Daily drug discovery research and pharma industry news — medicinal chemistry, pharmacology, computational drug discovery.https://pharmadigest.net/enhttps://pharmadigest.net/en/articles/2026-10-23-aimnet2-cpcm-ligand-strain-solvated/https://pharmadigest.net/en/articles/2026-10-23-aimnet2-cpcm-ligand-strain-solvated/Conventional strain estimates reference a single gas-phase minimum, which ignores solvent and distorts charged ligands whose internal electrostatics collapse them into compact structures in vacuo. AIMNet2-CPCM, a neural network potential trained on DFT-level energies and forces in a continuum solvent, handles neutral and charged species on equal footing. GPU batch inference makes a solvated global-minimum search feasible across a full screening library. Across roughly 8,000 PDB ligands, solvated strain rises with net charge, with a trend that holds up to a charge of −2.Fri, 23 Oct 2026 00:00:00 GMTComputational & AIligand strainneural network potentialAIMNet2computational chemistryconformational energyhttps://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-isomorphic-labs-valuation-ai-drug-discovery/https://pharmadigest.net/en/articles/2026-10-23-isomorphic-labs-valuation-ai-drug-discovery/STAT's AI Prognosis column asks what Isomorphic Labs' very high valuation says about AI's role in drug development. Separate reports describe early talks to raise new funds at a valuation of at least $40 billion, shortly after a roughly $2.1 billion round in May 2026; no financing has closed. The column also touches on the debate over AI and the cost of care.Fri, 23 Oct 2026 00:00:00 GMTIndustry NewsIsomorphic LabsAI drug discoveryvaluationfinancinghttps://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/2026-10-23-lilly-metis-ai-lnp-delivery-deal/https://pharmadigest.net/en/articles/2026-10-23-lilly-metis-ai-lnp-delivery-deal/Eli Lilly and Hong Kong-listed METiS TechBio agreed a collaboration worth up to about $1.1 billion to develop tissue-specific delivery technologies. METiS contributes its AiLNP platform for ionizable lipid discovery, combining a large lipid library, screening and a lipid language model. Metis gets a low double-digit-million upfront, plus development, regulatory and commercial milestones and single-digit tiered royalties; no candidates or indications were named.Fri, 23 Oct 2026 00:00:00 GMTIndustry NewsEli LillyMETiSlipid nanoparticlesAI drug deliverycollaborationhttps://pharmadigest.net/en/articles/2026-10-23-bcl9-beta-catenin-inhibitor-glioma/https://pharmadigest.net/en/articles/2026-10-23-bcl9-beta-catenin-inhibitor-glioma/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.Fri, 23 Oct 2026 00:00:00 GMTPharmacologyBCL9β-cateninWntglioblastomaprotein-protein interactionhttps://pharmadigest.net/en/articles/2026-10-22-gsk-fda-approval-hepatitis-b-functional-cure/https://pharmadigest.net/en/articles/2026-10-22-gsk-fda-approval-hepatitis-b-functional-cure/STAT reports that GSK has won FDA approval for its hepatitis B drug. The drug extended functional cures to far more patients than previous methods, according to the report. Details beyond the headline were not available to us; the product is understood to be the antisense bepirovirsen.Thu, 22 Oct 2026 00:00:00 GMTIndustry NewsGSKhepatitis BFDA approvalantisense oligonucleotidefunctional curehttps://pharmadigest.net/en/articles/2026-10-22-roivant-positive-trial-non-infectious-uveitis/https://pharmadigest.net/en/articles/2026-10-22-roivant-positive-trial-non-infectious-uveitis/STAT reports that Roivant announced positive trial results for its immune drug in non-infectious uveitis. The result could open a new market for the drug beyond its current indications. Only the headline and lede were available to us; the specific endpoints and data are not confirmed here.Thu, 22 Oct 2026 00:00:00 GMTIndustry NewsRoivantnon-infectious uveitistrial resultimmunologyhttps://pharmadigest.net/en/articles/2026-10-22-cofolding-models-ligand-placement-vs-protein-conformation/https://pharmadigest.net/en/articles/2026-10-22-cofolding-models-ligand-placement-vs-protein-conformation/AlphaFold3, RoseTTAFold3, Boltz-2 and Chai-1 were benchmarked on kinases and Class A GPCRs, families whose pharmacology depends on defined conformational states. Only complexes released after all four models' training cutoffs were used, plus one earlier control structure, to give a prospective test. Correct ligand placement turned out to be systematically decoupled from accurate prediction of the surrounding protein conformation.Thu, 22 Oct 2026 00:00:00 GMTComputational & AIcofoldingAlphaFold3Boltz-2Chai-1RoseTTAFold3computational screeninghttps://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/2026-10-22-roche-hansoh-adc-portfolio-collaboration/https://pharmadigest.net/en/articles/2026-10-22-roche-hansoh-adc-portfolio-collaboration/Roche and China's Hansoh signed a collaboration on a portfolio of early-stage antibody-drug conjugates, its second ADC deal after a 2025 CDH17 ADC license. Reports put the upfront at about $400 million plus a further $110 million after a year, with total potential payments above $15 billion and royalties. Hansoh leads early development through global phase 1a, after which Roche takes over development outside Greater China.Thu, 22 Oct 2026 00:00:00 GMTIndustry NewsRocheHansohADCChina licensingcollaborationhttps://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-china-draft-curbs-foreign-biopharma-acquisitions/https://pharmadigest.net/en/articles/2026-10-21-china-draft-curbs-foreign-biopharma-acquisitions/China is proposing new restrictions on foreign acquisitions of critical biopharma technologies as it seeks to keep control of its fast-growing drug development industry. Trade coverage of the draft (Fierce) describes it as targeting full transfers of proprietary cell and gene therapy, siRNA and pathogen gain-of-function platforms, while standard out-licensing and CRO/CDMO outsourcing appear to be exempt. The final text and timing are not confirmed.Wed, 21 Oct 2026 00:00:00 GMTIndustry NewsChinaregulationM&Aexport controlcell and gene therapysiRNAhttps://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/2026-10-21-sf-ga-pgp-substrate-to-nonsubstrate-redesign/https://pharmadigest.net/en/articles/2026-10-21-sf-ga-pgp-substrate-to-nonsubstrate-redesign/P-gp efflux limits bioavailability and CNS exposure, and ML substrate classifiers rarely translate into concrete design moves. SF-GA builds fragment synergy analysis into the mutation step of a genetic algorithm, biasing replacements toward substructures that co-occur in non-substrates. Against GA and reinforcement-learning baselines at a fixed evaluation budget it was competitive and gave the most synthetically accessible molecules, reporting the removed and inserted fragments for every accepted mutation.Wed, 21 Oct 2026 00:00:00 GMTComputational & AIP-glycoproteineffluxgenetic algorithmmolecular optimizationADMEhttps://pharmadigest.net/en/articles/2026-10-20-gilead-emvistegrast-swift-phase2-ulcerative-colitis/https://pharmadigest.net/en/articles/2026-10-20-gilead-emvistegrast-swift-phase2-ulcerative-colitis/Gilead's once-daily oral α4β7 integrin inhibitor emvistegrast (GS-1427) met its primary endpoint in the Phase 2 SWIFT study in ulcerative colitis. At the 200 mg dose, clinical remission at week 12 was roughly three times the placebo rate, with nominal significance and good tolerability. STAT's report is paywalled; figures here follow Gilead's own statement.Tue, 20 Oct 2026 00:00:00 GMTIndustry Newsulcerative colitisoralα4β7 integrinPhase 2https://pharmadigest.net/en/articles/2026-10-20-merck-kgaa-silence-therapeutics-acquisition/https://pharmadigest.net/en/articles/2026-10-20-merck-kgaa-silence-therapeutics-acquisition/Merck KGaA will acquire Silence in an all-cash deal at $20 per ADS, an equity value of about $1.3 billion, via a UK scheme of arrangement. The price is a 130% premium to the prior close, and Silence called it the outcome of a competitive sale process. The deal follows positive Phase 2 data for Silence's siRNA divesiran in polycythemia vera.Tue, 20 Oct 2026 00:00:00 GMTIndustry NewsM&AsiRNApolycythemia veraMerck KGaAhttps://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/2026-10-20-kinase-inhibitor-protonation-tautomer-shifts-mcce/https://pharmadigest.net/en/articles/2026-10-20-kinase-inhibitor-protonation-tautomer-shifts-mcce/Multi-conformation continuum electrostatics was applied to 37 co-crystal structures of nine kinase domains with 18 approved inhibitors. Protein net charge stayed largely stable on binding, whereas inhibitor charge states frequently shifted up or down. Binding can resolve two near-equal solution tautomers into one, creating free-energy differences of a few kcal/mol.Tue, 20 Oct 2026 00:00:00 GMTComputational & AIcomputational chemistrykinase inhibitorsprotonationtautomershttps://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/2026-10-19-charmm-gui-covalent-ligand-docker-autodock4/https://pharmadigest.net/en/articles/2026-10-19-charmm-gui-covalent-ligand-docker-autodock4/CGUI-CLD is a new CHARMM-GUI module that automates ligand preparation, ligand modification and docking runs for covalent ligands, built on AutoDock4. A knowledge-based library covers 66 warheads and 8 amino acids, so the post-reaction ligand geometry no longer has to be built by hand. Results are presented through a browser interface.Mon, 19 Oct 2026 00:00:00 GMTComputational & AIcovalent inhibitorsmolecular dockingvirtual screeningAutoDock4https://pharmadigest.net/en/articles/2026-10-19-lilly-gate-bioscience-sec61-collaboration-expansion/https://pharmadigest.net/en/articles/2026-10-19-lilly-gate-bioscience-sec61-collaboration-expansion/Lilly expanded its collaboration with Gate Bioscience to a potential value of up to $870M, from the original 2025 pact worth up to $856M. The expansion adds one target, with an option on a second; Gate gets an upfront payment, further payment if a second target is chosen, research funding and milestones. Gate's platform works on Sec61, the channel through which secreted and membrane proteins exit the cell; targets and indications are undisclosed.Mon, 19 Oct 2026 00:00:00 GMTIndustry NewsSec61partnershipsmall moleculeLillyhttps://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-pd-qsar-quantile-potency-extrapolation/https://pharmadigest.net/en/articles/2026-10-18-pd-qsar-quantile-potency-extrapolation/Standard QSAR struggles to predict analogs more potent than anything in its training set, which is exactly the lead-optimization question. Pairwise-Difference QSAR learns activity changes from descriptor differences between compound pairs, then aggregates the predictions. On ChEMBL-derived benchmarks across about a hundred targets with the most potent compounds held out, a low-quantile aggregation beat mean and kNN aggregation, direct QSAR and Chemprop.Sun, 18 Oct 2026 00:00:00 GMTComputational & AIQSARlead optimizationmachine learningChEMBLpairwise modelshttps://pharmadigest.net/en/articles/2026-10-18-lakefront-armed-cell-car-t-programs-sale/https://pharmadigest.net/en/articles/2026-10-18-lakefront-armed-cell-car-t-programs-sale/Lakefront Biotherapeutics, the former Galapagos, is selling its abandoned cell therapy programs to Armed Cell Therapeutics, a new Belgian company co-founded and chaired by ex-Galapagos CEO Paul Stoffels. Reported terms are a small upfront payment (single-digit millions of euros) plus up to roughly $230 million in milestones. The package covers two armed CAR-Ts nearing the clinic in non-Hodgkin lymphoma and small cell lung cancer, plus three early preclinical projects.Sun, 18 Oct 2026 00:00:00 GMTIndustry NewsCAR-Tcell therapydivestitureGalapagosLakefronthttps://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-revmed-rasonque-eu-approval-recommendation/https://pharmadigest.net/en/articles/2026-10-17-revmed-rasonque-eu-approval-recommendation/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.Sat, 17 Oct 2026 00:00:00 GMTIndustry NewsRevolution MedicinesdaraxonrasibRASpancreatic cancerEMAhttps://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-astrazeneca-insitro-ai-target-discovery-deal/https://pharmadigest.net/en/articles/2026-10-17-astrazeneca-insitro-ai-target-discovery-deal/AstraZeneca and insitro signed a collaboration to find novel drug targets for liver and heart diseases using AI. Reported terms: a modest upfront payment of $40 million, with milestones taking the total to about $1.5 billion. Terms come from search-snippet reporting of the Fierce Biotech article, which could not be opened directly.Sat, 17 Oct 2026 00:00:00 GMTIndustry NewsAstraZenecainsitroAItarget discoveryliver diseasehttps://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-merck-moderna-mrna-cancer-vaccine-keytruda-strategy/https://pharmadigest.net/en/articles/2026-10-17-merck-moderna-mrna-cancer-vaccine-keytruda-strategy/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.Sat, 17 Oct 2026 00:00:00 GMTIndustry NewsMerckModernamRNAcancer vaccineKeytrudahttps://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 probeciliogenesis