We have conceptualized and executed an efficient, eco-friendly, one-flask, synthetic approach to functionally enriched and potentially pharmacophoric tetracyclic indenodiazepinones through a base-medi...

As we mark Africa Day, I have been reflecting on how personal experiences can shape one’s life’s work and sense of purpose. Growing up in remote villages and townships in my home country of Zambia du...

The proliferation of artificial intelligence presents Africa’s drug discovery landscape with a transformative opportunity to accelerate research and development (R&D) to address the continent’s heavy ...

The design of novel small molecules with high selectivity for anticancer action remains a priority in the development of chemotherapy. A combination of the “privileged scaffold” of the chroman-4-one with rigid spirocyclic structures offers a strategy for modulating the specificity of action. A collection of 28 spirocyclohexane-chroman-4-one derivatives was screened using fluorescence cell coculture test, and compound 1 was selective in the breast cancer model. Structure–activity relationship analysis was performed within three rounds of optimization with rational synthesis of derivatives. Reduction of the carbonyl group to hydroxyl and incorporation of a dioxolane group into the spirocyclohexane ring reduced toxicity toward noncancerous VA13 and MCF10A cells. The lead compound 42 with this elaborated structure exhibited cytotoxicity against MCF7 cells (IC50 ≈ 3.8 μM) and remained significantly less cytotoxic to both noncancerous cells. It highlights the potential of spirocyclic-fused chroman-4-ones as selective cytotoxic agents through rigidifying the molecular scaffold and precisely tuning the functional group positioning.

Inhibitors of voltage-gated sodium channel 1.8 (NaV1.8) are anticipated to provide opioid-free treatment for acute pain and potentially chronic neuropathic pain. Herein, we report on the discovery of a novel series of NaV1.8 inhibitors characterized by high selectivity over other sodium channels. Utilizing a pharmacophore model trained on literature data, we identified the initial hit compound 1 through virtual screening. During the hit-to-lead optimization phase, we improved the potency and clearance of the lead compounds. Structural modifications and control of lipophilicity and other physicochemical parameters resulted in a favorable in vitro safety and drug–drug interaction profile for compound 24. Key to optimizing the clearance was the identification of a metabolic hotspot via metabolite identification (MetID) experiments. The lead compound 24 exhibited a long in vivo half-life and high exposure (Kp,uu) in the pain-relevant target tissue (DRG) in rat PK studies. These findings highlight potential of these compounds for further optimization as nonopioid therapeutics.

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...

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.

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...

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.

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...

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 ...

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.

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...

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...

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.

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.

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...

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...

About | 全球健康药物研发中心

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.

Kinesin spindle protein (KSP) represents a promising target for cancer therapy with a mechanism of action distinct from conventional microtubule agents. We previously identified S-trityl-L-cysteine (S...

The M1 receptor has long been investigated as a promising CNS drug target, yet further research is essential to fully elucidate compound’s Pharmacodynamic (PD) as well as Toxicokinetic (TK) effects. I...

Ferrocenyl–cyclo-(Gly-l-Pro) hybrids as novel inhibitors of ABCB1 and ABCG2 transporters were developed. These organometallic compounds were virtually nontoxic to colon cancer cells, their multidrug-r...

Targeting the capsid protein of the hepatitis B virus (HBV) has emerged as a promising strategy for developing new antiviral therapies. In this study, we report the discovery of a novel series of pyrrole oxo-carboxamide compounds as HBV capsid assembly modulators (CAMs) that block viral replication. Through a process of focused structure–activity relationship (SAR) optimization, we identified compound 12 (VNRX-9945), which exhibited excellent and broad antiviral activity against multiple HBV genotypes in vitro, along with favorable pharmacokinetic profiles across multiple species. Additionally, 12 demonstrated robust efficacy in the adeno-associated virus mouse model of HBV (AAV-HBV) infection. This compound has advanced into Phase 1 clinical trials to evaluate its safety and pharmacokinetics in healthy volunteers, to enable treatment of chronic HBV infections.

This study presents the chemical synthesis and biological evaluation of a series of gold(I)-N-heterocyclic carbene complexes as potential anticancer agents. The compounds demonstrated broad activity a...

Here we harnessed the unexplored binding interface between the 16-residue peptide (P) agonist and death receptor 5 (DR5). P is a solitary peptide ligand that mimics TRAIL (the natural ligand to death receptor) and is reported to control cancer growth in vivo selectively. We delved into the strategic merging of experimental and in silico structure–activity studies via the alanine scanning mutagenesis of P, wherein the disulfide bond was kept intact for structural integrity. Antiproliferative activity studies with these synthetic mutants on HCT116 cells enabled the mapping of the interaction engagement of each residue. Further, in silico docking and MD simulations led us to interpret and model the 3D interface of the binding site. Notably, Trp1, Leu4, Arg7, Ile8, Gln12, and Arg15 were projected experimentally as “hot-spot” residues crucial for primary interactions with DR5, which is predominantly supported via in silico investigations. This study is pivotal for developing new-generation peptide agonists that induce death receptor-mediated apoptosis.

Gastrin-releasing peptide receptor (GRPR) is a promising target for cancer radiotheranostics combining nuclear imaging with targeted radionuclide therapy. Improving the accumulation of radioligands in...