Discovery of a Colon-Targeted Prodrug As an Escherichia coli Biofilm Inhibitor for Treating Inflammatory Bowel Disease We hypothesized that the formation of biofilms contributes to the onset of inflammatory bowel disease and, thus, attempted to develop biofilm inhibitors as potential treatment options. We identified a...

Discovery of a Colon-Targeted Prodrug as an Escherichia coli Biofilm Inhibitor for Treating Inflammatory Bowel Disease

pubs.acs.org/doi/10.1021/... @pubs.acs.org

#MedicinalChemistry #DrugDiscovery #ProdrugDesign #InflammatoryBowelDisease #Pharmacology #Therapeutics #GutHealth #DrugDevelopment

Design, Synthesis, and Characterization of Prodrugs of Sulfonamide TLR4 Signaling Inhibitor TAK-242 (Resatorvid) We have previously reported two prodrug designs for the delivery of the potent TLR4 inhibitor TAK-242. Our initial design was used to covalently link TAK-242 to pancreatic islets using a linker to afford sustained delivery of the active drug after transplant. Those drug-eluting islets provided local inhibition of TLR4-linked inflammation and improved islet graft survival. Here, we describe a third family of TAK-242 prodrugs featuring two rate modulating sites, a self-immolative aniline-stabilized methylene spacer bonded directly to the sulfonamide nitrogen, an alcohol tether for bioconjugation, and a β-eliminative aryl-sulfone “trigger”. These prodrugs rapidly release TAK-242 after activation by β-elimination and a rapid subsequent 1,2-elimination, cleanly releasing the drug without detectable intermediates. This manuscript reports the preparation and characterization of a series of methylene-linked TAK-242 prodrugs, evaluating the impact of various modifications on drug release kinetics.

Design, Synthesis, and Characterization of Prodrugs of Sulfonamide TLR4 Signaling Inhibitor TAK-242 (Resatorvid) pubs.acs.org/doi/10.1021/... @pubs.acs.org

#MedicinalChemistry #DrugDesign #ProdrugStrategy #InflammationResearch #Immunology #Pharmacokinetics #Therapeutics #DrugDevelopment

Identification of Natural-Product Inhibitors of the 2C-Methyl-d-erythritol 4-Phosphate Pathway To tackle the emerging resistance against existing antibiotics, we screened natural-product (NP) libraries against two underexploited target enzymes from the 2C-methyl-d-erythritol 4-phosphate (MEP) p...

Identification of Natural-Product Inhibitors of the 2C-Methyl-d-erythritol 4-Phosphate Pathway

pubs.acs.org/doi/10.1021/... @pubs.acs.org

#ACSMedChemLett #NaturalProducts #AntibioticDiscovery #DrugDiscovery #MedicinalChemistry #MEPPathway #AntimicrobialResistance #InfectiousDiseases #GlobalHealth

Isoindolines and Isoindoline-1,3-diones as Nonpeptide ACE Inhibitors: An In Silico and In Vitro Modeling Approach Hypertension, a major cardiovascular risk factor, is often treated with peptide-derived angiotensin-converting enzyme inhibitors (ACEi), which can have several side effects. This study examined a new alternative: isoindoline and isoindoline-1,3-dione derivatives as nonpeptide ACE inhibitors. The synthesis and testing of these compounds involved both in silico molecular docking studies and optimized in vitro inhibitory kinetic assays, along with acute toxicity tests in mice. isoindoline-1,3-dione, D-05, demonstrated the strongest ACE inhibition in vitro (IC50 = 416.4 μM) and effectively bound to the enzyme’s catalytic active site in silico. Additionally, isoindoline-1,3-diones showed lower toxicity in mice (LD50 > 1600 mg/kg) compared to isoindolines (LD50 < 1000 mg/kg). This reduced toxicity is attributed to the presence of fewer reactive secondary metabolites. These promising results highlight the potential of isoindoline-1,3-diones as innovative nonpeptide ACE inhibitors and support further in vivo studies to verify their antihypertensive effects.

Isoindolines and Isoindoline-1,3-diones as Nonpeptide ACE Inhibitors: An In Silico and In Vitro Modeling Approach

pubs.acs.org/doi/10.1021/...

#KellyChibale #MedicinalChemistry #Hypertension #CardiovascularResearch #ACEInhibitors #DrugDiscovery #ComputationalChemistry

Discovery of Niclosamide Analogs with Potent Mitochondrial Uncoupling Activity and Reduced Mitochondrial Inhibition–Associated Toxicity Niclosamide, an FDA-approved anthelmintic, functions as a mitochondrial uncoupler with promising anticancer potential, yet its efficacy remains limited, often ascribed to poor bioavailability. We iden...

Discovery of Niclosamide Analogs with Potent Mitochondrial Uncoupling Activity and Reduced Mitochondrial Inhibition–Associated Toxicity
pubs.acs.org/doi/10.1021/...

#KellyChibale #MedicinalChemistry #CancerResearch #MitochondrialBiology #OncologyResearch #DrugDiscovery #QSAR

Maltose-Conjugated Thiosemicarbazones from Substituted Benzaldehydes: Synthesis and Inhibitory Activity against Gram-(+) and Gram-(−) Bacteria The increasing prevalence of multidrug-resistant bacteria necessitates the development of new antibacterial scaffolds with improved efficacy and safety. Thiosemicarbazones are known for their diverse ...

Maltose-Conjugated Thiosemicarbazones from Substituted Benzaldehydes: Synthesis and Inhibitory Activity against Gram-(+) and Gram-(−) Bacteria
pubs.acs.org/doi/10.1021/...

#KellyChibale #MedicinalChemistry #AntimicrobialResistance #AntibioticDiscovery #InfectiousDiseases #ChemicalBiology

Now also an Honorary Fellow of the #RoyalSocietyofChemistry, its highest accolade. Encouraging to see recognition of science that combines excellence, leadership and societal impact. Read more: www.rsc.org/news/2026-ho... #KellyChibale #HonoraryFellow #ChemicalSciences #H3D #GlobalScience

Design, Synthesis, and Structure–Activity Relationship Studies of 7H-Pyrrolo[2,3-d]pyrimidine Derivatives as Potent Casein Kinase 1α (CK1α) Inhibitors @acs.org pubs.acs.org/doi/10.1021/...

#KellyChibale #CancerResearch #Leukaemia #TargetedTherapy #KinaseInhibitors #MedicinalChemistry #DrugDiscovery

Characterization of the Formation of the Acyl Glucuronide Metabolite of 7-Carboxy-Cannabidiol in Human Liver, Kidney, and Intestinal Microsomes and In Vivo in Mice Acyl glucuronides are common metabolites of carboxylic acids. They can be reactive and cause adverse events. The acyl glucuronide metabolite of delta-9-tetrahydrocannabinol (THC) is abundant in humans after THC consumption but acyl glucuronide formation from the cannabidiol (CBD) metabolite 7-carboxy-cannabidiol (7-COOH-CBD) has not been previously described. Here, we identified and characterized both acyl and phenolic glucuronides of 7-COOH-CBD formed in human liver, kidney, and intestinal microsomes. The 7-COOH-CBD-acyl-glucuronide was mostly formed by UGT1A1 and UGT1A3, while the 7-COOH-CBD-phenolic-glucuronide was formed by UGT1A9. 7-COOH-CBD-acyl-glucuronide formation was also detected in vivo in mice. 7-COOH-CBD-acyl-glucuronide showed extensive acyl migration while 11-COOH-THC-glucuronide did not. Human serum albumin enhanced migration, while liver fatty acid binding protein (FABP1) protected against 7-COOH-CBD-acyl-glucuronide migration. When corrected for unbound fraction, FABP1 increased 7-COOH-CBD glucuronidation efficiency. These findings suggest that 7-COOH-CBD-acyl-glucuronide is a metabolite of CBD in humans and may play a role in CBD related liver toxicity.

Characterization of the Formation of the Acyl Glucuronide Metabolite of 7-Carboxy-Cannabidiol in Human Liver, Kidney, and Intestinal Microsomes and In Vivo in Mice pubs.acs.org/doi/10.1021/... @acs.org

#KellyChibale #DrugMetabolism #LiverToxicity #Pharmacokinetics #MedicinalChemistry #DrugSafety

AI-Assisted Discovery and Optimization of Small-Molecule TREM2 Agonists with Functional Microglial Activity Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglia-specific receptor whose loss-of-function variants increase Alzheimer’s disease (AD) risk. While antibody-based agonists have sho...

AI-Assisted Discovery and Optimization of Small-Molecule TREM2 Agonists with Functional Microglial Activity pubs.acs.org/doi/10.1021/... @acs.org

#KellyChibale #AlzheimersDisease #Neurodegeneration #AIDrugDiscovery #MedicinalChemistry #Neuroscience #DrugDiscovery

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'Un-LOK-ing a New Approach for Conformational Selective Targeting of STK10 (LOK)' from ACS Medicinal Chemistry Letters is an open access #ACSEditorsChoice.

📖 Read the article: buff.ly/jVrjw4E

@goetheuni.bsky.social @dkfz.bsky.social

For the 1-year anniversary of C2MCI’s International Research Network, today’s spotlight features Dr. Vinayak Singh & Dr. @kellychibale.bsky.social

Working with Dr. Chantelle Capicciotti, this project is examining nanocluster-bacterial interactions + their potential against antimicrobial resistance.

Eighth Replenishment Investment Case The Global Fund partnership has made remarkable progress in the fight against AIDS, tuberculosis (TB) and malaria over the last two decades – saving 70 million lives and reducing the combined death ra...

We must #StopAtNothing to defeat them. We must invest to finish the job.

www.theglobalfund.org/en/investmen...

Eighth Replenishment Investment Case The Global Fund partnership has made remarkable progress in the fight against AIDS, tuberculosis (TB) and malaria over the last two decades – saving 70 million lives and reducing the combined death ra...

The #GlobalFund partnership is fighting the deadliest infectious diseases in the most crisis-affected parts of the world. Through this partnership millions of lives have been saved. But there is still more work to do. HIV, TB & malaria have threatened humanity for far too long.

Discovery and Characterization of Zilurgisertib, a Potent and Selective Inhibitor of Activin Receptor-like Kinase-2 (ALK2) for the Treatment of Fibrodysplasia Ossificans Progressiva Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal-dominant disease leading to progressive soft tissue heterotopic ossification (HO) with no curative treatment available to date. It is caused by gain-of-function mutations in the activin A type-1 receptor ACVR1/ALK2, a member of the bone morphogenetic protein (BMP) type I receptor family. Most recent clinical trials in FOP have adopted for the first time on-target therapies to normalize the aberrant ALK2 receptor activity. Here we describe the discovery and preclinical characterization of zilurgisertib, a novel small-molecule inhibitor of ALK2 kinase with high biochemical and cellular potency, selectivity over other BMP and TGFβ signaling receptor kinases, and excellent oral bioavailability in preclinical species. Zilurgisertib fully suppresses HO in a pediatric mouse model of injury-induced FOP and therefore holds great potential as a novel targeted disease-modifying therapy for FOP. The candidate is being evaluated in clinical trials.

Zilurgisertib, a potent, selective ALK2 inhibitor, blocks aberrant signalling and prevents heterotopic ossification in fibrodysplasia ossificans progressiva (FOP) models and is now advancing as a first-in-class, disease-modifying therapy @pubs.acs.org pubs.acs.org/doi/10.1021/... #KellyChibale

Discovery of a Novel G9a-Selective Inhibitor for Hepatocellular Carcinoma Treatment Epigenetic dysregulation, particularly aberrant histone methylation orchestrated by histone methyltransferases (HMTs), is a fundamental driver of hepatocellular carcinoma (HCC). Among these HMTs, H3K9-specific methyltransferase G9a is markedly upregulated and promotes tumorigenesis. However, current G9a inhibitors lack sufficient selectivity and potency. Here, we identified compound 1071, a novel selective G9a inhibitor with a distinct chemical scaffold, which demonstrates superior cellular activity compared with the existing G9a inhibitor UNC0638. Mechanistically, compound 1071 reduces H3K9me2 levels and modulates the expression of key G9a targets, including p21, FOXO1, and PD-L1. Moreover, compound 1071 exhibits potent antitumor activity in both subcutaneous and c-Myc-driven HCC models, outperforming the first-line drug sorafenib without significant toxicity. This study establishes compound 1071 as a promising lead for G9a-targeted HCC therapy, advancing epigenetic drug discovery.

Epigenetic dysregulation drives hepatocellular carcinoma via G9a upregulation. In #ACSMedChemLett, Mu et al. report a novel & selective G9a inhibitor that lowers H3K9me2, restores tumour suppressor expression & outperforms sorafenib in models @pubs.acs.org pubs.acs.org/doi/10.1021/...
#KellyChibale

Optimization of Hsp90/Aha1 Small-Molecule Disruptors Via the Evaluation of Amide Bioisosteres Recent structure–activity relationships (SAR) were established around KU-177, the parent scaffold for an Hsp90/Aha1 small-molecule disruptor, which suggested that the central amide linker adopted a ci...

New analogues of the Hsp90/Aha1 disruptor KU-177 reported by Catalfano et al. in #ACSMedChemLett reveal that a cis-amide linker is key for inhibition; a sulfonamide-containing compound showed strong efficacy, solubility & metabolic stability @pubs.acs.org pubs.acs.org/doi/10.1021/...
#KellyChibale

#KellyChibale #AIinScience #Pharmacogenomics #MalariaResearch #TuberculosisResearch #PrecisionMedicine #AfricaScience #GlobalHealth #DrugDiscovery

Artificial intelligence coupled to pharmacometrics modelling to tailor malaria and tuberculosis treatment in Africa - Nature Communications Authors analyzed malaria and tuberculosis drugs to create a pharmacometric model. They used an AI pipeline that prioritized pharmacogenetic drug-gene pairs with an emphasis on high variant frequency g...

(5/5) Despite being the most genetically diverse continent, Africa’s unique pharmacogenetic profiles remain underrepresented in global research. Our work helps to bridge that gap. Read the full open-access article here: www.nature.com/articles/s41...

Artificial intelligence coupled to pharmacometrics modelling to tailor malaria and tuberculosis treatment in Africa - Nature Communications Authors analyzed malaria and tuberculosis drugs to create a pharmacometric model. They used an AI pipeline that prioritized pharmacogenetic drug-gene pairs with an emphasis on high variant frequency g...

(4/5) The significance of this work? Differences in how individuals and populations respond to medicines often arise from genetic variation in drug-metabolising enzymes and transporters – key factors influencing safety and efficacy.

Artificial intelligence coupled to pharmacometrics modelling to tailor malaria and tuberculosis treatment in Africa - Nature Communications Authors analyzed malaria and tuberculosis drugs to create a pharmacometric model. They used an AI pipeline that prioritized pharmacogenetic drug-gene pairs with an emphasis on high variant frequency g...

(3/5) By focusing on #malaria and #tuberculosis – two major diseases on the African continent, yet both understudied pharmacogenetically – we aim to improve treatment outcomes and advance precision medicine for the continent.

Artificial intelligence coupled to pharmacometrics modelling to tailor malaria and tuberculosis treatment in Africa - Nature Communications Authors analyzed malaria and tuberculosis drugs to create a pharmacometric model. They used an AI pipeline that prioritized pharmacogenetic drug-gene pairs with an emphasis on high variant frequency g...

(2/3) Here, we introduce an #AI-driven pipeline combining machine learning, pharmacometrics modelling to uncover drug-gene pairs of pharmacogenetic interest and propose dose adjustments tailored to African populations.

Artificial intelligence coupled to pharmacometrics modelling to tailor malaria and tuberculosis treatment in Africa - Nature Communications Authors analyzed malaria and tuberculosis drugs to create a pharmacometric model. They used an AI pipeline that prioritized pharmacogenetic drug-gene pairs with an emphasis on high variant frequency g...

(1/5) Our latest collaborative research project between @H3DCentre and @ersilia.io has recently been published in #NatCommun! Africa’s immense genetic diversity makes optimising drug treatments complex; this gap leads to limited pharmacogenetic data and suboptimal therapies for African populations.

Honoured to be named an @astmh.bsky.social Distinguished International Fellow and to deliver the Commemorative Lecture at the Closing Plenary in Toronto. Partnership across borders is vital to advancing global health innovation.

🔗 www.astmh.org

#KellyChibale #ASTMH #GlobalHealth #TropicalMedicine

Delivered a seminar at @tsinghuauniversity.bsky.social University where next-gen antimalarials and shared insights from #ACSMedChemLett was discussed. My privilege to engage with global colleagues in science.

🔗https://www.acs.org/about.html

#KellyChibale #MalariaResearch #DrugDiscovery

Attended the #GHDDI SAB meeting in Beijing (4–6 Nov), where members reviewed project progress and joined the Joint Steering Committee alongside #GatesFoundation and GHDDI leadership. Powerful partnerships continue to drive innovation in global health.

🔗 Read more: www.ghddi.org/en/about

Africa finally has its own drug-regulation agency — and it could transform the continent’s health If it gets things right, the first major regulator of medicines to launch for 30 years could empower Africa to tackle African challenges around health and disease.

(4/4) Read our full Comment in @Nature: www.nature.com/articles/d41...

#KellyChibale #AfricanMedicinesAgency #PublicHealth #ClinicalResearch #DrugDiscovery #GlobalHealth #AfricaScience #Pharmacogenomics

Africa finally has its own drug-regulation agency — and it could transform the continent’s health If it gets things right, the first major regulator of medicines to launch for 30 years could empower Africa to tackle African challenges around health and disease.

(3/4) The AMA seeks to embed African data into global drug discovery. By harmonising regulations, boosting local trials and promoting Africa-led pharmacogenomics and biobanking, the AMA can help to ensure that treatments are safe, effective and equitable for all people of African ancestry.

Africa finally has its own drug-regulation agency — and it could transform the continent’s health If it gets things right, the first major regulator of medicines to launch for 30 years could empower Africa to tackle African challenges around health and disease.

(2/4) Africa holds the world’s greatest genetic diversity, yet less than 3% of global clinical trials occur here. Too often, drugs and vaccines are designed, tested and approved elsewhere – making some treatments ineffective or even harmful for Africans.

Africa finally has its own drug-regulation agency — and it could transform the continent’s health If it gets things right, the first major regulator of medicines to launch for 30 years could empower Africa to tackle African challenges around health and disease.

(1/4) Over a decade in the making, the African Medicines Agency (AMA) has officially launched – a milestone for Africa’s public health and scientific sovereignty. The AMA aims to make drug regulation, research and discovery more relevant to African biology and the continent’s needs.