Hit-to-lead, SAR, lead optimization, targeted protein degradation and new chemical modalities.https://pharmadigest.net/enhttps://pharmadigest.net/en/articles/2026-10-23-brd9-protac-mouse-crbn-vhl-species-gap/https://pharmadigest.net/en/articles/2026-10-23-brd9-protac-mouse-crbn-vhl-species-gap/Widely used CRBN- and VHL-based BRD9 degraders such as dBRD9 and VZ185 are much less potent in mouse cells, even though BRD9 itself is highly conserved. The gap points to species differences in the E3 ligases, notably the Crbn I391 residue and structural variation in VHL, which likely hamper ternary complex formation. Expressing human CRBN or VHL, or introducing a CrbnI391V mutation, restored potency in mouse cells and improved BRD9 degradation in vivo.Fri, 23 Oct 2026 00:00:00 GMTMedicinal ChemistryPROTACBRD9CRBNVHLspecies selectivityhttps://pharmadigest.net/en/articles/2026-10-23-pyrroloquinoline-antitubulin-drug-resistant/https://pharmadigest.net/en/articles/2026-10-23-pyrroloquinoline-antitubulin-drug-resistant/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.Fri, 23 Oct 2026 00:00:00 GMTMedicinal Chemistrytubulinantimitoticdrug resistancepyrroloquinolineSARhttps://pharmadigest.net/en/articles/2026-10-23-sting-inhibitor-tetrahydropyrazolopyrazine-oral/https://pharmadigest.net/en/articles/2026-10-23-sting-inhibitor-tetrahydropyrazolopyrazine-oral/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.Fri, 23 Oct 2026 00:00:00 GMTMedicinal ChemistrySTINGcGAS-STINGautoimmuneinflammationoral small moleculehttps://pharmadigest.net/en/articles/2026-10-23-tlr7-tlr8-pyridone-indole-antagonists-brd4-offtarget/https://pharmadigest.net/en/articles/2026-10-23-tlr7-tlr8-pyridone-indole-antagonists-brd4-offtarget/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.Fri, 23 Oct 2026 00:00:00 GMTMedicinal ChemistryTLR7TLR8lupusoff-targetstructure-based designhttps://pharmadigest.net/en/articles/2026-10-22-inhaled-ddr-inhibitors-pyrrolopyrimidine-ipf/https://pharmadigest.net/en/articles/2026-10-22-inhaled-ddr-inhibitors-pyrrolopyrimidine-ipf/Structure-based design delivered two 5:6 heterocyclic series with strong DDR1/DDR2 affinity and a promising kinome selectivity profile. An inhaled-by-design strategy then tuned potency, physicochemical and in vitro ADME properties toward lung-restricted compounds. Compound 25 combined antifibrotic activity in a TGF-β-induced in vitro fibrosis model with a favorable pharmacokinetic profile for local delivery.Thu, 22 Oct 2026 00:00:00 GMTMedicinal ChemistryDDR1DDR2inhaledidiopathic pulmonary fibrosislung retentionhttps://pharmadigest.net/en/articles/2026-10-22-macrocyclic-cdk7-pyrazolotriazine-oral-selective/https://pharmadigest.net/en/articles/2026-10-22-macrocyclic-cdk7-pyrazolotriazine-oral-selective/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.Thu, 22 Oct 2026 00:00:00 GMTMedicinal ChemistryCDK7macrocyclekinase selectivityoral bioavailabilitytriple-negative breast cancerhttps://pharmadigest.net/en/articles/2026-10-22-mkk3-non-atp-competitive-modulators-ulcerative-colitis/https://pharmadigest.net/en/articles/2026-10-22-mkk3-non-atp-competitive-modulators-ulcerative-colitis/ATP-competitive p38 inhibitors failed in the clinic partly through poor kinome selectivity, so the authors targeted the upstream kinase MKK3 through a non-ATP-competitive pocket. The lead, (R)-48, suppressed TNF-α production, was highly orally bioavailable and showed dose-dependent efficacy with clear PK/PD relationships in mouse ulcerative colitis models. Biophysical data (HDX-MS) were used to probe how the compounds engage MKK3.Thu, 22 Oct 2026 00:00:00 GMTMedicinal ChemistryMKK3allostericTNF-αulcerative colitisoral small moleculehttps://pharmadigest.net/en/articles/2026-10-22-ttk-monovalent-degrader-monomethyl-fumarate-rnf126/https://pharmadigest.net/en/articles/2026-10-22-ttk-monovalent-degrader-monomethyl-fumarate-rnf126/Appending an electrophilic monomethyl fumarate handle to a TTK inhibitor gave a single-warhead degrader, with no E3 ligand attached. The lead compound drove TTK degradation and showed stronger antiproliferative activity than the parent inhibitor across several cancer cell lines. Mechanistic work points to the E3 ligase RNF126, which the compound stabilizes in complex with TTK, leading to ubiquitination and proteasomal turnover.Thu, 22 Oct 2026 00:00:00 GMTMedicinal ChemistryTTKmonovalent degradercovalentRNF126targeted protein degradationhttps://pharmadigest.net/en/articles/2026-10-22-ube2d2-electrophile-first-covalent-aminothiazole/https://pharmadigest.net/en/articles/2026-10-22-ube2d2-electrophile-first-covalent-aminothiazole/An electrophile-first screen, combined with X-ray crystallography, found a covalent hit that engages two cysteines (C85 and C111) of UBE2D2. Structure-guided SAR on the amide and ester groups removed binding to C111 while improving engagement of C85. The optimized analog inhibited UBE2D2 activity in vitro and suppressed proliferation of A549 lung cancer cells.Thu, 22 Oct 2026 00:00:00 GMTMedicinal ChemistryUBE2D2E2 enzymecovalent fragmentselectrophile-first screeningchemical probehttps://pharmadigest.net/en/articles/2026-10-22-yks-34-pde4b-selective-ipf/https://pharmadigest.net/en/articles/2026-10-22-yks-34-pde4b-selective-ipf/The authors set out to improve on the only approved PDE4B-preferential drug, nerandomilast, which is only about 9-fold selective over PDE4D. YKS-34 is a potent PDE4B inhibitor with more than 1000-fold selectivity over PDE4A, PDE4C and PDE4D. It suppressed TGF-β-driven fibroblast activation and LPS-induced TNF-α release in vitro, and showed favorable PK with accumulation in lung tissue.Thu, 22 Oct 2026 00:00:00 GMTMedicinal ChemistryPDE4Bidiopathic pulmonary fibrosisisoform selectivityPDE4Dlung PKhttps://pharmadigest.net/en/articles/2026-10-21-cenpb-oligotac-dna-protac-nsclc/https://pharmadigest.net/en/articles/2026-10-21-cenpb-oligotac-dna-protac-nsclc/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.Wed, 21 Oct 2026 00:00:00 GMTMedicinal ChemistryPROTACOligoTACCENPBtargeted protein degradationNSCLChttps://pharmadigest.net/en/articles/2026-10-21-dcn1-ube2m-inhibitor-herg-reduction/https://pharmadigest.net/en/articles/2026-10-21-dcn1-ube2m-inhibitor-herg-reduction/The earlier tool compound NAcM-OPT blocked the DCN1–UBE2M interaction, was orally available and slowed xenograft growth, but carried significant hERG affinity that stalled development. The authors systematically modified the scaffold to cut hERG binding while keeping DCN1 engagement. Lead compound 110 matched the parent in biochemical and cellular potency, with better physicochemical properties and improved selectivity against hERG.Wed, 21 Oct 2026 00:00:00 GMTMedicinal ChemistryDCN1neddylationhERGlead optimizationprotein-protein interactionhttps://pharmadigest.net/en/articles/2026-10-21-fgfr3-selective-inhibitors-perspective/https://pharmadigest.net/en/articles/2026-10-21-fgfr3-selective-inhibitors-perspective/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.Wed, 21 Oct 2026 00:00:00 GMTMedicinal ChemistryFGFR3kinase selectivityperspectivebladder cancerachondroplasiahttps://pharmadigest.net/en/articles/2026-10-21-iwy357-pyrazine-carboxamide-antimalarial/https://pharmadigest.net/en/articles/2026-10-21-iwy357-pyrazine-carboxamide-antimalarial/A P. falciparum growth-inhibition screen identified a new pyrazine-2-carboxamide series for blood-stage malaria. Lead optimization improved anti-plasmodial potency and metabolic stability and reduced CYP2D6 inhibition risk, giving IWY357. A single dose was fully curative in a Pf-humanized SCID mouse model, resistance selection showed a high barrier, and the compound has progressed through GLP toxicology into phase 1.Wed, 21 Oct 2026 00:00:00 GMTMedicinal Chemistrymalariaphenotypic screeninglead optimizationPlasmodium falciparumclinical candidatehttps://pharmadigest.net/en/articles/2026-10-20-epoxysuccinate-covalent-sars-cov-2-plpro-inhibitors/https://pharmadigest.net/en/articles/2026-10-20-epoxysuccinate-covalent-sars-cov-2-plpro-inhibitors/Covalent PLpro inhibitors were designed by combining an epoxysuccinamide warhead for Cys-111 with groove-binding features borrowed from non-covalent inhibitors. The compounds showed very high enzymatic potency and strongly reduced viral titres in cell culture. The flexible hydrazide linker was cleaved by hepatic carboxylesterases, and alternative linkers did not work, so the series is metabolically limited.Tue, 20 Oct 2026 00:00:00 GMTMedicinal Chemistrycovalent inhibitorsSARS-CoV-2PLproantiviralhttps://pharmadigest.net/en/articles/2026-10-20-parp1-selective-cns-penetrant-triazolopyridinyl-piperazine/https://pharmadigest.net/en/articles/2026-10-20-parp1-selective-cns-penetrant-triazolopyridinyl-piperazine/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.Tue, 20 Oct 2026 00:00:00 GMTMedicinal ChemistryPARP1CNSlead optimizationoncologyhttps://pharmadigest.net/en/articles/2026-10-20-protac-unbound-exposure-e3-target-engagement/https://pharmadigest.net/en/articles/2026-10-20-protac-unbound-exposure-e3-target-engagement/Twenty PROTACs with varied E3 ligands, linkers and target binders were profiled in intracellular NanoBRET competition assays against cereblon and VHL tracers. Apparent potency spread widely when referenced to applied concentration, and passive Caco-2 permeability explained little of it. Correcting for measured intracellular unbound exposure shrank the spread dramatically, matching values from permeabilized cells.Tue, 20 Oct 2026 00:00:00 GMTMedicinal ChemistryPROTACcell permeabilitytarget engagementNanoBREThttps://pharmadigest.net/en/articles/2026-10-20-isg15-uba7-alphalisa-high-throughput-screen/https://pharmadigest.net/en/articles/2026-10-20-isg15-uba7-alphalisa-high-throughput-screen/ISG15 and its E1 enzyme UBA7 drive ISGylation, a pathway linked to treatment resistance in cancer, yet no inhibitors exist. The authors built an AlphaLISA assay for the ISG15–UBA7 interaction with strong robustness metrics for high-throughput use. A pilot screen of a small library gave a handful of hits, two of which also reduced ISGylation in cells.Tue, 20 Oct 2026 00:00:00 GMTMedicinal ChemistryHTSAlphaLISAISG15ubiquitin-likehttps://pharmadigest.net/en/articles/2026-10-19-chemophototherapy-repurposed-anthracenediones-photosensitizers/https://pharmadigest.net/en/articles/2026-10-19-chemophototherapy-repurposed-anthracenediones-photosensitizers/TD-DFT screening of a curated library of approved anticancer drugs picked out chromophore-bearing candidates with favourable photophysics. Mitoxantrone, pixantrone, daunorubicin and epirubicin generated reactive oxygen species on irradiation and showed enhanced cytotoxicity in breast cancer cells. One molecule thus supplies both the chemotherapy and the photodynamic effect, avoiding a two-component conjugate.Mon, 19 Oct 2026 00:00:00 GMTMedicinal Chemistrychemophototherapydrug repurposingphotosensitizerTD-DFThttps://pharmadigest.net/en/articles/2026-10-19-hsa-fe4-ferric-agent-triple-negative-breast-cancer/https://pharmadigest.net/en/articles/2026-10-19-hsa-fe4-ferric-agent-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.Mon, 19 Oct 2026 00:00:00 GMTMedicinal Chemistrymetallodrugchemodynamic therapyferroptosisalbumin deliveryhttps://pharmadigest.net/en/articles/2026-10-18-benzodiazepine-antimalarial-pfset3-g9a/https://pharmadigest.net/en/articles/2026-10-18-benzodiazepine-antimalarial-pfset3-g9a/Eighteen new 3H-1,5-benzodiazepines were made and tested against chloroquine-sensitive and resistant P. falciparum strains, with HepG2 cytotoxicity as a first selectivity check. Several compounds were active in the low micromolar range, with different members showing the best potency and the best selectivity. The two leads were only weak inhibitors of human G9a; docking, MM-GBSA and MD were used to propose binding to parasite PfSET3.Sun, 18 Oct 2026 00:00:00 GMTMedicinal ChemistryantimalarialbenzodiazepinePfSET3G9adockinghttps://pharmadigest.net/en/articles/2026-10-18-bptf-phd-bromodomain-bivalent-inhibitor/https://pharmadigest.net/en/articles/2026-10-18-bptf-phd-bromodomain-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.Sun, 18 Oct 2026 00:00:00 GMTMedicinal ChemistryBPTFepigenetic readerbromodomainPHD fingerbivalent ligandhttps://pharmadigest.net/en/articles/2026-10-18-myc-de-novo-protein-binders-tumor-growth/https://pharmadigest.net/en/articles/2026-10-18-myc-de-novo-protein-binders-tumor-growth/Designed proteins target conserved epitopes in MYC, including intrinsically disordered motifs needed for its oncogenic activity. They bind MYC tightly in vitro; in cells they engage MYC, disrupt MAX pairing and reshape MYC-associated complexes. Expressing the binders curbed proliferation across several MYC-dependent hematopoietic, liver, pancreatic and patient-derived models, and depleted tumor cells in an orthotopic pancreatic model.Sun, 18 Oct 2026 00:00:00 GMTMedicinal ChemistryMYCde novo protein designintrinsically disordered proteinstranscription factorhttps://pharmadigest.net/en/articles/2026-10-18-rab27a-macrocyclic-peptide-effector-free-crystal/https://pharmadigest.net/en/articles/2026-10-18-rab27a-macrocyclic-peptide-effector-free-crystal/mRNA display against the RAB27A effector-binding interface produced macrocyclic peptide hits, which were optimized into IMP2660. IMP2660 binds RAB27A tightly and disrupts RAB27A–effector interactions. Its co-crystal structure with active-state RAB27A, solved without any effector, maps the effector-binding surface for structure-guided design.Sun, 18 Oct 2026 00:00:00 GMTMedicinal ChemistryRAB27Amacrocyclic peptidemRNA displaysmall GTPaseprotein-protein interactionhttps://pharmadigest.net/en/articles/2026-10-17-mrgprx2-pyrazolopyrimidine-incb187175/https://pharmadigest.net/en/articles/2026-10-17-mrgprx2-pyrazolopyrimidine-incb187175/MRGPRX2 drives IgE-independent mast cell activation and is linked to urticaria, atopic dermatitis and pseudoallergic reactions. Scaffold hybridization and SAR gave pyrazolopyrimidine antagonists active in both Gq/IP1 and β-arrestin assays. Fixing solubility and CYP inhibition liabilities led to INCB187175, orally exposed across species, which blocked degranulation in primary human mast cells and mast cell activation in vivo.Sat, 17 Oct 2026 00:00:00 GMTMedicinal ChemistryMRGPRX2GPCRmast cellurticariaoral antagonisthttps://pharmadigest.net/en/articles/2026-10-17-rhoj-n-terminal-pocket-terconazole/https://pharmadigest.net/en/articles/2026-10-17-rhoj-n-terminal-pocket-terconazole/RhoJ is nearly identical to Cdc42 in sequence but carries a unique N-terminal extension, which simulations show forms an allosteric pocket on binding PAK3. Structure-based virtual screening against that pocket flagged the antifungal terconazole as a possible binder. In live cells, an optimized BRET2 biosensor showed terconazole reduces the RhoJ–PAK3 interaction in a dose-dependent way.Sat, 17 Oct 2026 00:00:00 GMTMedicinal ChemistryRhoJRho GTPasevirtual screeningmolecular dynamicsangiogenesishttps://pharmadigest.net/en/articles/2026-10-17-brain-penetrant-egfr-tki-crystal-structures/https://pharmadigest.net/en/articles/2026-10-17-brain-penetrant-egfr-tki-crystal-structures/Several EGFR TKIs redesigned for blood-brain barrier penetration were studied by X-ray crystallography and potency assays. The BBB-enhancing groups engage varied regions of the EGFR kinase domains, and biochemical and cellular potency generally improved. Salt-bridge-forming moieties combined with certain halogen substitutions worked best, pointing to a 'two-for-one' design logic.Sat, 17 Oct 2026 00:00:00 GMTMedicinal ChemistryEGFRBBB penetrationX-ray crystallographykinase inhibitorCNShttps://pharmadigest.net/en/articles/2026-10-17-cereblon-cys287-allosteric-covalent-inhibitor/https://pharmadigest.net/en/articles/2026-10-17-cereblon-cys287-allosteric-covalent-inhibitor/Cysteine-directed chemoproteomic screening found covalent ligands for Cys287, an allosteric pocket far from the thalidomide-binding site. Lead VVD-105917 broadly blocks degradation of neosubstrates driven by IMiDs and CELMoDs. Cryo-EM shows it traps cereblon in its open, inactive state, and ligand order matters. A previously reported ligand at the same site promotes closure instead, so the pocket is 'sign-switchable'.Sat, 17 Oct 2026 00:00:00 GMTMedicinal Chemistrycerebloncovalentchemoproteomicstargeted protein degradationcryo-EMhttps://pharmadigest.net/en/articles/2026-10-17-hdac11-yp200-indole-hydroxamate-nsclc/https://pharmadigest.net/en/articles/2026-10-17-hdac11-yp200-indole-hydroxamate-nsclc/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.Sat, 17 Oct 2026 00:00:00 GMTMedicinal ChemistryHDAC11hydroxamic acidNSCLClead optimizationhttps://pharmadigest.net/en/articles/2026-10-17-ttbk1-2-5-azaindole-probe-ciliogenesis/https://pharmadigest.net/en/articles/2026-10-17-ttbk1-2-5-azaindole-probe-ciliogenesis/The 5-azaindole inhibitor 13 is potent against tau tubulin kinases 1 and 2 and active in cells. In-cell kinome profiling showed few off-targets; follow-up NanoBRET work narrowed them to CDK11A/B, CK1δ and PIKfyve. A close analogue, compound 5, lacks in-cell TTBK affinity and serves as a negative control; compound 13 blocks TTBK2 autophosphorylation and impairs primary cilia formation in RPE-1 cells.Sat, 17 Oct 2026 00:00:00 GMTMedicinal ChemistryTTBK1TTBK2kinasechemical probeciliogenesishttps://pharmadigest.net/en/articles/2026-10-16-cysteine-reactive-early-mitotic-inhibitors/https://pharmadigest.net/en/articles/2026-10-16-cysteine-reactive-early-mitotic-inhibitors/A cell-based high-content imaging screen was built to catch early mitotic spindle assembly defects. Run against a 3,520-compound cysteine-reactive library, it found a microtubule depolymerizer, a spindle-positioning disruptor and compounds that disturb spindle structure and chromosome alignment. Two hits caused mitotic arrest and reduced cancer cell viability (preprint; not yet peer reviewed).Fri, 16 Oct 2026 00:00:00 GMTMedicinal Chemistrycovalent screeningmitosishigh-content screeningpreprinthttps://pharmadigest.net/en/articles/2026-10-16-elevenostat-not-hdac11-selective-probe/https://pharmadigest.net/en/articles/2026-10-16-elevenostat-not-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.Fri, 16 Oct 2026 00:00:00 GMTMedicinal ChemistryHDAC11HDAC6chemical probeselectivity profilinghttps://pharmadigest.net/en/articles/2026-10-16-nav17-aminopyrimidine-state-independent-probe/https://pharmadigest.net/en/articles/2026-10-16-nav17-aminopyrimidine-state-independent-probe/An automated patch-clamp screening cascade, built to deprioritize classic local-anesthetic pore binders, yielded an aminopyrimidine hit that was optimized into compound 6. Compound 6 combined balanced resting- and inactivated-state potency, selectivity over NaV1.5 and a tetrodotoxin-like isoform profile that includes NaV1.1. SAR pointed to the aminopyrimidine core and a methylene-linked aniline as key determinants of this profile.Fri, 16 Oct 2026 00:00:00 GMTMedicinal ChemistryNaV1.7painion channelautomated patch clampSARhttps://pharmadigest.net/en/articles/2026-10-16-anti-apoptotic-bax-inhibitors-egfr-scaffold/https://pharmadigest.net/en/articles/2026-10-16-anti-apoptotic-bax-inhibitors-egfr-scaffold/A virtual screen flagged EGFR inhibitors, including dacomitinib and gefitinib-like cores, as possible BAX binders. Systematic modification built a first SAR for BAX inhibition and reduced EGFR kinase activity considerably. The series showed better BAX inhibition in vitro, in cells and in iPSC-derived brain organoids, with drug-like properties.Fri, 16 Oct 2026 00:00:00 GMTMedicinal ChemistryBAXapoptosisvirtual screeningkinase inhibitor repurposingneurodegenerationhttps://pharmadigest.net/en/articles/2026-10-16-bcl6-protac-oxazinoquinolinone-dlbcl/https://pharmadigest.net/en/articles/2026-10-16-bcl6-protac-oxazinoquinolinone-dlbcl/Scaffold hopping from the BCL6 ligand BI-3802 gave a new tricyclic oxazinoquinolinone binder. Linker and CRBN-recruiter tuning produced compound 15, a PROTAC that degraded BCL6 quickly and potently, in a CRBN- and proteasome-dependent way. It strongly suppressed BCL6-dependent DLBCL cell growth, and oral dosing inhibited tumor growth in an OCI-LY1 xenograft without evident toxicity.Fri, 16 Oct 2026 00:00:00 GMTMedicinal ChemistryPROTACBCL6DLBCLscaffold hoppinghttps://pharmadigest.net/en/articles/2026-10-16-gta182-mta-cooperative-prmt5-cns/https://pharmadigest.net/en/articles/2026-10-16-gta182-mta-cooperative-prmt5-cns/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.Fri, 16 Oct 2026 00:00:00 GMTMedicinal ChemistryPRMT5MTAP deletionsynthetic lethalityCNS penetrationhttps://pharmadigest.net/en/articles/2026-10-16-slc6a19-allosteric-inhibitors-oral/https://pharmadigest.net/en/articles/2026-10-16-slc6a19-allosteric-inhibitors-oral/Virtual screening against the allosteric pocket seen in the SLC6A19/cinromide cryo-EM structure gave a starting hit. A second, partially overlapping pocket from a further cryo-EM structure inspired merged analogues, leading to a potent, selective, orally bioavailable compound 20. Compound 20 was weaker on mouse than on non-human primate SLC6A19, yet oral dosing raised urinary amino acid excretion dose-dependently.Fri, 16 Oct 2026 00:00:00 GMTMedicinal ChemistrySLC6A19transportercryo-EMvirtual screeningallosterichttps://pharmadigest.net/en/articles/2026-10-16-tau-lrp1-hts-small-molecule-inhibitors/https://pharmadigest.net/en/articles/2026-10-16-tau-lrp1-hts-small-molecule-inhibitors/The team built a quantitative assay set around purified LRP1 ligand-binding domain 4, using fluorescence polarization, split luciferase and TR-FRET. Tau, RAP and a peptide ligand competed for overlapping binding sites with nanomolar-range affinities across formats. A screen on this platform identified small-molecule inhibitors of the interaction, a starting point against tau uptake and spread.Fri, 16 Oct 2026 00:00:00 GMTMedicinal ChemistryHTSTauLRP1protein-protein interactionAlzheimer's diseasehttps://pharmadigest.net/en/articles/2026-10-15-chd4-macrocycle-nurd-interaction-hub/https://pharmadigest.net/en/articles/2026-10-15-chd4-macrocycle-nurd-interaction-hub/mRNA display against CHD4's SANT-SLIDE domain yielded small macrocyclic peptides that block its interaction with GATAD2A, a core step in building the NuRD complex. The screen pointed to a second binding site on CHD4; CDK2AP1 was confirmed to bind there, and the CHD4–GATAD2A–CDK2AP1 ternary complex structure was determined. Disrupting NuRD induces fetal hemoglobin, a validated therapeutic strategy for sickle cell disease and other β-hemoglobinopathies.Thu, 15 Oct 2026 00:00:00 GMTMedicinal ChemistrymacrocyclesmRNA displayprotein-protein interactionfetal hemoglobinhttps://pharmadigest.net/en/articles/2026-10-15-cinchona-ammonium-long-acting-nerve-block/https://pharmadigest.net/en/articles/2026-10-15-cinchona-ammonium-long-acting-nerve-block/Ammonium salts built on natural cinchona alkaloids were explored as local anesthetics; the bicyclic quincoridine skeleton beat acyclic and monocyclic analogues. Lead CLA-1-3 blocked the rat sciatic nerve for more than 50 hours and potently inhibited voltage-gated sodium channels. A second compound, CLA-3-5, gave a sensory-selective block lasting up to about 3 hours at 0.30–0.60% concentration.Thu, 15 Oct 2026 00:00:00 GMTMedicinal Chemistrylocal anestheticsnatural productssodium channelpainhttps://pharmadigest.net/en/articles/2026-10-15-lrrk2-g2019s-selective-octahydrocyclopentapyrrole/https://pharmadigest.net/en/articles/2026-10-15-lrrk2-g2019s-selective-octahydrocyclopentapyrrole/Structure-guided hybridization produced an indazole-based LRRK2 series; the initial piperidine compounds were potent but barely distinguished wild-type from G2019S mutant kinase. Replacing the piperidine with an octahydrocyclopenta[c]pyrrole widened the selectivity window while keeping good potency; compound 34 represents the new chemotype. The authors pitch it as an alternative starting point for next-generation, Parkinson's-directed LRRK2 inhibitors.Thu, 15 Oct 2026 00:00:00 GMTMedicinal ChemistryLRRK2kinase inhibitorParkinson's diseasemutant selectivityhttps://pharmadigest.net/en/articles/2026-10-15-oral-stat6-degrader-ww-210-atopic-dermatitis/https://pharmadigest.net/en/articles/2026-10-15-oral-stat6-degrader-ww-210-atopic-dermatitis/Replaces the earlier phosphopeptide-based STAT6 PROTAC with non-peptide degraders designed for oral dosing. WW-210 degraded STAT6 at very low concentrations with a wide selectivity window over other STAT family members. It showed measurable oral bioavailability and degraded STAT6 in blood and spleen; in an atopic dermatitis mouse model it eased skin lesions, lowered serum IgE and reduced mast cell infiltration.Thu, 15 Oct 2026 00:00:00 GMTMedicinal ChemistryPROTACSTAT6atopic dermatitisoral degraderhttps://pharmadigest.net/en/articles/2026-10-15-gtp-state-kras-g12c-covalent-keto-indolizine/https://pharmadigest.net/en/articles/2026-10-15-gtp-state-kras-g12c-covalent-keto-indolizine/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.Thu, 15 Oct 2026 00:00:00 GMTMedicinal ChemistryKRAScovalent inhibitorHTSoncologyhttps://pharmadigest.net/en/articles/2026-10-15-covalent-fragment-lysine-shp2-latch-site/https://pharmadigest.net/en/articles/2026-10-15-covalent-fragment-lysine-shp2-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.Thu, 15 Oct 2026 00:00:00 GMTMedicinal Chemistrycovalent fragmentslysine targetingSHP2FBDDhttps://pharmadigest.net/en/articles/2026-10-14-benzothiophene-mprb-antivirulence-tuberculosis/https://pharmadigest.net/en/articles/2026-10-14-benzothiophene-mprb-antivirulence-tuberculosis/The earlier hit BTP15 protects host cells from Mtb-induced death by blocking phagosomal escape through MprB inhibition, but had poor pharmacokinetics. New benzothiophene analogues were screened for MprB inhibition, microsomal stability, toxicity and ex vivo efficacy in THP-1 and MRC-5 cells. The aim is a virulence-blocking route that avoids killing the bacterium directly, which may reduce resistance pressure.Wed, 14 Oct 2026 00:00:00 GMTMedicinal Chemistrytuberculosisantivirulencehistidine kinasebenzothiophenehttps://pharmadigest.net/en/articles/2026-10-14-dcl1191-tfeb-inhibitor-from-eltrombopag/https://pharmadigest.net/en/articles/2026-10-14-dcl1191-tfeb-inhibitor-from-eltrombopag/TFEB, a transcription factor long seen as undruggable, was approached starting from eltrombopag, which has weak TFEB inhibitory activity alongside its Tpo-R agonism. SAR optimisation gave DCL1191, which binds TFEB, disrupts TFEB–DNA binding and shows reduced Tpo-R and MITF activity; modelling and mutagenesis support the binding mode. It represses TFEB target genes, blocks autophagic flux and is orally bioavailable, with activity in autophagy-hyperactivated glioblastoma cells.Wed, 14 Oct 2026 00:00:00 GMTMedicinal ChemistryTFEBtranscription factorautophagydrug repurposinghttps://pharmadigest.net/en/articles/2026-10-14-hdac6-l2-pocket-inhibitors-lung-cancer/https://pharmadigest.net/en/articles/2026-10-14-hdac6-l2-pocket-inhibitors-lung-cancer/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.Wed, 14 Oct 2026 00:00:00 GMTMedicinal ChemistryHDAC6structure-based designautophagylung cancerhttps://pharmadigest.net/en/articles/2026-10-14-pdia3-n-hydroxyindole-carboxamide-antivirals/https://pharmadigest.net/en/articles/2026-10-14-pdia3-n-hydroxyindole-carboxamide-antivirals/PDIA3, an ER oxidoreductase involved in folding glycosylated viral envelope proteins, is an underexplored host target for antivirals. A new N-hydroxyindole-2-carboxamide class, exemplified by AV22, inhibits PDIA3 and shows broad activity against major human respiratory viruses. In coronavirus-infected cells AV22 raised release of non-infectious particles and reduced disulfide bond formation in spike.Wed, 14 Oct 2026 00:00:00 GMTMedicinal ChemistryPDIA3host-targeted antiviralrespiratory virusescoronavirushttps://pharmadigest.net/en/articles/2026-10-14-peptide-like-del-403200-compounds-diversity/https://pharmadigest.net/en/articles/2026-10-14-peptide-like-del-403200-compounds-diversity/A three-cycle, peptide-like DEL of 403,200 compounds was built, with a chemical space model of 4,774 commercial amino acids used to find under-represented building blocks. Affinity selections were run against three targets to compare library performance. Selection against carbonic anhydrase II recovered the known sulfonamide pharmacophore, supporting the computational design approach.Wed, 14 Oct 2026 00:00:00 GMTMedicinal ChemistryDELDNA-encoded librarylibrary designchemical spacehttps://pharmadigest.net/en/articles/2026-10-14-pi4kiiib-hdac-dual-inhibitors-hcv/https://pharmadigest.net/en/articles/2026-10-14-pi4kiiib-hdac-dual-inhibitors-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.Wed, 14 Oct 2026 00:00:00 GMTMedicinal ChemistryPI4KIIIβHDACdual inhibitorhepatitis Chost-directed