenotype-led off-target triage: odd toxicity in cell panels, a mechanistic guess, then SAR that separates the two activities. Endosomal TLR7/8 antagonists need to be both cell-permeable and cleanly selective, and BRD4 is an easy trap for flat heteroaromatics. I would check the pyridone's binding mode in the TLR7/8 dimer interface before borrowing the fix for other scaffolds.
Oral STING inhibitor D4 protects against severe acute pancreatitis in mice
- SAR work identified D4, which binds STING directly and blocks its oligomerization and downstream TBK1/IRF3 signalling.
- In macrophages it restored phagocytosis, autophagic flux and mitochondrial function while dampening NLRP3-linked pyroptosis.
- D4 was orally exposed and well tolerated at high dose, and cut pancreatic injury and enzyme levels in a caerulein/LPS model; STING knockdown looked similar.
Most STING programs chase agonists for oncology; an orally available inhibitor for an acute inflammatory indication is a different bet. The knockdown phenocopy is reassuring on mechanism, but I'd want to know how it behaves across species, since STING ligand pockets are notoriously species-dependent, and whether an acute dosing window is realistic in patients.
Discovery of Novel STING Inhibitors for the Treatment of Severe Acute Pancreatitis ↗
Ferulic acid-based PROTAC degrades TLR4 to protect endothelial cells
- Six PROTACs built on ferulic acid, a weakly active natural product, were tested for TLR4 degradation and migration in HUVECs.
- The lead, FP-4, degraded TLR4 and dampened TLR4/MyD88–NF-κB signaling plus TNF-α, ICAM-1 and VCAM-1 expression.
- Protection was also seen in zebrafish, extending PROTAC use beyond oncology.
Using a PROTAC to rescue a weak natural-product binder is clever, but TLR4 is a membrane receptor and the evidence here is thin on which E3 ligase is engaged and on ternary-complex dependence. I'd ask for rescue experiments with ligase and proteasome inhibitors before believing the mechanism.
Boronic acid ENPP1 inhibitors stay active across tumor-relevant pH
- ENPP1 hydrolyzes cGAMP in the tumor microenvironment and so dampens STING-driven antitumor immunity.
- Inspired by the phosphate-based inhibitor STF-1084, the team made non-nucleotide inhibitors with a boronic acid zinc-binding group, leading to compound 36, which stays potent across pH.
- Compound 36 boosted cGAMP-mediated STING activation in vitro and gave tumor growth inhibition as monotherapy in a syngeneic CT26 model, with a synergistic effect alongside oxaliplatin and no observed toxicity.
Phosphate- and phosphonate-type ENPP1 binders have always struggled with permeability and exposure, so swapping in a boronic acid zinc binder is a cleaner route. Designing for acidic-pH activity is the smart part, since that is where the enzyme works. Single-agent efficacy by IP dosing is modest, so oral exposure and boronic acid stability are my next questions.
Development of pH-Resilient Boronic Acid ENPP1 Inhibitors for STING-Mediated Cancer Immunotherapy ↗
Chiral imidazoquinolines show stereochemistry-dependent TLR7/8 agonism and antagonism
- A library of chiral imidazoquinolines was made and profiled in HEK-Blue hTLR7 and hTLR8 reporter assays.
- The SAR identified a potent dual TLR7/8 agonist and, from the same family, a dual antagonist.
- Activity depended on stereochemistry, likely because the two enantiomers interact differently in the TLR7/8 binding pocket.
Seeing both an agonist and an antagonist come out of one imidazoquinoline family, steered by stereochemistry, is a good argument for making both enantiomers early. For an adjuvant or autoimmune program, that switch is useful, but reporter-cell data alone only gets it to a hit; cytokine profiling in primary cells would tell me whether it holds up.
Istradefylline-derived thienopyrimidinones give an oral NLRP3 inhibitor for colitis
- The anti-Parkinsonian drug istradefylline showed modest NLRP3 inhibition, and optimizing it gave a thienopyrimidinone series.
- Lead L22 was roughly tenfold more potent than istradefylline, bound the NLRP3 NACHT domain directly and blocked inflammasome assembly.
- It was orally bioavailable, eased symptoms in a DSS colitis model and looked safe in acute and subacute toxicity studies.
Starting from a marketed drug's off-target activity gives a head start on drug-likeness, and direct NACHT-domain binding is what you want to see. NLRP3 is a busy field, so the real test is how L22 compares with clinical-stage inhibitors on potency and brain or gut exposure.
AstraZeneca Takes a $2B Stake in Summit to Pair Ivonescimab with Its ADCs
- AstraZeneca is buying $2B of convertible preferred stock, giving it about 12% of Summit's common stock (about 10.6% fully diluted).
- The first combination pairs Summit's PD-1xVEGF bispecific ivonescimab with AstraZeneca's CLDN18.2-directed ADC in gastrointestinal cancers; a memorandum of understanding covers a broader program with more AstraZeneca ADCs.
This is AstraZeneca buying a seat rather than a pipeline: equity plus combination rights instead of an acquisition or license, keeping it close to a PD-1xVEGF class it doesn't own without paying for the asset outright. The bet is that ADC plus PD-1xVEGF combinations become a next oncology backbone, with AstraZeneca's ADC portfolio as the partner of choice. The broader MOU is non-binding, so definitive terms are the thing to watch.
AstraZeneca scales Summit's PD-1xVEGF strategy with $2B investment to fuel ADC combinations ↗
Dihydropyridine Scaffold Yields New Caspase-1 Blockers
- Reports a new series of caspase-1-targeting small molecules built on a dihydropyridine scaffold, a heterocyclic chemotype more commonly associated with calcium-channel drugs.
- Characterizes inhibitory activity with in vitro fluorescence-based enzymatic assays and extends the work into cell-imaging studies of caspase-1 activity.
- Positions the compounds as early leads given caspase-1's central role in inflammasome-driven inflammatory signaling.
Dihydropyridines have spent decades gating L-type calcium channels, so watching the core get repointed at caspase-1 is a nice reminder that a synthetically tractable, well-behaved scaffold doesn't have to stay in its original target class. The summary is thin on potency and selectivity numbers, though — as written, this reads as chemotype diversification for an inflammasome target, not yet a validated lead.
Novel Dihydropyridine Series Delivers Potent Caspase-1 Antagonists
- A new series of dihydropyridine-derived small molecules is reported as antagonists of caspase-1, a cysteine protease central to inflammasome signaling.
- Caspase-1 activation drives maturation of the pro-inflammatory cytokines IL-1β and IL-18, making it a longstanding target in inflammation and inflammasome-related disease research.
- The dihydropyridine scaffold, more commonly associated with calcium-channel pharmacology, is explored here as a chemotype for caspase-1 antagonism.
- Compound activity was characterized using in vitro fluorescence-based enzymatic assays to gauge caspase-1 antagonism.
- Cell imaging was used alongside the biochemical assays to examine compound behavior and target engagement in a cellular context.
- The study, published in ChemMedChem, presents this dihydropyridine series as a structure-activity starting point for further caspase-1/inflammasome-directed medicinal chemistry.
First reaction: that's a nifedipine scaffold sitting in a caspase-1 SAR table. Bold, slightly nervy move — DHPs are about as pharmacologically 'loaded' as chemotypes get, so before getting excited about any hit here I'd want an L-type calcium-channel counter-screen and a broader Cav/hERG panel run immediately; that vasodilatory liability doesn't vanish just because you've redirected the scaffold at a protease. Caspase-1 itself is a reasonable target — druggable active-site cysteine, real precedent from peptidomimetic inhibitors — but selectivity across the caspase family, not potency, is the real hurdle here. The fluorescence assay plus cell imaging is the right combo methodologically: biochemical IC50s alone can't distinguish real antagonism from aggregation, chelation, or off-target channel hits, so imaging buys an early cellular engagement check before committing to a full selectivity panel.
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.
Approved Ataxia Drug Repurposed to Degrade STING via 'Molecular Crowbar'
- Omaveloxolone is an FDA-approved Nrf2-activating drug, originally approved for Friedreich's ataxia, now repurposed as a STING-targeting agent.
- It binds the base of STING's ligand-binding domain, destabilizing the protein's folded structure.
- This triggers K27-linked polyubiquitination of STING and its subsequent degradation by the proteasome — a "molecular crowbar" mechanism.
- Unlike classical PROTAC-style bifunctional degraders, omaveloxolone acts as a single small molecule, directly destabilizing STING rather than using a ligand-linker-E3-ligase construct.
- In aged mice, omaveloxolone treatment reduced STING-pathway-driven inflammation, a hallmark of age-related "inflammaging."
A monovalent degrader that's neither a classic PROTAC nor a molecular glue — that's the interesting bit. "Molecular crowbar" reads like marketing, but mechanistically it sounds like ligand-induced conformational destabilization exposing a degron: closer to hydrophobic-tag logic than E3-recruitment chemistry, no linker or ternary-complex engineering required. Chemically elegant, if it holds up. The real draw is that omaveloxolone's safety and PK are already banked — repurposing means skipping a decade of tox work if this translates. But my triage instinct says this is serendipitous polypharmacology, not designed SAR; the Nrf2 pharmacophore was never built for STING's pocket. It's also secondary-sourced with no primary structural data yet — I'd want a co-crystal or HDX-MS confirming direct engagement before trusting the crowbar story over generic proteostasis stress.
BioNTech's CTLA-4 Drug Nearly Doubles Survival in Lung Cancer Trial, But Raises Tolerability Concerns
- Gotistobart (BNT316/ONC-392), a CTLA-4-targeting monoclonal antibody from BioNTech and partner OncoC4, is designed to selectively deplete regulatory T cells within the tumor microenvironment.
- Updated stage 1 data from the global Phase 3 PRESERVE-003 trial were presented at the IASLC 2026 World Conference on Lung Cancer.
- The trial enrolled previously treated metastatic squamous non-small cell lung cancer (NSCLC) patients whose disease had progressed on prior immunotherapy and chemotherapy.
- Gotistobart nearly doubled median overall survival to 18.5 months versus 10.0 months for docetaxel chemotherapy, a statistically significant and clinically meaningful benefit (hazard ratio 0.56).
- Fierce Biotech's coverage noted the drug poses a tolerability challenge alongside this survival benefit.
- The pivotal stage 2 portion of PRESERVE-003 is ongoing at more than 160 sites worldwide.
CTLA-4 carries baggage — ipilimumab's toxicity effectively exiled the class to combo-backup duty, so gotistobart's whole pitch is "selective Treg depletion solves what ipi couldn't." A tolerability flag showing up in the very same headline as the efficacy win is the tension to watch, not a footnote. That said, nearly doubling median OS (18.5 vs 10.0 months, HR 0.56) in post-IO/chemo squamous NSCLC is a genuinely hard bar to clear — this is BioNTech's most credible non-mRNA oncology proof point yet, a real diversification lever beyond the vaccine franchise. It's also OncoC4's asset first: a clean stage 2 readout would meaningfully strengthen OncoC4's hand on deal economics with BioNTech, not just validate the science. Market-wise, the OS number is a legitimate re-rating catalyst, but "tolerability concerns" in the same breath keeps enthusiasm capped until discontinuation and grade 3+ rates surface from the pivotal cohort.
BioNTech's CTLA-4 drug improves survival in phase 3 cancer trial but poses tolerability challenge ↗
BioNTech/OncoC4's Gotistobart Nearly Doubles Survival in Hard-to-Treat Lung Cancer Ahead of Pivotal Readout
- BioNTech and OncoC4 reported stage 1 overall-survival data from the phase 3 PRESERVE-003 trial in metastatic squamous NSCLC, ahead of the pivotal stage 2 readout.
- Gotistobart (BNT316/ONC-392) is a pH-sensitive anti-CTLA-4 antibody designed to selectively deplete regulatory T cells in the tumor microenvironment, a differentiated mechanism versus conventional CTLA-4 blockers like ipilimumab.
- In 87 randomized patients who had progressed on prior PD-(L)1 and platinum chemotherapy, median overall survival nearly doubled: 18.5 months with gotistobart versus 10.0 months with docetaxel (HR 0.56).
- Grade ≥3 treatment-related adverse events were similar between arms (44.4% vs 48.8%), with a manageable safety profile.
- Pivotal stage 2, with overall survival as the primary endpoint, is now underway at 160+ global sites.
The differentiator here is mechanism, not just efficacy: a pH-selective, tumor-restricted Treg-depletion approach delivering a near-doubling of OS over docetaxel with grade ≥3 toxicity roughly flat to chemo is the tolerability profile ipilimumab-based regimens have never cleared — that's the real competitive wedge against BMS's checkpoint franchise and every less-selective CTLA-4 follower. Eighty-seven patients and an HR of 0.56 is directional, not confirmatory, but it's a strong enough signal in a chemo-refractory population with no compelling 2L+ standard to justify running 160+ sites into stage 2 ahead of topline data. Bigger picture: this is BioNTech executing its post-COVID pivot — building a wholly-owned, mechanistically differentiated oncology franchise rather than leaning on mRNA vaccine partnerships. A pivotal win makes gotistobart the company's first major non-mRNA solid-tumor asset with real blockbuster optionality.
BioNTech sets survival standard in hard-to-treat cancer ahead of pivotal readout ↗
Ivonescimab Beats Keytruda on Survival in Phase 3 NSCLC Trial
- Ivonescimab (Akeso/Summit's PD-1 x VEGF bispecific) reduced risk of death by 27% vs. Merck's Keytruda in the Phase 3 HARMONi-2 trial.
- Trial enrolled treatment-naive, PD-L1-positive advanced NSCLC patients in China.
- Median overall survival: 30.75 months for ivonescimab vs. 22.57 months for Keytruda.
- Adds to the trial's earlier primary PFS win — a 49% reduction in progression/death risk (11.14 vs. 5.82 months).
- Fourth Phase 3 ivonescimab readout to hit its OS endpoint, bolstering the case for combining PD-1 blockade with anti-VEGF activity in one bispecific.
- Akeso (China) and Summit Therapeutics (ex-China licensee) are co-developing the drug as a head-to-head Keytruda challenger.
A head-to-head overall-survival win over Keytruda is about as rare an event as oncology drug development produces — Merck's franchise has fended off nearly every direct challenger for a decade, and ivonescimab is now four-for-four on OS across its Phase 3 program. That changes the calculus for Summit, whose ex-China license from Akeso looked speculative at signing and now looks like one of the shrewder biotech deals in recent memory — every data cut adds leverage for future pricing, partnering, or M&A conversations. It's also the clearest advertisement yet for the China-originated-asset licensing wave Western biotechs have been chasing: a domestically-developed bispecific outrunning the world's best-selling drug in its own trial. For Merck, it lands squarely as Keytruda nears patent cliff — this isn't a niche subtype win, it's a direct share threat in frontline NSCLC, the franchise's core indication.
Akeso details survival win for its PD-1xVEGF drug versus Keytruda ↗
Solstice Oncology Launches with $225M Series A, Licenses CTLA-4 Antibody from Harbour BioMed
- Solstice Oncology launched publicly with an oversubscribed $225 million Series A round, led by a major life-sciences investment firm with support from several other biotech investors.
- Harbour BioMed granted Solstice an exclusive ex-Greater-China license plus an equity stake to develop porustobart, a next-generation Fc-enhanced CTLA-4 antibody Harbour BioMed discovered.
- Solstice aims to move the antibody into earlier, neoadjuvant use ahead of surgery, rather than reserving it for later-line metastatic cancer.
- The approach is backed by earlier data showing porustobart plus a PD-1 inhibitor produced encouraging, durable responses in hard-to-treat MSS colorectal cancer patients without liver metastases.
- New funds will support a Phase 2 trial combining porustobart with Keytruda, plus a separate Phase 2 colon cancer study opening enrollment later this year.
• Textbook China-to-West playbook: a Western syndicate (RA Capital-led) capitalizes a new US NewCo to develop a China-originated clinical asset outside Greater China — now the default route for getting Chinese-discovered biologics into global markets. • License-plus-equity, not a straight license, is the tell: Harbour BioMed keeps upside tied to Solstice's success rather than taking cash alone, and an oversubscribed $225M Series A for a single asset signals unusually strong investor conviction. • The real strategic bet is timing — pushing porustobart into neoadjuvant use instead of crowded late-line CTLA-4/PD-1 combinations is differentiated, but also less-trodden regulatory and commercial ground. • Everything hinges on execution: the prior 'encouraging' late-line colorectal data is rationale, not proof; the coming Keytruda-combo and colon cancer Phase 2 readouts are the real test of the thesis.
Fierce Biotech Fundraising Tracker '26: Encoded finagles $275M series F; Solstice rises with $225M ↗