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

Bheka Thina (“Look At Us”): The Emergence of an Integrated Drug Discovery Ecosystem in South Africa

📢 In #ACSMedChemLett, Woodland, Veale and Chibale trace the evolution of #drugdiscovery in South Africa—from roots in natural products chemistry to an integrated modern discovery ecosystem—and reflect on how @pubs.acs.org has supported the field as @acs.org turns 150 🌍 pubs.acs.org/doi/full/10....

Optimizing Drug Discovery in Resource-Limited Settings: Multi-Parameter Optimization and Data-Driven Workflows The discovery of novel chemical entities for therapeutic use is a resource-intensive process. Given the constraints of drug discovery resources, it is crucial to allocate assets thoughtfully. This stu...

#Drugdiscovery is costly! 💸 Nchinda and Menzel's new Microperspective in #ACSMedChemLett maps gaps in resource-limited labs and proposes a workflow using free tools to efficiently guide chemical entities through data-driven decision-making processes: pubs.acs.org/doi/10.1021/...

💊 In #ACSMedChemLett, Mmonwa et al. report a human PDGFRA kinase inhibitor with potent antiplasmodium activity. Medicinal chemistry optimisation improved potency, selectivity and ADME, yielding compounds that inhibit haemozoin formation and kill late-stage parasites: pubs.acs.org/doi/10.1021/...

A Novel Class of Orally Bioavailable Phenylglycine–Benzoxaborole Conjugates with Antimalarial Activity and Potentially Novel Mechanism of Action A new class of benzoxaboroles with a phenylglycine appendage was found to display in vitro blood stage activity against the human malaria parasite Plasmodium falciparum (Pf). Structure–activity relati...

📢 Now out in #ACSMedChemLett! Morake et al. show that phenylglycine-based benzoxaboroles show potent in vitro activity against the human #malaria parasite with good selectivity, solubility, metabolic stability and encouraging in vivo efficacy in mice 🐭 pubs.acs.org/doi/full/10....

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

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

Make a nomination! The 2026 Philip A. Portoghese Early Career Award for the Advancement of Medicinal Chemistry recognizes two outstanding early career investigators in the field of medicinal chemistry research.

The deadline for nomination is December 1, 2025. Thank you! #ACSMedChemLett #JMedChem

Pharmacophore-Based Structure Optimization of S-Trityl-l-Cysteine Derivatives for Cytotoxic Payload Applications 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...

In #ACSMedChemLett, Ichida et al. report diverse new S-trityl-L-cysteine derivatives as inhibitors of kinesin spindle protein (a promising cancer target), including feasibility studies as cytotoxic payloads for antibody-drug conjugates pubs.acs.org/doi/10.1021/...

Discovery of a Novel sp3-Rich M1 Positive Allosteric Modulators (PAMs) Chemotype via Scaffold Hopping 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...

The M1 receptor is a promising CNS drug target. In #ACSMedChemLett, Bungard et al. reveal an sp3-rich N-cyclopentyl pyrazole-based M1 positive allosteric modulator scaffold – a useful SAR starting point for structurally distinct chemotypes. pubs.acs.org/doi/10.1021/...

Design, Synthesis, and Biological Evaluation of Ferrocenyl–Cyclo-(Gly-l-Pro) Hybrids Sensitizing Multidrug-Resistant Cancer Cells to Anticancer Agents 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...

Recently reported in #ACSMedChemLett, Błauż et al. synthesised and investigated a series of ferrocenyl–cyclo-(Gly-L-Pro) hybrids which were shown to sensitise multidrug-resistant cancer cells to anticancer agents

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

#CancerResearch #DrugResistance

Peptidylarginine Deiminase (PAD) Inhibitor Optimization through Displacement of a Trapped Water Molecule Excess protein citrullination, a post-translational modification converting arginine to citrulline, has been associated with a range of autoimmune and neurological disorders, as well as cancers. Prote...

What a great team this was here at #PfizerChemistry! Discovery of an allosteric PAD2/4 inhibitor that kicks out an embedded water and opens up additional binding pocket – fun synthetic project this one was #ACSMedChemLett asap #ChemSky

Discovery of VNRX-9945, a Potent, Broadly Active Capsid Assembly Modulator as a Clinical Candidate for the Treatment of Chronic Hepatitis B Virus Infection 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.

In #ACSMedChemLett Liu et al. report a compound (VNRX-9945) with excellent antiviral activity against multiple #hepatitisBvirus genotypes in vitro, favourable PK profiles across multiple species, and efficacy in a mouse model of disease. pubs.acs.org/doi/10.1021/... #MedicinalChemistry #KellyChibale

#CancerResearch #DrugDiscovery #MedicinalChemistry #TubulinInhibitors #ColchicineSite #TargetedTherapy #InnovativeScience #ACSMedChemLett #ACSBioMed #ProdrugDevelopment

VanNatta et al. report in #ACSMedChemLett their SAR studies on potent colchicine site inhibitors of tubulin polymerisation. Efficacy studies of the corresponding prodrug salts demonstrated the potential of these analogues as cancer therapies. pubs.acs.org/doi/10.1021/...

Gold(I) N-Heterocyclic Carbene Complexes as Ferroptosis Inducing Anticancer Agents 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...

In #ACSMedChemLett, Schlegel et al. report the synthesis and evaluation of gold(I)-N-heterocyclic carbene complexes as potential anticancer agents, representing the first example of a gold(I)-N-heterocyclic carbene complex inducing ferroptosis

Full article here: pubs.acs.org/doi/10.1021/...

Introducing the Potential Binding Interface between the TRAIL-Mimicking Peptide and DR5 via Alanine Scan 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.

Introducing the potential binding interface between a TRAIL-mimicking peptide and DR5 via alanine scan. Tripathi et al. used experimental + in silico methods to learn how this 16-residue peptide binds to the death receptor DR5.
pubs.acs.org/doi/10.1021/... #CancerResearch #ACSMedChemLett

Development of Novel Gastrin-Releasing Peptide Receptor-Targeted Radioligand with Albumin Binder to Improve Accumulation in Tumor 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...

Gastrin-releasing peptide receptor is a promising target for #cancer #radiotheranostics.

In #ACSMedChemLett, Tsuchihashi et al. report a novel GRPR-targeted radioligand with favourable pharmacokinetics & a high-level accumulation in tumours.

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

#OncologyInnovation

Development of a Cyclic TMTP1-Based PET Probe for Visualization of Hepatocellular Carcinoma TMTP1 is a tumor-homing peptide that selectively targets highly metastatic tumor cells with XPNPEP2 identified as its potential targeting receptor. Although TMTP1-based molecular probes have been expl...

Targeting amino acids other than Cys, Ser & Thr is an emerging strategy in covalent probe design. This study by Doak et al. in #ACSMedChemLett describes the reaction between a novel allene warhead and a His residue in the E. coli DsbA enzyme. Read here: pubs.acs.org/doi/10.1021/... #DrugDiscovery

An Estrogen Receptor β Agonist with AR Antagonist Activity from a Modern Asymmetric De Novo Steroid Synthesis While the androgen receptor (AR) has long been a molecular target of prostate cancer therapeutics, the estrogen receptor β (ERβ) has more recently become of interest in this area of chemotherapeutic s...

The oestrogen receptor β (ERβ) is a promising drug target for #tumoursuppression.

In #ACSMedChemLett, Bucknam et al. describe the power of modern asymmetric de novo synthesis of estranes to identify potent and selective agonists of ERβ

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

Heteroaryl Glutarimides and Dihydrouracils as Cereblon Ligand Scaffolds for Molecular Glue Degrader Discovery Stabilization of cereblon (CRBN)/neosubstrate complexes with molecular glues followed by degradation of those neosubstrates is an emerging strategy in drug discovery with compelling potential to target certain proteins that were previously considered to be undruggable. In this context, the discovery of novel CRBN ligands is an important area of ongoing research that holds promise to expand the scope of proteins that can be targeted through this mode of action. Herein, we describe the synthesis and evaluation of CRBN ligands featuring heteroaryl glutarimide and dihydrouracil scaffolds. We identified a subset of heteroaryl glutarimides exhibiting potent CRBN binding and increased chemical stability in cell culture media compared with traditional immunomodulatory drugs (IMiDs). This indicates that the scaffolds described herein could become useful starting points for the discovery of novel molecular glue degraders.

Cool work by Genentech. Lots of new and improved imides for PROTAC and glues to try out. pubs.acs.org/doi/epdf/10.... #ACSMedChemLett