RAS pathway
16 articles
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 ↗
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 ↗
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.
Covalent fragments reach lysines in the SHP2 allosteric latch site
- Combines an electrophile-first covalent fragment screen with a ligand-first strategy to target lysines in the allosteric latch site of SHP2 phosphatase.
- Computational and experimental analyses support the binding mode, and the work yields what the authors call the first potent, cell-active allosteric covalent inhibitors at this site.
- It shows the latch site is covalently tractable, opening routes to new allosteric SHP2 chemotypes.
Lysine-directed covalent chemistry is far rarer than cysteine, so a workflow that actually delivers cell-active hits on a lysine is the takeaway, more than SHP2 itself. My caveat is reactivity versus stability: lysine electrophiles can be hydrolytically fragile or reversible, so I'd want proteome-wide selectivity data before calling anything a probe.
Fragment-Based Covalent Targeting of Lysines at the Allosteric Latch Site of SHP2 ↗
Isoform-selective ULK1 PROTAC gives longer autophagy suppression than an inhibitor
- ATP-competitive inhibitors struggle to separate ULK1 from the near-identical ULK2, so the authors built cereblon-recruiting degraders instead.
- Structure-guided optimization gave MR-9036, which degrades ULK1 without touching ULK2 or IMiD neo-substrates, with ternary complex formation and proteasome dependence confirmed.
- After compound washout it kept autophagy suppressed longer than the clinical ULK1/2 inhibitor DCC-3116, with antitumor activity in KRAS G12C NSCLC models.
Selectivity between paralogs is where degraders can beat occupancy-driven drugs, and this is a clean example. What I'd check next is whether ULK2 compensation shows up in vivo, and whether washout durability holds in a model with realistic drug exposure rather than a pulse.
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.
DNA origami carrying a barnase variant is built to cleave mutant KRAS mRNA
- Mutant KRAS variants are structurally diverse and lack druggable pockets, which has limited small-molecule inhibitors.
- The authors assemble a degrader on a six-helix-bundle DNA origami scaffold that targets the mRNA rather than the protein.
- One module pairs an engineered barnase variant with a programmable recognition strand, cutting RNA directly without relying on endogenous cellular machinery; a second module is designed for cell penetration.
If KRAS has no pocket worth chasing, going after the mRNA is a fair dodge, and a catalytic barnase gives a clean mechanism: sequence-guided cleavage, no reliance on endogenous machinery. But I would want to see the data before getting excited. How well does the recognition strand discriminate single-base mutants from wild-type KRAS, given barnase's cleavage is catalytic and unforgiving of leakage? And does it survive delivery, with real potency in cells and a sensible comparison to siRNA or ASO?
Can ternary-complex scoring rank close PROTAC linker analogues? A matched-pose test
- Linker optimization in targeted protein degradation is still largely empirical.
- The preprint asks whether current computational methods can rank close linker analogues before synthesis, the finest chemical differences yet tested.
- It uses a matched-pose design on VHL-recruiting SHP2 degraders to isolate the effect of the linker.
- This is a preprint, not yet peer reviewed; the snippet-level abstract available limits detail on the outcome.
Linker tweaks are where PROTAC campaigns burn months of synthesis, so an honest test of whether scoring can separate near-identical analogues is more useful than another headline-grabbing benchmark. Matched poses remove the usual excuse that the method just got the geometry wrong. Even a negative answer helps: it tells us to keep building degradation and cooperativity assays rather than trusting a docked score.
Shutting down JNK signaling resensitizes KRAS G12D-resistant pancreatic cancer cells
- Pancreatic cancer cells that adapt to KRAS G12D inhibition can be pushed back toward sensitivity by suppressing the JNK pathway more completely.
- Selective covalent inhibitors of MAP2K4, MAP2K7, or both were used to probe how much JNK suppression is needed.
- Stronger JNK blockade disables the feedback loop that reactivates KRAS signaling in resistant cells.
- Inhibitor-sensitive cells gain no benefit, so the vulnerability is specific to the resistant state.
If this holds up, the interesting part is the logic: resistance to a KRAS G12D inhibitor runs through JNK feedback, so you hit the node that rewires the pathway, not KRAS again. Covalent engagement of MAP2K4 and MAP2K7 is a neat way to ask how deep the suppression must be, though kinase selectivity between the two will be the real SAR headache. Sparing sensitive cells is the encouraging bit; it's abstract-level so far.
Merck Licenses China-Origin KRAS G12D Inhibitor SPR2015 for $400M Upfront
- Merck & Co. entered an exclusive global license agreement with Shanghai-based SciBrunch Therapeutics for SPR2015, an investigational oral KRAS G12D molecular-glue inhibitor.
- SciBrunch will receive $400 million upfront, with total deal value up to $2.13 billion including milestone payments.
- The deal reflects a growing trend of U.S. pharma companies in-licensing China-originated oncology assets.
This plugs Merck's biggest KRAS gap: everyone's crowded into G12C, but G12D — more common in pancreatic and colorectal cancer — has stayed stubbornly undrugged with covalent chemistry. A molecular-glue approach, if it works, sidesteps that entirely. The modest 19% upfront-to-total ratio signals early-stage derisking, not a validated asset — expect Western rivals to scramble for the remaining China-origin G12D candidates.
Chemists Report New Allosteric SHP2 Inhibitors Built on an Azaindole Scaffold
- SHP2 is a cytosolic protein tyrosine phosphatase implicated in oncogenic RTK and immune checkpoint signaling, making it a closely watched cancer/immuno-oncology target.
- Earlier allosteric SHP2 inhibitors have reached clinical trials but can face resistance mutations or PK limitations, motivating further chemotype exploration.
- This preprint reports a new series of N-aryl-1H-azaindole-derived allosteric SHP2 inhibitors, shifting away from orthosteric (active-site) inhibition approaches.
That shallow, conserved catalytic pocket is exactly why orthosteric SHP2 programs never went anywhere in my hands—no surprise this moves allosteric. But the irony's real: clinical allosteric inhibitors like TNO155 already picked up resistance mutations right in that allosteric tunnel, so a new chemotype needs to show it escapes those hotspots, not just re-occupy the same pocket with a different scaffold.
Degrading CK1δ to Disarm 'Undruggable' NRAS-Mutant Melanoma
- Targets CK1δ, an upstream kinase that stabilizes oncogenic NRAS mutant protein, as an indirect strategy against NRAS-driven melanoma.
- Reports discovery of compound 8u, a selective small-molecule degrader rather than a simple catalytic inhibitor.
- The degrader approach achieves high selectivity for CK1δ over closely related CK1 isoforms, addressing a limitation of earlier inhibitors.
- Treatment destabilizes mutant NRAS protein and suppresses oncogenic signaling in melanoma models.
Smarter to go after 'undruggable' mutant NRAS through the kinase that stabilizes it than to keep chasing the mutant protein directly, and a degrader — not a catalytic inhibitor — is what finally buys the CK1 paralog selectivity this target class has chronically lacked. Compound 8u reads like a real template, not just a tool compound to prove the hypothesis.
New CK1δ-Targeting Degraders Curb NRAS-Mutant Melanoma Growth
- Building on prior work identifying CK1δ as an upstream stabilizer of oncogenic NRAS, the team developed small-molecule degraders that trigger CK1δ's proteasomal breakdown.
- Chemical optimization focused on achieving selectivity for CK1δ over its close paralogs CK1α and CK1ε, which share highly similar kinase domains.
- Iterative structure-activity relationship analysis across a synthesized compound series balanced degradation potency, isoform selectivity, and cellular activity.
- Degrading CK1δ removed its support for oncogenic NRAS protein stability, lowering NRAS levels and dampening downstream signaling in melanoma cells.
- In NRAS-mutant melanoma cell models, the optimized degraders suppressed proliferation, positioning CK1δ degradation as a potential strategy for an otherwise hard-to-drug oncogenic driver.
CK1δ/α/ε selectivity is the real fight here — those kinase domains are similar enough that classic ATP-competitive chemistry rarely holds up cleanly; if they're threading that needle with a degrader, ternary-complex geometry, not just binary affinity, is probably doing the selectivity work, which is the whole pitch for going bifunctional over yet another inhibitor. Smart use of event-driven pharmacology to reach something genuinely undruggable — NRAS has no covalent handle like G12C, so knocking down an upstream stabilizer is a legitimate end-run, not a gimmick. Still want to see the actual chemotype and E3 handle before getting excited — 'synthesized series, iterative SAR' tells me nothing about scaffold novelty or synthetic cost, and degrading a kinase with this many substrates makes me nervous about toxicity beyond the CK1α story. If selectivity and PK hold up in vivo, this is a template worth stealing for other 'stabilizer' targets propping up undruggable oncoproteins.
GSK licenses HUTCHMED's first-in-class KRAS-EGFR conjugate HMPL-A830 in deal worth up to $1.3B
- HUTCHMED and a GSK subsidiary signed an exclusive development and license agreement for HMPL-A830, described as a first-in-class KRAS-EGFR Antibody-Targeted Therapy Conjugate (ATTC).
- HMPL-A830 pairs a highly selective, potent small-molecule KRAS inhibitor payload with an anti-EGFR antibody, delivering the inhibitor selectively to EGFR-expressing tumor cells while also blocking EGFR signaling.
- GSK gains worldwide development and commercialization rights excluding Mainland China, Hong Kong, Macau and Taiwan, which HUTCHMED retains.
- Deal terms: $110 million upfront, up to $1.295 billion in additional development, regulatory and commercial milestone payments, plus tiered royalties on net sales.
- HUTCHMED will conduct the global Phase 1 program, expected to start in H2 2026, after which GSK takes over subsequent clinical development and commercialization.
- Initial clinical development will focus on colorectal, pancreatic and lung cancers.
Another Western major fills its oncology pipeline via China-origination rather than in-house discovery — GSK joins a fast-growing queue of ADC/conjugate deals mining HUTCHMED's pipeline for de-risked-but-early assets. The math is telling: $110M upfront against a $1.295B ceiling is roughly 8.5% at signing — real conviction, heavily hedged, standard for a preclinical/Phase 1 asset where GSK is paying mostly for optionality until clinical data lands. The ATTC design — a small-molecule KRAS payload riding an EGFR antibody — is a genuinely differentiated angle in an overcrowded KRAS field, avoiding classic cytotoxic-ADC toxicity while adding tumor-selective targeting. And HUTCHMED keeping Greater China rights again signals its now-familiar playbook: license out ex-China, retain commercial control at home.
GSK to license Hutchmed's KRAS-EGFR cancer drug for $110M upfront ↗
Lysine-Targeted Covalent Fragments Open a New Allosteric Route to Inhibit SHP2
- Researchers built a combined screening pipeline pairing covalent fragment screening with a ligand-first design strategy to find chemical matter that reacts with lysine side chains rather than the more commonly targeted cysteines.
- The work focuses on the allosteric "latch" region of SHP2 phosphatase, a regulatory site distinct from the enzyme's catalytic pocket and from previously drugged allosteric tunnel sites.
- Computational modeling and experimental characterization were used together to guide fragment selection and to understand how covalent attachment at latch-site lysines affects the protein's conformational behavior.
- The approach yielded inhibitors described as the first potent, cell-active covalent compounds acting through this latch site, indicating the pocket can support functional, drug-like engagement rather than only structural characterization.
- The findings position lysine-directed covalent chemistry as a viable route for allosteric SHP2 modulation and provide a starting chemotype and site for further medicinal chemistry optimization.
Lysine-directed covalency is the real bet here, more than the new pocket itself: warhead chemistry and selectivity triage are far less mature than for cysteine acrylamides, so the first thing I'd pull up is proteome-wide lysine reactivity data before trusting the cell activity. The latch site itself is also genuinely new — it sits apart from where SHP099/TNO155-type allosteric inhibitors already bind, so this isn't retreading crowded IP. Getting cell-active hits straight out of fragment screening is a strong signal for this pocket's shape or a hyperreactive lysine — but fragment-to-lead on Lys chemistry means slower SAR cycles than we're used to with Cys warheads. Real value: a fresh chemotype and site for a target whose allosteric space was starting to feel exhausted.
Fragment-Based Covalent Targeting of Lysines at the Allosteric Latch Site of SHP2 ↗
BridgeBio Oncology Narrows BBO-8520 Focus to 2L+ NSCLC Plus Pembrolizumab
- BridgeBio Oncology Therapeutics narrowed the development scope of its lead ON/OFF-state KRAS inhibitor BBO-8520, focusing specifically on second-line-plus (2L+) NSCLC in combination with checkpoint inhibitor pembrolizumab, trimming a broader earlier-stage development plan.
- The move follows new data showing a strong objective response rate for the combination in patients whose lung cancer had already progressed on a prior KRAS G12C inhibitor, with a somewhat lower but still meaningful response rate across all doses tested.
- BBO-8520 holds FDA Fast Track designation for previously treated, KRAS G12C-mutated metastatic NSCLC.
- The company still runs two other Phase 1 KRAS-pathway programs: BBO-11818, a pan-KRAS (ON/OFF) inhibitor with Fast Track designation in pancreatic ductal adenocarcinoma, and BBO-10203, a RAS-PI3Kα interaction inhibitor enrolling the multi-tumor BREAKER-101 basket trial.
- The narrowing reads as a deliberate focusing of resources on the most differentiated combination signal, not a full retreat from the asset.
BBO-8520 sits in a brutal field — Amgen's sotorasib, Mirati/BMS's adagrasib, and Revolution Medicines' RAS(ON) inhibitors are all fishing in the same post-G12C-progression pool, so a strong response signal there is worth more to BridgeBio than thin coverage spread across earlier lines. Narrowing scope rather than killing the asset outright reads as capital discipline: in a funding environment that punishes diffuse spend, concentrating trial resources on the combination with the clearest data is the rational move, not a retreat. The two other KRAS programs (BBO-11818, BBO-10203) staying active confirms the platform bet is intact — this is portfolio triage, not a pipeline unraveling. Read the stock dip as the market's reflexive reaction to the word "narrows," not a verdict on the science; this is strategic analysis, not investment advice.
BridgeBio Oncology slides as it tightens the scope of its KRAS program ↗