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#小分子/降解剂

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Oct 15Thu
  1. biorxiv.org40

    A Multi-Kinase Inhibitor Screen Identifies mTOR Signaling as a Vulnerability in Advanced Prostate Cancer.

    Loss of the receptor tyrosine kinase AXL is linked to treatment resistance, aggressive phenotypes, and shorter overall survival in prostate cancer. Screening isogenic CRISPR-generated AXL-knockout cells against 1,814 kinase inhibitors identified Torin-2, which showed an ~18-fold lower IC50 in AXL-knockout than AXL-wildtype cells. PRISM/DepMap analysis confirmed a selective vulnerability to PI3K/AKT/mTOR pathway inhibition, pointing to mTOR inhibition as a therapeutic strategy for AXL-deficient prostate cancer.

  2. nature.com81

    Capillary-selective vasodilation through myosin inhibition halts ischaemic cascades

    Myosin inhibition produces vasodilation that is selective for capillaries and halts the cascades that follow ischaemia, as reported in this work on microvascular obstruction. The approach targets the capillary level, where pericyte-mediated constriction has been linked to no-reflow after ischaemia in the brain, heart and kidney. No quantitative outcome data are reported here.

    Why it matters: It addresses capillary-level no-reflow, a mechanism implicated in stroke, myocardial infarction and kidney injury.

Oct 14Wed
  1. biorxiv.org52

    Co-targeting KRAS and BCL-2 induces pyroptosis and antitumor tertiary lymphoid structures

    Co-targeting KRAS and BCL-2 synergistically triggers GSDME-mediated pyroptosis in KRAS G12D-mutant lung tumors, which are metabolically vulnerable through weakened HK1 interaction and reduced spare respiratory capacity compared with G12C. The combination induces functional tertiary lymphoid structures in vivo, and depletion experiments show the antitumor efficacy depends on B cells. It also drives membrane attack complex deposition in situ and elicits memory antitumor responses.

Oct 10Sat
  1. doi.org49

    JAK-inhibitor treatment induces rapid yet incomplete immune reconstitution in STAT1 gain-of-function

    JAK inhibitors produced rapid but incomplete immune reconstitution in two STAT1 gain-of-function patients carrying p.R321S and p.T385M mutations. Changes were seen as early as 1 week after treatment: T cells rebalanced toward a homeostatic status, TCR repertoire diversity increased quickly, and transcriptional dysregulation in monocytes improved, though defects such as natural killer deficiency persisted in one patient. The work defines both the therapeutic reach and the limits of JAK inhibition in STAT1 GOF.

Oct 9Fri
  1. biorxiv.org48

    Targeting ribosome biogenesis sensitizes PARPi-resistant triple-negative breast cancer

    Inhibiting ribosome biogenesis with BMH-21 resensitizes PARPi-resistant triple-negative breast cancer to olaparib. The drug combination was synergistic in 4 PARPi-resistant cell lines and in 3 BRCA wild-type TNBC cell lines with intrinsic PARPi resistance, but not in parental cells. In MDAMB231 cells, the combination increased γH2AX-positive cells up to 7.3-fold, SA-β-gal staining 5.6-fold and p21 3.6-fold, findings mirrored with CX-5461. Patient cohort data linked ribosomal pathway activity to MYC, proliferation, DNA damage and senescence.

Oct 6Tue
  1. biorxiv.org56

    Binding kinetics enable tumor-selective MAPK and growth suppression by a Type 1 RAF Inhibitor

    The Type 1 RAF inhibitor ELV-3111 exploits fast binding dissociation to drive paradoxical MAPK hyperactivation in normal tissues while sparing RAS-mutant tumors, where RAF is already primed. This yields selective MAPK and growth suppression in RAF-dimer-driven models. Combined with a MEK inhibitor, it produced durable regressions in RAS-mutant and BRAF-mutant models, including one refractory to current therapies, with favorable tolerability.

  2. biorxiv.org55

    KRAS-driven metabolic reprogramming of enhanced MFSD2A-mediated lysophosphatidylcholine scavenging promotes survival and progression of pancreatic ductal adenocarcinoma

    Oncogenic KRAS upregulates MFSD2A, driving PDAC cells to scavenge extracellular unsaturated lysophosphatidylcholines and sustain AKT-mediated survival. Plasma lipidomics across 93 newly-diagnosed resectable PDAC cases, 43 chronic pancreatitis patients, and 93 matched controls showed pronounced reductions in circulating LysoPCs associated with PDAC. Blocking MFSD2A or restricting LysoPCs suppressed AKT signaling, increased apoptosis, and slowed tumor growth, and repurposing edelfosine against this axis produced anti-cancer effects in vitro.

  3. biorxiv.org50

    Revisiting AXL as a therapeutic target in soft tissue sarcoma: dubermatinib and bemcentinib effects are largely independent of AXL inhibition

    The AXL inhibitors dubermatinib and bemcentinib reduce viability and induce apoptosis in HT-1080 and SK-LMS-1 soft tissue sarcoma cell models, but shRNA-mediated AXL knockdown fails to reproduce these antiproliferative effects or alter drug sensitivity. Transcriptomic changes induced by the drugs correlate weakly with AXL knockdown, and most drug-regulated genes are AXL-independent. Although STS shows high median AXL mRNA expression in TCGA data, AXL expression was not associated with patient survival, so the rationale for AXL-directed therapy may be reconsidered.

  4. biorxiv.org47

    A Novel ACLY Inhibitor Induces Transcriptional and Metabolic Reprogramming to Overcome Tyrosine kinase inhibitor Resistance in Lymphoma

    The novel ACLY inhibitor VCB1 blocked recombinant human ACLY with an IC of 0.9 uM and suppressed growth of lymphoma cells, retaining potency in TKI-resistant models: 1.62 uM in lorlatinib-resistant SUPM2-LR1000 cells and 0.278 uM in BTK inhibitor-resistant mantle cell lymphoma cells, where the existing inhibitor BMS-303141 was far less active. Multi-omics profiling showed VCB1 suppressed de novo lipogenesis, activated the integrated stress response with induction of ATF4, DDIT3 and related genes, and disrupted nucleotide biosynthesis. The work identifies ACLY as an actionable vulnerability for overcoming TKI resistance in lymphoma.

  5. biorxiv.org47

    A Novel NO Donor 3A72 Activates Mitochondrial-Associated Endoplasmic Reticulum Membrane Structures to Induce Ferroptosis in Triple-Negative Breast Cancer

    The nitric oxide donor 3A72, a furan-coumarin-based compound, suppresses triple-negative breast cancer cell proliferation and restricts xenograft tumor growth, with efficacy matching paclitaxel but with enhanced safety and reduced systemic toxicity. Mechanistically, 3A72 releases NO to cause calcium overload, binds IP3R and ACSL4, and converges on mitochondria-associated ER membranes, where ROS generation couples with lipid remodeling to drive ferroptosis through malondialdehyde accumulation. The findings identify the MAMs calcium-lipid hub as a structural scaffold for antitumor drug development.

Oct 3Sat
  1. nature.com54

    Loss of lineage fidelity underpins drug resistance in Kras -mutant lung cancer

    In genetically engineered mouse models of Kras-mutant lung cancer, lineage fidelity was shown to modulate drug-tolerant residual disease, distinct trajectories of therapeutic resistance, and dependence on oncogenic KRAS. The work points to loss of lineage fidelity as a mechanism underlying the acquired resistance that limits durable clinical responses to KRAS inhibition.

Oct 1Thu
  1. Nat Med53

    Oral small-molecule GLP-1 receptor agonist safiglipron in early type 2 diabetes: a randomized, double-blind, placebo-controlled trial.

    Once-daily oral safiglipron reduced HbA1c by 1.20 to 1.45 percentage points versus placebo at 32 weeks in 284 adults with early type 2 diabetes managed with diet and exercise alone (OUTSTAND-1, phase 3). HbA1c below 7.0% was reached by 71.4-77.8% of safiglipron recipients versus 25.0% on placebo, with modest weight loss and mostly mild or moderate gastrointestinal adverse events. It offers an oral GLP-1 receptor agonist option taken without fasting or dietary restrictions.

    Why it matters: Phase 3 evidence that an oral small-molecule GLP-1 receptor agonist matches injectable-class glycemic efficacy.

  2. biorxiv.org41

    The Smac mimetic drug Xevinapant sensitizes triple negative breast cancer to radiotherapy-induced cell death in a TNFα dependent manner

    The Smac mimetic Xevinapant (AT406) sensitized triple-negative breast cancer cell lines to radiotherapy-induced cell death in vitro, with clonogenic assays in MDA-MB-231 cells showing a dose-enhancing factor of 1.57. Radiosensitization was significantly enhanced by TNF and mediated by TNF-dependent apoptosis, assessed by western blotting, flow cytometry and cell cycle analysis. The findings support combining radiotherapy with Xevinapant to improve local control in TNBC.

  3. nature.com61

    GPCR antagonism via rewiring of receptor trafficking and degradation

    Bifunctional antibodies termed GTACs, which bind both a GPCR and the constitutively internalizing transferrin receptor 1, drive receptor endocytosis and lysosomal degradation, silencing signalling instead of competing with ligands. GTACs depleted and antagonized AT1R, RXFP1, CCR6 and BILF1, blocking chemotaxis in primary immune cells, suppressing angiotensin-potentiated contraction in iPSC-derived cardiomyocytes and inhibiting constitutive BILF1 signalling. GTACs showed more than 10-100-fold greater potency and improved efficacy over conventional antagonists, and the approach extended to APJ, A2AR and M3R.

    Why it matters: Offers a degradation-based alternative for GPCRs that resist classical competitive antagonism.

Sep 30Wed
  1. biorxiv.org51

    Dual inhibition of p38α MAPK and Casein kinase δ/ϵ as a novel treatment strategy for AR-independent and taxane-resistant advanced prostate cancer

    TAK-715, a dual inhibitor of p38 MAPK and Casein kinase δ/ε, showed efficacy against metastatic castration-resistant prostate cancer (mCRPC), including taxane-resistant lines and a highly aggressive metastatic variant, as a single agent and combined with taxanes. Its apoptotic effects occur via a mitochondrial-mediated pathway, and pathway analysis of bulk tumor RNA sequencing pointed to mitochondrial dysfunction and cell cycle arrest as top networks, with HES1 the top differentially expressed gene. Single-cell transcriptomics showed TAK-715 erodes subclonal populations driving cancer stemness, metastasis, and drug resistance, with findings validated in silico across multiple patient datasets.

Sep 29Tue
  1. biorxiv.org53

    SMYD3 protein degraders in HPV-negative head and neck squamous cell carcinoma.

    SMYD3 PROTACs, unlike catalytic inhibitors that lack phenotypic efficacy, degrade SMYD3 and curb proliferation and invasion in HPV-negative HNSCC cell lines. The compound IAP-08 degrades SMYD3 with a DC50 of about 177 nM and Dmax of about 90%, forms ternary complexes with XIAP E3 ligase, and shows favorable pharmacokinetics in vivo. Degradation, but not enzymatic inhibition, reprograms cell cycle, EMT and type I IFN response genes, supporting clinical development of IAP-08 in a disease where SMYD3 is overexpressed in about 60% of tumors.

    Why it matters: It reframes SMYD3 as undruggable by inhibitors alone and provides a degrader with in vivo feasibility for HPV-negative HNSCC.

  2. nature.com47

    Psychedelic protects against chemotherapy-induced nerve damage

    Pretreatment with the psychedelic drug psilocybin prevented chemotherapy-induced peripheral neuropathy in preclinical models. The work, reported in Science by Heles and colleagues, links the effect to preservation of mitochondrial trafficking, a mechanism damaged by platinum-based chemotherapy. The finding points to a way to protect against this dose-limiting adverse effect without altering the chemotherapy itself.

    Why it matters: A psychedelic drug prevented chemotherapy-induced peripheral neuropathy in preclinical models by preserving mitochondrial trafficking.

Sep 28Mon
  1. biorxiv.org69

    Pathway-wide base editing charts chemical-genetic interactions in MAPK signaling

    Base editor scanning across 22 MAPK genes, performed under pathway hyperactivation or inhibition at various nodes, produced a chemical-genetic interaction map of the RAS-RAF-MEK-ERK cascade. Drug resistance mutations often arose in proteins other than the direct drug target, catalytically impaired CRAF mutants gave bidirectional resistance and sensitization to structurally similar MEK inhibitors, and an allosteric site was found in the KRAS N-terminus. The work establishes BE scanning as a scalable method for network-level chemical-genetic mapping in a major oncogenic pathway.

    Why it matters: It charts chemical-genetic interactions across an oncogenic pathway and finds resistance mutations away from the drug target.

Sep 23Wed
  1. nature.com42

    Chiral oxazolidinones via biocatalytic aziridination of unactivated alkenes

    Engineered haemproteins catalyse an aziridination and ring-expansion cascade that converts simple unactivated alkenes directly into enantioselective chiral oxazolidinones, including 5-(S)-aminomethyl oxazolidinone scaffolds used in next-generation antibiotics against multidrug- and extensively drug-resistant Mycobacterium tuberculosis. The work extends haemprotein nitrene transfer beyond conjugated systems such as styrenes to unactivated alkenes, and computational analysis shows that mutations introduced by directed evolution control the enantioselectivity.

  2. nature.com70

    A design approach for bitopic kinase inhibitors

    A design strategy for bitopic kinase inhibitors used systematic analysis of ligand choice, linkage vector and linker length. Applying it to ABL1 and EGFR produced bitopic inhibitors, among them an ABL1 inhibitor with enhanced activity against resistance mutations and reduced off-target toxicity. The work offers a generalizable route to bitopic inhibitor design.

    Why it matters: Provides a generalizable design framework yielding an ABL1 inhibitor active against resistance mutations with less off-target toxicity.

Sep 22Tue
  1. medrxiv.org59

    Targeting Polθ Helicase with RP-3467: Preclinical Validation and Clinical Response in a gBRCA1 ovarian cancer patient with an acquired PARPi resistance mutation in TP53BP1

    RP-3467, a selective small-molecule inhibitor of DNA polymerase theta, suppresses Polθ enzymatic activity, abrogates microhomology-mediated end joining, and induces synthetic lethality in homologous recombination-deficient models. Combined with PARP inhibitors olaparib or rucaparib, it produced sustained tumor regression across multiple xenograft and patient-derived xenograft models without added systemic toxicity. In a phase 1 trial (NCT06560632), a heavily pretreated germline BRCA1-mutant ovarian cancer patient with a TP53BP1 loss-of-function mutation achieved a confirmed partial response to RP-3467 plus olaparib by RECIST v1.1.

    Why it matters: First clinical response to a Polθ inhibitor in a PARPi-resistant HRD ovarian cancer patient with mechanistic preclinical support.

Sep 18Fri
  1. Nature62

    TRI-611, a selective, brain-penetrant molecular glue degrader of ALK.

    TRI-611, a brain-penetrant molecular glue degrader, bridges the ALK kinase domain and the CRL4 adaptor CRBN through a degron interface distinct from the kinase active site, yielding proteome-wide selectivity. It degrades all ALK fusion protein forms tested, including wild-type and TKI-resistant versions, driving regression of subcutaneous and intracranial tumour models of ALK-positive NSCLC, alone and synergistically with ALK TKIs. It is described as the first clinical-stage molecular glue degrader targeting an oncogenic gene fusion.

    Why it matters: It offers an orthogonal, degradation-based option for ALK-positive NSCLC after progression on approved TKIs.

Sep 15Tue
  1. Cell65

    Copper ion-induced MYH9 polymerization executes cuproptosis.

    MYH9 (myosin heavy-chain 9) acts as an executioner of cuproptosis: copper binding induces MYH9 polymerization, which disrupts the actin cytoskeleton and causes cuproptotic cell death. The compound HThPA triggers this process by binding the nuclear receptor Nur77, depleting the copper chelate glutathione and releasing free copper from intracellular stores. Physiological copper levels were higher in drug-resistant tumor cells and clinical samples, increasing their susceptibility to HThPA-induced cuproptosis, suggesting a treatment strategy for drug-resistant tumors.

    Why it matters: It names a protein executing cuproptosis and links elevated copper in drug-resistant tumors to a candidate treatment strategy.

Sep 10Thu
  1. Nature49

    Synthesis of pyrroles from isoxazoles by an O-to-C skeletal edit.

    Pyrroles can now be made directly from isoxazoles by an O-to-C skeletal edit that swaps the single differing ring atom in a one-pot sequence. The key intermediate is an N-propargylic enaminone, giving a retrosynthetic disconnection orthogonal to traditional pyrrole syntheses. A predictive computational model captures the conformational features controlling the reaction outcome, enabling regioselective access to otherwise elusive pyrrole scaffolds.

    Why it matters: It converts isoxazoles to pyrroles with a single-atom ring edit, opening new routes to medicinally relevant scaffolds.

Sep 5Sat
  1. Cell44

    Complete biosynthesis of the anticancer cephalotaxinone and homoerythratine.

    The complete biosynthetic pathways of cephalotaxinone and homoerythratine, alkaloids from endangered Cephalotaxus species related to the leukemia drug homoharringtonine, have been identified using multi-omics analysis and synthetic standards. Two highly homologous P450 enzymes, CfCYP2 and CfCYP3, catalyze a rare divergent oxidation yielding two structurally distinct alkaloids, and key residues controlling this divergence were pinpointed. Both pathways were reconstituted in N. benthamiana, opening a route to production independent of limited natural resources.

    Why it matters: It removes the supply bottleneck for homoharringtonine by enabling biosynthesis of its core alkaloids in a plant host.

Sep 3Thu
  1. Sci Adv70

    A multi-functional oral small molecule targeting energy and lipid metabolism to treat obesity and related metabolic disorders.

    An orally bioavailable small molecule, 5-tetradecyloxy-2-furoic acid (TOFA), alleviated obesity, abnormal glucose homeostasis and fatty liver-related disease without affecting food intake or muscle mass. TOFA inhibits acetyl-CoA carboxylases 1 and 2 and activates PPARalpha/delta, raising energy expenditure and rebalancing lipid synthesis. It also acted more than additively with the incretin analogs semaglutide and tirzepatide to improve obesity, dyslipidemia and insulin resistance.

    Why it matters: It offers an oral option that raises energy expenditure rather than suppressing appetite, and combines with incretin analogs.

Aug 31Mon
  1. nature.com63

    Macropinocytosis-mediated recyclable LYTACs (McR-TACs) for receptor-independent protein degradation

    The paper introduces macropinocytosis-mediated recyclable LYTACs (McR-TACs), a receptor-independent approach to degrading extracellular and membrane proteins. The design is meant to exploit macropinocytosis so that the degrader is recycled and can act on its target across multiple cycles, addressing the reliance of conventional lysosome-targeting chimeras on specific cell-surface receptors. The title positions the work within the extracellular targeted protein degradation field.

    Why it matters: It proposes a receptor-independent, recyclable design for lysosome-targeting chimeras, a new entry in targeted protein degradation.

Aug 29Sat
  1. NEJM Evid44

    Metformin in High Metabolic Risk Pregnancies - A Patient-Level Meta-Analysis.

    Metformin did not reduce gestational diabetes in high metabolic risk pregnancies without diabetes in an individual participant data meta-analysis of seven double-blind, placebo-controlled trials including 2297 pregnancies, with an adjusted odds ratio of 1.00 (95% CI 0.71 to 1.41) by WHO 1999 criteria. Metformin was associated with longer gestation (mean difference 0.30 weeks), lower odds of preterm birth (adjusted OR 0.64; 95% CI 0.47 to 0.89), marginally lower fasting glucose, and larger neonatal head circumference, at the cost of more gastrointestinal side effects. This shifts metformin's role in pregnancy from GDM prevention toward neonatal and delivery timing benefits.

  2. Cancer Cell42

    Tumor cells recruit macrophage bodyguards to outlast chemotherapy.

    Chemoresistant bladder tumors contain spatially organized niches where EMT-like CD44high cancer cells pair with SPP1/PARP14high macrophages that protect them from chemotherapy. Inhibiting PARP14 converts this protective niche into an inflammatory state that sensitizes tumors to cisplatin. The work identifies a macrophage-dependent mechanism of chemoresistance and a druggable target.

Aug 25Tue
  1. Science79

    SGLT2 inhibitors activate pantothenate kinase in the human heart.

    SGLT2 inhibitors reduce mortality in heart failure by directly activating pantothenate kinase 1 (PANK1), the rate-limiting enzyme in coenzyme A synthesis, rather than through their known glucose transport target. Stable isotope infusions showed the drugs stimulate CoA synthesis and fuel use in human cardiac tissue, and binding at physiological concentrations was mapped by in silico modeling and confirmed by mutagenesis. PANK activation proved necessary and sufficient to increase contractility of human cardiomyocytes, identifying a plausible mechanism for the clinical benefit.

    Why it matters: It identifies a molecular target that may explain why SGLT2 inhibitors reduce mortality in heart failure.

Aug 21Fri
  1. Nature82

    A biased allosteric modulator is a molecular glue for β2AR dimerization.

    AP-7-168, a β-arrestin-biased negative allosteric modulator of the β2-adrenergic receptor, acts as a molecular glue that stabilizes β2AR homodimers. Cryo-EM structures show two AP-7-168 molecules packing in a pocket formed by transmembrane helices 3, 4 and 5 of two protomers, locking a dimeric conformation that selectively prevents β-arrestin coupling and drives nanocluster formation in cells. This identifies ligand-stabilized dimerization as a strategy for GPCR modulation.

    Why it matters: It shows a small molecule can bias GPCR signalling by gluing receptor dimers together.

Aug 15Sat
  1. Cancer Cell40

    Menin in normal and malignant megakaryopoiesis.

    Menin inhibitor therapy causes severe thrombocytopenia through an unknown mechanism. Work by Wen et al. published in Cancer Cell shows that menin is a key component of normal megakaryopoiesis and identifies menin as a therapeutic vulnerability in myeloproliferative neoplasms. This links the platelet toxicity of menin inhibition to menin's role in megakaryocyte development.

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