Laws M, Hind CK, Nahar KS
… +12 more, Clifford M, Marsh C, Al Adhami T, Louis B, Xu M, Alyemni SO, Haider S, Hassan M, Gargate N, Wand ME, Sutton JM, Rahman KM
We report a novel Efflux Resistance Breaker (ERB) strategy for designing antibiotics intrinsically resistant to efflux, using fluoroquinolones as a model class. ERB-modified fluoroquinolones showed enhanced intracellular...We report a novel Efflux Resistance Breaker (ERB) strategy for designing antibiotics intrinsically resistant to efflux, using fluoroquinolones as a model class. ERB-modified fluoroquinolones showed enhanced intracellular accumulation and markedly improved antibacterial activity, with up to 512-fold reduction in MIC (MIC 0.03-2 μg/mL) across multidrug-resistant bacteria. Lead compounds () and () demonstrated potent activity against MRSA, (including MDR and PRSP), and (VanA, VanB and VanD), as well as and . The compounds inhibited both wild-type and S84L mutant DNA gyrase (IC ∼ 3.8 μg/mL) and achieved a > 4-log bacterial load reduction in a murine thigh infection model at oral doses of 50 mg/kg. Favorable oral and intravenous PK/PD profiles, absence of toxicity at 1200 mg/kg/day, and no hERG, CYP450, or off-target liabilities were observed. ERB technology provides a promising strategy for designing antibiotics that are intrinsically less susceptible to efflux.
Natural products (NPs) and their derivatives have long been important components of antitumor drugs. Nevertheless, traditional natural product derivatives are generally limited by tumor-targeting deficiency and toxicity...Natural products (NPs) and their derivatives have long been important components of antitumor drugs. Nevertheless, traditional natural product derivatives are generally limited by tumor-targeting deficiency and toxicity to normal tissue. Particularly, there remains a lack of effective strategies to improve antitumor efficacy and reduce the toxicity of natural product derivatives. Herein, a series of heat shock protein 90 (Hsp90) inhibitor-evodiamine (an NP from ) conjugates were rationally designed, binding extracellular Hsp90 (eHsp90), which could mediate endocytosis to improve the antitumor efficacy of evodiamine derivatives. Notably, conjugate demonstrated a potent antitumor efficacy. It exhibited significant antiproliferative activity (IC = 7.7 nM) and high Hsp90 inhibitory activity (IC = 19.4 nM). Furthermore, conjugate achieved excellent tumor growth inhibition upon intraperitoneal injection (12 mg/kg; TGI = 72.9%) and oral administration (24 mg/kg; TGI = 61.2%).
The surge in multidrug-resistant (MDR) pathogens necessitates novel therapeutic strategies. Here, we report the rational design of C4-VG7, an -terminal butyrylated lipopeptide engineered from a compact, cationic, helix-c...The surge in multidrug-resistant (MDR) pathogens necessitates novel therapeutic strategies. Here, we report the rational design of C4-VG7, an -terminal butyrylated lipopeptide engineered from a compact, cationic, helix-compatible segment of the marine conotoxin αO-GeXIVA. Through stepwise structural optimization─from constrained cyclic prototypes to lipidated derivatives─C4-VG7 was identified as a lead candidate with potent, broad-spectrum activity against MDR ESKAPE pathogens, including clinical isolates (MIC ≈1 μM). Mechanistically, C4-VG7 exhibits multimodal bactericidal action: C4-tail-mediated membrane depolarization is consistent with early membrane disruption followed by intracellular DNA association and oxidative stress. In murine models of MRSA and infections (skin and peritonitis), C4-VG7 achieved efficacy comparable to polymyxin B with significantly reduced hepatonephrotoxicity. Thus, C4-VG7 represents a systemically viable, well-tolerated candidate for combating MDR ESKAPE infections.
Shikonin is a natural naphthoquinone with anticancer activity; however, its therapeutic potential is limited by modest potency and suboptimal drug-like properties. To address these limitations, we designed and synthesize...Shikonin is a natural naphthoquinone with anticancer activity; however, its therapeutic potential is limited by modest potency and suboptimal drug-like properties. To address these limitations, we designed and synthesized 31 shikonin derivatives through a medicinal chemistry hybridization strategy that retained the redox-active naphthoquinone core while introducing privileged structural motifs frequently associated with enhanced biomolecular interactions and cellular activity. Structure-activity relationship analysis identified compound as a lead, exhibiting approximately 10-fold greater antiproliferative potency than shikonin, with preferential sensitivity observed in gastric cancer cell lines relative to other tested cancer types and normal gastric epithelial cells. The anticancer activity of was further validated in a gastric cancer xenograft model in vivo. Proteomic profiling and mechanistic studies revealed activation of the integrated stress response (ISR) and reactive oxygen species (ROS) pathways, which were also enriched in gastric cancer data sets, leading to the induction of both apoptosis and ferroptosis. Collectively, these findings establish a structure-dependent optimization of shikonin-derived naphthoquinones and identify as a promising lead compound for further development of redox-active anticancer agents.
BRD9, a distinctive subunit of the ncBAF complex, is a critical regulator of acute myeloid leukemia (AML). Here, we designed, synthesized, and evaluated a series of BRD9 PROTACs. Among them, compound () was identified a...BRD9, a distinctive subunit of the ncBAF complex, is a critical regulator of acute myeloid leukemia (AML). Here, we designed, synthesized, and evaluated a series of BRD9 PROTACs. Among them, compound () was identified as a highly potent and selective BRD9 degrader. efficiently induced BRD9 degradation in multiple AML cell lines, including MV4-11, MOLM-13, MOLM-16, Kasumi-1. Mechanistic studies revealed that induces BRD9 degradation in a time-, dose-, CRBN-, and proteasome-dependent manner. Notably, potently inhibited the proliferation of a panel of AML cell lines, with particularly strong activity observed in MV4-11 cells (IC = 33 nM). Administration of at 10 and 20 mg/kg (i.p.) achieved tumor growth inhibition (TGI) rates of 70 and 79%, respectively, with a favorable safety profile in the MV4-11 xenograft model. Collectively, these findings underscore the potent preclinical efficacy of and support its advancement as a promising therapeutic candidate for AML.
Pidoux N, Roh L, Nicolet N
… +14 more, Marti R, Le Rouzic A, Prompt C, Fix J, Duquerroy S, Rey F, Rameix-Welti MA, Keck M, Barbe P, Garcin D, Mottet-Osman G, Larcher T, Galloux M, Nyanguile O
Respiratory syncytial virus infection (RSV) is a major global health concern, particularly in infants and elderly populations. In this work, we have screened and identified 3 double-stapled peptides derived from a minima...Respiratory syncytial virus infection (RSV) is a major global health concern, particularly in infants and elderly populations. In this work, we have screened and identified 3 double-stapled peptides derived from a minimal domain of the RSV F heptad repeat, namely , , and , which are potent inhibitors of RSV fusion and remain active against viral escape mutants resistant to small-molecule fusion inhibitors. Our structural activity relationship (SAR) analysis demonstrates that combining a limited set of staples is sufficient to achieve high antiviral potency. X-ray crystallography revealed that the enhanced potency of and primarily arises from strong hydrophobic interactions between the N-terminal staple and the trimeric HR1 coiled coil of RSV F. pharmacokinetic, imaging, and feasibility studies in RSV-infected Balb/c mice further support intranasal administration as a promising route for delivering these stapled peptides to the lung, highlighting their potential as therapeutics against RSV.
Zhuo J, Li YL, Qian DQ
… +27 more, Burns DM, Mei S, Rafalski M, Xu M, Cao G, Pan Y, Jia Z, Jalluri R, Epling LB, Fenalti G, Deller MC, Procak J, Covington M, He X, Collins R, Stubbs M, Burke K, Oliver J, Margulis A, Boer J, Wynn R, Scherle P, Diamond S, Newton R, Zhang Y, Metcalf B, Yao W
Aberrant JAK2 signaling is a key driver in cancers such as myeloproliferative neoplasms (MPNs), whereas JAK1 acts as a central mediator of autoimmune and inflammatory diseases. Since JAK2 supports blood cell production,...Aberrant JAK2 signaling is a key driver in cancers such as myeloproliferative neoplasms (MPNs), whereas JAK1 acts as a central mediator of autoimmune and inflammatory diseases. Since JAK2 supports blood cell production, its inhibition can lead to anemia and other cytopenias, making selective JAK1 inhibition a potentially safer therapeutic strategy opposed to dual JAK1/JAK2 inhibition. We initially identified novel scaffold , which selectively inhibited JAK1 over JAK2. Iterative breakthroughs led to the discovery of povorcitinib (INCB054707, ), which showed improved pharmacokinetics due to intramolecular hydrogen bonding of the amide moiety and a reduced ring size in the hinge binding motif. Protein crystallography suggested that JAK1 selectivity was conferred by the amide's alkyl group accessing a small lipophilic groove formed by the P-loop conformation of JAK1 that was distinct from JAK2. In murine arthritis models, povorcitinib demonstrated dose-dependent efficacy and reduced inflammatory signaling, supporting its therapeutic potential in immunological disorders.
Covalent inhibition has re-emerged as a central strategy in drug discovery, yet most successes have focused on cysteine residues. Expanding covalent design to other nucleophilic amino acids offers new opportunities to ov...Covalent inhibition has re-emerged as a central strategy in drug discovery, yet most successes have focused on cysteine residues. Expanding covalent design to other nucleophilic amino acids offers new opportunities to overcome resistance, broaden ligandable targets, and modulate protein function beyond enzyme active sites. Among these, lysine is an attractive target due to its high abundance, structural diversity, and roles in catalysis and protein-protein interactions (PPIs). This Perspective advances recent insights into lysine-directed covalent chemistry, highlighting electrophilic warheads with tunable reactivity and selectivity, including activated esters, benzaldehyde derivatives, 2-formylphenylboronic acid, sulfur(VI) fluorides, and photoactivatable scaffolds. Representative applications in kinase inhibition, transthyretin stabilization, and PPI modulation illustrate the breadth of this approach. Emerging directions integrating reversible covalency and targeted degradation further underscore the potential of lysine covalency for next-generation covalent drug discovery. Challenges associated with lysine targeting, including achieving selectivity and minimizing off-target reactivity, are also briefly discussed.
Qi C, McCammant MS, Li Y
… +26 more, Zhu W, Yu Z, Carlsen P, Han H, Zhao L, Zhang F, Huang T, Gan P, Qian D, Hoang G, He C, Mei S, Harris JJ, Gallion A, Hansbury M, Mason J, Stump K, Kurzeja-Lipinski K, DiRamio A, Covington M, Koblish H, Diamond S, Wang H, Scherle P, Yao W, Wang X
Suppression of immune checkpoint pathways enables tumor cells to take over immunoregulatory functions, promoting cell growth and proliferation. Elevated adenosine production in the tumor microenvironment suppresses immun...Suppression of immune checkpoint pathways enables tumor cells to take over immunoregulatory functions, promoting cell growth and proliferation. Elevated adenosine production in the tumor microenvironment suppresses immune checkpoint control through activation of A adenosine receptors on immune cells. While A antagonists originally developed for CNS indications have entered oncology, their potency may be insufficient to challenge locally high adenosine concentrations within the tumor microenvironment for receptor occupancy. Here, we describe the discovery of INCB106385 (), a potent dual A/A antagonist identified from in-house screening efforts. Compound exhibits high potency at both receptors, favorable drug-like properties, and limited CNS penetration. In preclinical studies, it demonstrated robust pharmacokinetics across species and significant efficacy in a multiday CT26 mouse colon carcinoma model. These findings supported the advancement of INCB106385 into Phase 1 clinical trials (NCT04580485, NCT04989387) for cancer immunotherapy.
Josien H, Nair AG, Ding FX
… +39 more, Guo Y, Chen YH, Rao AU, Liu J, Tong L, Sun Z, Lo MM, Tucker TJ, Embrey MW, Shahripour A, Wu C, Bianchi E, Branca D, Kuethe JT, Lee J, Thaisrivongs DA, Bulger PG, Zhu X, Ha SN, Johnston JM, Klein DJ, Orth P, Hong MR, Buevich AV, Gao Q, Zokian HJ, Koeplinger KA, Tracy RW, Hafey MJ, Buist N, Bueters T, Alleyne C, Bass A, Campeau LC, Johns DG, Garbaccio RM, Vachal P, Walji A, Wood HB
Herein, we report the discovery process of enlicitide (MK-0616, compound ), an orally active macrocyclic peptide therapeutic against PCSK9 for LDL-C reduction. To overcome development bottlenecks in a prior lead (compoun...Herein, we report the discovery process of enlicitide (MK-0616, compound ), an orally active macrocyclic peptide therapeutic against PCSK9 for LDL-C reduction. To overcome development bottlenecks in a prior lead (compound ) in a timely manner (sulfur oxidation liability, low solubility, azido potential manufacturing hazard, and alkene isomeric complexity), we deployed a novel scalable solution-phase modular fragment assembly (North/East/South/West/tail), which allowed us to accelerate the design-make-test-analyze (DMTA) cycle and preclinical profiling. Design solutions were quickly validated through this approach (a northern lactam staple, an -benzylamide southern spacer, an RCM-derived cross-link in conjunction with solvent-exposed motifs to modulate solubility) and delivered compounds with low picomolar potency, improved solubility, stability, and PK from which enlicitide (MK-0616, compound ) was selected for clinical progression. This modular strategy may act as a template to accelerate late-stage issue-driven SAR in highly engineered macrocyclic peptides.
G protein-coupled receptor 52 (GPR52) has been identified as a promising therapeutic target for the treatment of schizophrenia, psychiatric disorders, and other human neurological diseases. A series of novel 2,3-disubsti...G protein-coupled receptor 52 (GPR52) has been identified as a promising therapeutic target for the treatment of schizophrenia, psychiatric disorders, and other human neurological diseases. A series of novel 2,3-disubstituted pyrazine derivative GPR52 agonists have been designed, synthesized, and biologically evaluated. Through the exploration of the structure-activity relationship, several potent GPR52 agonists (, , , and ) were identified, with EC values in the nanomolar range (26-70 nM). Further studies on indicate that it has excellent pharmacokinetic properties in mice and rats, as well as brain permeability (brain/plasma ratio = 1.6 and 3.1, respectively). , compound () significantly inhibits MK-801-induced hyperlocomotor behaviors in zebrafish larvae and mice. Overall, our research results have identified an effective, orally bioavailable, and brain-permeable GPR52 agonist (), which is a promising candidate for the development of antischizophrenia drugs.
The receptor tyrosine kinase-like orphan receptor 1 (ROR1) is aberrantly overexpressed in multiple malignancies and has emerged as a clinically relevant biomarker for tumor staging and therapeutic decision-making. Here,...The receptor tyrosine kinase-like orphan receptor 1 (ROR1) is aberrantly overexpressed in multiple malignancies and has emerged as a clinically relevant biomarker for tumor staging and therapeutic decision-making. Here, we developed a series of PR7-derived ROR1-targeted radiotracers, including linear and cyclic analogues, and systematically evaluated their specificity and . All radiotracers showed high stability in saline and fetal bovine serum for at least 90 min and rapid tumor accumulation within 30 min post-injection in MC38 tumor-bearing mice. Among them, [Ga]Ga-LP4 achieved favorable tumor targeting and tumor-to-nontumor ratios in PET imaging with predominant renal clearance. Notably, compared with [F]AlF-NP1 reported in our previous study, [Ga]Ga-LP4, which incorporates -methylation and carboxyl amidation, demonstrated improved metabolic stability. Collectively, these findings identify [Ga]Ga-LP4 as a promising ROR1-targeted imaging probe and highlight useful peptide optimization strategies.
The management of hyperuricemia and gout remains constrained by the narrow therapeutic index of current drugs. To improve the druggability of our previously identified URAT1 inhibitor , we replaced its carboxylic acid wi...The management of hyperuricemia and gout remains constrained by the narrow therapeutic index of current drugs. To improve the druggability of our previously identified URAT1 inhibitor , we replaced its carboxylic acid with a sulfonamide group. A total of 40 novel derivatives were synthesized, among which 23 derivatives exhibited robust serum uric acid-lowering activity. Lead compound (bearing a -bromobenzenesulfonamide) exhibited potent URAT1 inhibition (IC = 0.19 μM) and significantly lowered serum uric acid in hyperuricemic mice (96.8% reduction) and rats (91.9% reduction). Notably, compound also inhibited IL-1β activity (IC = 3.39 μM), which may enhance its therapeutic potential in gout by targeting disease-associated inflammation. Compound demonstrated favorable pharmacokinetics (half-life: 6.3 h, oral bioavailability: 20.1%) and high safety (MTD > 1000 mg/kg). These results establish compound as a promising dual-acting candidate for gout therapy.
ENPP1 is emerging as a potential target for cancer immunotherapy due to its negatively regulatory effect on the STING pathway via hydrolysis of cGAMP. Herein, we report the identification and optimization of compound st...ENPP1 is emerging as a potential target for cancer immunotherapy due to its negatively regulatory effect on the STING pathway via hydrolysis of cGAMP. Herein, we report the identification and optimization of compound starting from hit compound . is a potent and selective ENPP1 inhibitor featuring a novel pyrrolo[1',2':1,6]pyrimido[5,4-]pyridazin-6(5)-one core scaffold. It exhibited substantial inhibitory activity against ENPP1 with an IC value of 9.5 nM, while showing weak inhibition against ENPP2/3. In the cGAMP-mediated STING pathway, this compound effectively enhanced the expression of downstream genes and promoted the phosphorylation of the relevant protein. Moreover, it displayed favorable pharmacokinetic properties and no evident cytotoxicity. In a 4T1 syngeneic mouse model, oral administration of compound demonstrated significant antitumor effects and enhanced the efficacy of both anti-PD-1 antibody and chemotherapy, with good tolerability. Collectively, these results highlight the potential of compound to potentiate STING-mediated antitumor immunity.
Recently, bioorthogonal reactions have been widely applied in drug delivery. However, conventional bioorthogonal reactions, such as the uncontrollable coupling between tetrazine (TZ) and -cyclooctene (TCO), lack effectiv...Recently, bioorthogonal reactions have been widely applied in drug delivery. However, conventional bioorthogonal reactions, such as the uncontrollable coupling between tetrazine (TZ) and -cyclooctene (TCO), lack effective control. To address this, we designed a light-triggered bioorthogonal system, enabling spatiotemporal control. Upon 2 min irradiation with a blue LED (20 W), was fully released from . It subsequently reacted with TCO-conjugated probes () and prodrugs (), enabling bioimaging and active drug release (). Meanwhile, exhibited greater cell permeability, leading to consistently higher intracellular concentrations both in vitro and in vivo post-TZ reactions. This strategy presents a promising approach to circumvent the existing efficacy and toxicity limitations of -mediated chemoimmunotherapy. Consequently, the tumor-specific accumulation of potently inhibited cell proliferation and potentiated tumor immune response in both cellular and animal models. Collectively, this work presents a feasible and effective therapeutic regimen.
Biofilm-related infections pose a growing global health threat and demand novel therapeutic agents. Although Daptomycin is effective against Gram-positive bacteria and biofilms, the emergence of resistant strains necessi...Biofilm-related infections pose a growing global health threat and demand novel therapeutic agents. Although Daptomycin is effective against Gram-positive bacteria and biofilms, the emergence of resistant strains necessitates next-generation derivatives. Herein, a library of aryl-Daptomycin was successfully constructed by postmodification of Daptomycin at the tryptophan residue. The lead compound exhibited improved antibacterial activity, antibiofilm efficacy, and stability compared with Daptomycin, and also showed rapid killing of both planktonic and persister cells. studies, significantly reduced drug-resistant bacterial counts and biofilm burdens in mouse models of skin wound infection and catheter-related biofilm infection. Mechanistic studies revealed that it exerts antibacterial activity by inducing membrane depolarization and disruption, while it inhibits biofilm formation by downregulating the gene and blocking the system. Moreover, molecular dynamics simulations confirmed the higher tetrameric stability of compared with Daptomycin. Collectively, represents a promising candidate for clinical treatment of bacterial infections.
This work performed a unique conjugation of metronidazole with berberine via thiazolidinedione to afford a novel structural skeleton of metronidazolyl vinylthiazolidionyl tetrahydroberberines (MVTs) with multitargeting a...This work performed a unique conjugation of metronidazole with berberine via thiazolidinedione to afford a novel structural skeleton of metronidazolyl vinylthiazolidionyl tetrahydroberberines (MVTs) with multitargeting antibacterial potential to conquer bacterial resistance. Most of the prepared MVTs exhibited an effective activity against most of the tested bacteria. Notably, butyl MVT (MIC = 0.005 mM) demonstrated the strongest antibacterial activity against 25923, being 3- and 69-fold more active than norfloxacin and berberine, respectively. Low hemolysis, cytotoxicity, and drug resistance, effective biofilm eradication, and efficient transport by human serum albumin suggested the favorable druggability of MVT . Highly active MVT could cause bacterial death through multitargeting effects, including disrupting the bacterial membrane, triggering oxidative stress, and intercalating into DNA without cleaving DNA. Moreover, MVT was more potent than norfloxacin against 25923. These medicinal chemobiological investigations demonstrated MVTs as potential multitargeting antibacterial candidates for alleviating bacterial resistance.
Fiore A, Scarano A, Antonini G
… +16 more, Corfù AI, Sicuro L, Faggiano S, Celesia A, Tesoriero C, Pacchiana R, Vettori A, Arslanbaeva L, Minucci S, Pallavicini I, Mollica L, Tamborini L, Donadelli M, Conti P, Bruno S, Borsari C
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer, driven by metabolic reprogramming. Since direct glycolytic enzyme inhibition is limited by toxicity, indirect glycolysis modulation through inhibition of t...Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer, driven by metabolic reprogramming. Since direct glycolytic enzyme inhibition is limited by toxicity, indirect glycolysis modulation through inhibition of the kinase activity of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) may offer a safer therapeutic strategy. Herein, we report the first-in-class covalent PFKFB3 inhibitor (), targeting a previously unexplored cysteine. Enzyme assays, site-directed mutagenesis, and mass spectrometry confirmed covalent binding and kinetic selectivity for PFKFB3. Compound reduced viability across multiple PDAC cell lines and suppressed PDAC growth in zebrafish xenografts. Its combination with standard chemotherapeutics revealed synergistic effects. Although the limited cellular activity of restricts its use as a chemical probe in biological studies, we proved for the first time the druggability of a previously unexplored cysteine in PFKFB3. Our work represents a significant achievement in the selective targeting of this kinase, paving the way for an innovative mechanism of action for PFKFB3 inhibitors.