Oncology
96 articles
Pyrroloquinoline antitubulin agents keep activity in paclitaxel- and daunorubicin-resistant cells
- A library of 1H-pyrrolo[3,2-c]quinolines was made and mapped by SAR, yielding compounds with low-nanomolar antiproliferative potency and very large selectivity over normal fibroblasts.
- The best derivatives kept activity in daunorubicin- and paclitaxel-resistant sublines and showed low efflux ratios, suggesting limited cross-resistance.
- A lead showed rapid absorption, moderate half-life and limited brain penetration, but zebrafish embryo toxicity pointed to a narrow therapeutic window.
Tubulin binders that dodge P-gp efflux are always of interest, and low efflux ratios plus retained activity in resistant lines is the right first filter. The zebrafish result is the honest sting in the tail: potent antimitotics often have a thin margin, so selectivity over fibroblasts in culture will not settle the safety question. I would look next at the binding site and how far the scaffold can be tuned toward a wider window.
A small-molecule BCL9/β-catenin blocker is tested in glioblastoma cells
- Because BCL9, a β-catenin coactivator, had lacked small-molecule inhibitors, its therapeutic value in glioblastoma had not been tested pharmacologically.
- The new inhibitor ZD37-28R was predicted by docking to bind β-catenin, and it disrupted the BCL9/β-catenin interaction in vitro.
- It suppressed β-catenin-driven transcription and reduced proliferation and migration of U87-MG and U251 glioblastoma cells.
Wnt/β-catenin has been a graveyard for small molecules, and a BCL9-selective PPI blocker is a more tractable angle than hitting β-catenin broadly. The open questions are the usual PPI ones: direct biophysical evidence of binding rather than docking, selectivity against other β-catenin partners, and brain exposure for a glioma indication. Treat this as target validation work, not a lead yet.
Macrocyclic pyrazolotriazine CDK7 inhibitor combines kinome-wide selectivity with oral exposure
- Structure-based optimization of a 17-membered macrocyclic pyrazolo-triazine scaffold gave a potent CDK7 inhibitor.
- It showed no significant off-target activity across a panel of more than 400 kinases, addressing the poor selectivity of earlier CDK7 inhibitors.
- In cells it caused cell-cycle arrest, suppressed transcription and lowered c-Myc, especially in triple-negative breast cancer lines, with oral bioavailability and linear PK.
A clean result across 400+ kinases is rare for CDK7, where the covalent field has leaned on THZ-type warheads. A non-covalent macrocycle that is also orally exposed is the profile I'd actually want to pick up for a transcriptional-addiction indication. The open question is on-target toxicity, since selectivity among kinases won't spare you CDK7's role in normal transcription.
A DNA-based PROTAC degrades CENPB in TKI-resistant lung cancer models
- CENPB, the sequence-specific DNA-binding protein at centromeres, is overexpressed in aggressive cancers, yet has no direct inhibitors.
- CENPB OligoTAC links a CENPB-binding oligodeoxynucleotide to an E3 ligase ligand, driving CENPB ubiquitination and proteasomal degradation, centromere disruption and apoptosis.
- It was active in NSCLC models resistant to first-, second- and third-generation TKIs, with little toxicity to normal cells, good serum stability and a favorable in vivo PK and tolerability profile.
Using the protein's own DNA recognition sequence as the warhead sidesteps the need for a small-molecule pocket, which is the appeal for transcription-factor-like targets. The open questions I would press on are delivery beyond mouse models, oligonucleotide manufacturing cost, and whether the selectivity for tumor over normal cells holds up when CENPB is expressed everywhere.
Centromere-Targeting Chimeras for Combating Cancer Drug Resistance ↗
Perspective: how structure-guided design finally delivered FGFR3-selective inhibitors
- Second-generation pan-FGFR inhibitors proved the concept but were limited by toxicities from inhibiting FGFR1, FGFR2 and FGFR4.
- Despite high structural homology across the family, structure-guided work has produced the first FGFR3-selective inhibitors to reach clinical evaluation.
- The Perspective covers the biological rationale, the design strategies behind the selectivity and emerging indications, including bladder cancer and achondroplasia.
Isoform selectivity inside a highly conserved kinase family is a good test of how far structure-based design really goes, and FGFR3 now has clinical-stage answers. The achondroplasia angle is the interesting one: a chronic, pediatric-adjacent indication raises the tolerability bar far above oncology, which is exactly where selectivity pays off.
Replacing saruparib's carboxamide yields an oral, brain-penetrant PARP1-selective inhibitor
- Aimed at CNS malignancies, the program replaced the carboxamide of saruparib with a series of heterocycles, targeting PARP1 over PARP2 to limit haematological toxicity.
- Caco-2 efflux, rather than the usual MDR1-MDCK assay, was used as a progression filter to select compounds with good unbound brain exposure.
- The lead compound was orally bioavailable and caused tumour regression in xenografts at a low dose, with a projected low clinical dose.
Swapping the primary carboxamide is a bold move, since that group anchors the nicotinamide pocket, and the heterocycles evidently kept the binding. The more useful lesson is the filter: if Caco-2 efflux predicts unbound brain exposure better than MDR1-MDCK, plenty of CNS programs may be discarding good compounds.
Albumin-carried Fe(III) complex drives ferroptosis and immune activation in triple-negative breast cancer
- A series of Fe(III) compounds was optimized to Fe4, which was strongly cytotoxic to TNBC cells, and packaged as human serum albumin nanoparticles (HSA-Fe4).
- Structural analysis placed Fe4 in the IB subdomain of HSA, with His-146 coordinating the iron centre.
- In vivo, Fe4 and HSA-Fe4 curbed tumour growth and metastasis through Fenton-type chemodynamic therapy, ferroptosis and immune activation.
Defining the albumin binding site down to the coordinating histidine is what makes this more than a nanoparticle paper: it gives you a handle for ligand SAR. Still, a redox-active iron species hitting ferroptosis, Fenton chemistry and immunity at once is hard to deconvolve, and I'd ask for selectivity against normal tissue before reading anything into the efficacy.
European regulators recommend Revolution Medicines' Rasonque for pancreatic cancer
- Following FDA approval, European regulators have recommended approval of Revolution Medicines' Rasonque (daraxonrasib) for pancreatic cancer, per STAT+.
- The recommendation moves the RAS(ON) inhibitor toward a second major market.
- This summary rests on the article's teaser; a separate search could not confirm the EU opinion.
If confirmed, a quick EU follow-on after the US nod shows how fast an oral RAS(ON) inhibitor with a clear survival benefit in a deadly cancer can move. For analysts the questions now shift to pricing, reimbursement and label expansion beyond second-line pancreatic disease. It also validates the tri-complex approach for peers still chasing KRAS in the same tumor type.
STAT+: RevMed's pancreatic cancer drug nears European approval ↗
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.
Merck and Moderna say their mRNA cancer vaccine plan still needs a lot of exploring
- At the STAT Summit, Moderna's Stephen Hoge and Merck's Dean Li discussed pairing Keytruda with personalized mRNA cancer vaccines.
- Both executives framed the first positive results as a start, with much left to work out.
- This summary rests on the article's teaser, not the full text.
Pairing a personalized vaccine with Keytruda protects Merck's franchise as PD-1 exclusivity ages, so Merck has a strategic reason beyond the science. The executives' caution about what comes next is telling: the open questions are tumor types, dosing settings and manufacturing scale. Rivals with other neoantigen approaches should read it as a bar to clear.
Merck and Moderna have 'lot of exploring to do' after initial cancer vaccine success ↗
Molecular glue RPT04402 restores PP2A trimer assembly in high-grade uterine cancer
- The paper describes RPT04402, a molecular glue that restores formation of the PP2A AαB56αC heterotrimer in high-grade uterine cancer.
- Recurrent PPP2R1A scaffold mutations in these tumors impair holoenzyme assembly, which the glue is designed to rescue.
- Company reports describe regressions in preclinical PP2A-mutant models and a license to SpringWorks; this summary rests on the title and secondary sources, not the full text.
Phosphatases are famously hard to drug, so a glue that rebuilds a specific heterotrimer rather than inhibiting an active site is a smart route around that. Here the mutation defines both the patient population and the mechanism, a tidy match. I'd watch how selective it is among the many PP2A B-subunit complexes, since activating the wrong ones is the obvious tolerability worry.
Verastem reports encouraging early data for its oral KRAS G12D inhibitor in pancreatic cancer
- Verastem presented early results for its KRAS G12D inhibitor, studied in more than 200 patients with advanced solid tumors including metastatic pancreatic cancer and others.
- Other coverage describes anti-tumor activity and a manageable safety profile across pancreatic, colorectal and lung cancers.
- This summary rests on the public lead of a paywalled STAT piece plus secondary reports, so details are limited.
KRAS G12D in pancreatic cancer is the biggest open space after G12C, and early activity with clean liver safety is what the field needs to see. The competitive question is durability against other G12D programs, including those from large players. Registration-directed Phase 2 trials and Fast Track status give Verastem a credible path, but single-arm early data can flatter.
STAT+: Verastem’s KRAS inhibitor shows promise in pancreatic cancer ↗
Gilead licenses three dual-masked T-cell engagers from Vir in a deal worth up to about $1.9B
- Vir will discover, design and optimize three T-cell engagers against solid-tumor antigens on its dual-masked PRO-XTEN platform; Gilead holds exclusive rights to nominate candidates and then develops and commercializes them.
- Vir receives $90M up front ($65M cash plus a $25M equity investment) and $45M in near-term preclinical milestones.
- Up to $1.74B in development, regulatory and commercial milestones and tiered royalties could follow.
This is Gilead's third T-cell engager move in a short stretch (Merus, Ouro, now Vir), so the oncology thesis is clearly masked, conditional-activation TCEs for solid tumors. For Vir, it's the second platform deal this year and non-dilutive cash that lets it fund its own pipeline; the equity premium shows Gilead's commitment. Preclinical risk stays high.
Vir CEO sees ‘opportunity to do more deals’ after striking $1.9B Gilead pact for dual-masked TCEs ↗
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.
HTS-derived covalent inhibitors hit active, GTP-bound KRAS G12C
- Approved KRAS G12C drugs mostly trap the inactive GDP state and face resistance; this series targets the active GTP-bound state instead.
- A keto-indolizine HTS hit with an aniline-derived acrylamide binds Cys12 in the switch-II pocket; crystallography shows the warhead engaging the γ-phosphate of a GTP analogue.
- Optimization gave compound 17, orally bioavailable in preclinical species, which prolongs disruption of KRAS–cRAF binding and ERK signalling and produced complete regression in a pancreatic cancer xenograft.
Using the γ-phosphate to position the warhead is neat: GTP-state selectivity comes from the nucleotide itself, not only the pocket. The comparison I'd want is against RAS(ON) tri-complex inhibitors, which need cyclophilin A while this doesn't. Acrylamide reactivity and proteome-wide cysteine selectivity also matter more here than for GDP-state binders.
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.
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.
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.
Brain-penetrant colchicine-site tubulin ligand nominated for glioma
- Only temozolomide and vorasidenib are approved brain-permeable, orally available drugs for brain cancers, so the team sought new brain-penetrant options.
- SAR work yielded a new class of highly brain-penetrant tubulin ligands; co-crystal structures confirm colchicine-site binding, with the tubulin βT7 and αT5 loops flipped relative to the colchicine-bound state.
- SAR showed high sensitivity to substitution with few indispensable moieties, leading to compound 40 as the clinical candidate.
Tubulin binders that actually cross the blood-brain barrier usually die on P-gp efflux or neurotoxicity, so a tight series with strong brain exposure is notable. The flipped βT7/αT5 loops hint at a binding mode worth docking my own colchicine-site scaffolds against. Chronic neurotoxicity is still the question.
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 ↗
ArriVent's first-line EGFR exon 20 NSCLC phase 3 misses its primary endpoint
- Fierce Biotech reports that ArriVent's phase 3 FURVENT trial of the EGFR inhibitor firmonertinib missed its primary progression-free survival endpoint by blinded central review in first-line EGFR exon 20 insertion NSCLC.
- The higher dose showed only a modest numerical edge over platinum chemotherapy and the lower dose did numerically worse, while investigator-assessed results looked more favorable.
- ArriVent's shares fell sharply on the news.
A small central-review margin over chemo, in a setting where J&J's Rybrevant-plus-chemo regimen has already set a higher bar, leaves firmonertinib hard to position in exon 20. The investigator-versus-central gap gives ArriVent a regulatory conversation but a thin commercial story. The PACC-mutation ALPACCA study now looks like the company's real value driver.
Dutch court halts Merck's subcutaneous Keytruda in several European countries
- STAT reports a Dutch court ordered Merck to stop manufacturing and marketing its subcutaneous Keytruda formulation in several European countries.
- Only the public lede was readable, so the plaintiff, grounds and scope are unverified here.
Subcutaneous Keytruda is Merck's main defense against the coming pembrolizumab biosimilar era, so any European delay hits that lifecycle plan directly. How long the order lasts and whether it is overturned on appeal matters more than the headline, and the case echoes the broader fight over SC hyaluronidase formulation patents.
STAT+: Merck suffers a setback in Europe over its new Keytruda formulation ↗
Oral POLQ polymerase inhibitors regress BRCA2-null tumors with olaparib
- POLQ drives microhomology-mediated end joining, making it a synthetic-lethal target in homologous-recombination-deficient cancers.
- Optimizing a weak biochemical hit gave benzimidazole/purine inhibitors; compound 37 is potent, selective and orally active.
- In BRCA2-deficient DLD-1 cells it was antiproliferative and boosted olaparib, with no effect in HR-proficient cells; chronic oral dosing with olaparib regressed xenografts.
A polymerase-domain inhibitor that is both oral and selective for the HR-deficient setting is what this target has been missing. The HR-proficient null result is the key control, so I'd now look at resistance and how it stacks against the helicase-domain approaches.
Caribou Biosciences winds down after failing to fund late-stage CAR-T trial
- STAT reports the Doudna co-founded company is shutting down after failing to raise the money needed for a late-stage trial of its off-the-shelf CAR-T therapy for lymphoma.
- Other coverage describes the company stopping development of its two clinical cell therapy candidates and cutting most staff while exploring a merger or sale.
- Only the public STAT+ summary was available, so details beyond that are unverified.
A flagship CRISPR-era CAR-T name folding over a funding gap says the off-the-shelf cell therapy thesis is struggling to raise money against autologous products and bispecifics. It reads more as a financing failure than a clean scientific verdict, so watch whether the assets and data find a buyer.
STAT+: Caribou Biosciences, biotech co-founded by Jennifer Doudna, is shutting down ↗
A macrocyclic BI-4020-based PROTAC degrades C797S-resistant EGFR
- HQY1480 is a PROTAC built on the macrocyclic fourth-generation EGFR inhibitor BI-4020, with the linker and E3 ligand optimized systematically.
- It degraded several clinically relevant EGFR mutants at low nanomolar concentrations, and proteomics showed no detectable off-target degradation.
- It outperformed BI-4020 in xenografts, including osimertinib-resistant models, and degraded EGFR in patient-derived xenografts.
Starting from a macrocycle rather than a classical TKI is the smart move: it sidesteps the poor PK and selectivity that EGFR PROTACs usually inherit from their warheads. I'd want to see how the degrader holds up against compound-specific resistance mutations, and whether the favorable PK survives scale-up beyond mouse.
4-Aminoquinazoline PKMYT1 inhibitors cut H-bond donors for CCNE1-amplified tumors
- A hydrogen-bond donor-to-acceptor conversion was used to lower the donor count of a 4-aminoquinazoline PKMYT1 series and improve drug-likeness.
- Lead 12f was a nanomolar enzyme inhibitor, potent in OVCAR-3 ovarian cells and synergistic with PARP inhibitors.
- With acceptable oral PK, it showed efficacy in an OVCAR-3 xenograft and was well tolerated.
Trimming HBDs is a clean, transferable tactic for improving permeability and oral exposure in a kinase series. The PARP-inhibitor synergy is the commercially interesting part, but PKMYT1 is crowded, so I'd check selectivity against other kinases and how 12f compares with the clinical frontrunners.
Merck pays $400M upfront for SciBrunch's preclinical KRAS G12D inhibitor
- Merck took exclusive worldwide rights to SPR2015, an oral preclinical KRAS G12D (ON) inhibitor from Shanghai-based SciBrunch.
- SciBrunch gets $400M upfront, with total potential value of $2.13B across milestones.
- The deal has already closed.
$400M upfront for a preclinical asset is striking and shows how heated the KRAS G12D race has become, with China-originated assets now priced like clinical ones. For Merck it's a late entry into a field where it needs a differentiated ON-state profile, and the one to watch is first-in-human data.
Genmab's Rina-S posts durable phase 2 responses in platinum-resistant ovarian cancer
- Genmab reported phase 2 RAINFOL-01 data for the ADC rinatabart sesutecan (Rina-S): a 45.9% confirmed response rate in 109 heavily pretreated patients.
- Median progression-free survival was 9.5 months; TD Cowen analysts called that clearly better than the 5.6 months cited for AbbVie's Elahere.
- Activity was reported regardless of prior Elahere treatment and in patients with low or no FRα expression.
Cross-trial comparisons flatter whoever runs the later study, so I'd discount the 'clearly superior' framing. Still, activity in low-FRα and post-Elahere patients is the more interesting claim: it widens the addressable population beyond Elahere's high-expressor label. It also supports the case for the ProfoundBio buy.
Genmab's latest phase 2 data spur claim ADC is 'clearly superior' to AbbVie's Elahere ↗
Pyridazine nicotinamides as a new FTO inhibitor chemotype for AML
- A 67-compound SAR campaign on pyridazine-containing nicotinamides gave E6 as the most active FTO inhibitor, with binding confirmed by MST, CETSA and DARTS.
- E6 was active against MOLM-13 cells, raised global m6A, upregulated ASB2 and RARA and lowered c-Myc.
- It showed acceptable CYP safety and PK and inhibited MOLM-13 xenograft growth.
Another FTO series, but the useful part is the new scaffold: FTO chemotypes are still thin, and most earlier ones lean on the same few motifs. Potency is modest, so I'd treat E6 as a starting point and look for selectivity over ALKBH5 and other AlkB family members before reading too much into the cell phenotype.
Oral isoindolinone GSPT1 glue degrader LG-NE-29 targets glioblastoma models
- A viability-based phenotypic screen flagged GSPT1 as a vulnerability in glioblastoma cells, where resistance to temozolomide arises quickly.
- Optimizing an isoindolinone series for metabolic stability gave LG-NE-29, a molecular glue that drives CRBN-dependent ubiquitination and proteasomal degradation of GSPT1.
- It is reported to avoid the metabolic weaknesses of earlier scaffolds, and to be orally bioavailable with activity in glioblastoma xenograft models.
Isoindolinone CRBN glues usually die on metabolism, so fixing that liability is the real story here. Before I believe it, I'd want the GSPT1 DC50/Dmax, proteome-wide selectivity (IKZF1/3, other neosubstrates), and oral PK with brain exposure. GSPT1 degradation is also broadly cytotoxic, so the therapeutic window in normal cells matters.