Verma VA, Grandner JM, Parr BT
… +32 more, Zeng M, Ashley M, Wang Y, Beroza P, Carione P, Johnson KM, Oh AJ, Murray JM, Kiefer JR, Moffat JG, Prangley M, Merrick K, Vartanian S, Hafner M, Orr CJ, Segal E, Levy ES, Wang J, Xu Z, Wang S, Liu G, Niu Y, Li X, Zhang Q, Ma Z, Sun M, Wu Z, Zhao W, Li Y, Zhang L, Magnuson SR, Samy KE
Targeting HR-positive breast cancer via the inhibition of CDK4 and CDK6 has become the standard of care. However, progression inevitably occurs, and emerging data suggest the implication of CDK2 in this resistance mechan...Targeting HR-positive breast cancer via the inhibition of CDK4 and CDK6 has become the standard of care. However, progression inevitably occurs, and emerging data suggest the implication of CDK2 in this resistance mechanism. As part of our efforts to target this resistance, we embarked on a medicinal chemistry campaign to selectively inhibit CDK2 over the broadly essential CDK1. In order to obtain selectivity against CDK1, we utilized a molecular dynamics approach focused on interaction with a conserved lysine in the active site. Additionally, we uncovered a unique mechanism of clearance driven by both metabolism and efflux in rats and demonstrated that we could counter efflux-driven clearance with high permeability. Our efforts resulted in compound , which was potent against CDK2, exhibited good selectivity vs CDK4 and CDK1, and had pharmacokinetic properties that enabled evaluation in a CDK2 xenograft model of cancer, where it achieved nearly 80% tumor growth inhibition.
Inhibition of the Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2) represents a promising therapeutic strategy for cancer. However, resistance to SHP2 inhibition, mediated by multiple mechanisms, ha...Inhibition of the Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2) represents a promising therapeutic strategy for cancer. However, resistance to SHP2 inhibition, mediated by multiple mechanisms, has limited the clinical efficacy of SHP2 inhibitor monotherapy. Herein, we identified that nicotinamide phosphoribosyltransferase (NAMPT) inhibition could potentially overcome resistance to SHP2 inhibition in tumor cells. Compound was identified as the most potent dual inhibitor targeting SHP2 and NAMPT, exhibiting high inhibitory activity against both SHP2 and NAMPT. effectively inhibited proliferation in -insensitive tumor cell lines and reversed programmed cell death ligand 1 (PD-L1)-mediated immunosuppression. Furthermore, displayed significant antitumor efficacy in an MDA-MB-231 mouse model and strongly promoted antitumor immunity in a 4T1 mouse model. Our results identified as a promising dual SHP2 and NAMPT inhibitor, providing a novel therapeutic strategy for overcoming resistance to allosteric SHP2 inhibition.
Yin J, Srivastava S, Tang X
… +15 more, Galbraith C, Uchenunu O, Miller J, Liu Y, Crescenzi I, Kiyota T, Kurinov I, Costa-Mattioli M, Laufer R, Aman A, Rottapel R, Ramnauth J, Haakonsen DL, Uehling DE, Sicheri F
The RNA-dependent protein kinase PKR regulates responses to viral infection and has emerging roles in memory formation. Inhibition of PKR enhances long-term memory in mice and reverses cognitive decline in models of agin...The RNA-dependent protein kinase PKR regulates responses to viral infection and has emerging roles in memory formation. Inhibition of PKR enhances long-term memory in mice and reverses cognitive decline in models of aging and Alzheimer's disease. However, existing PKR inhibitors have poor selectivity and pharmacokinetic properties, limiting therapeutic development. Here, we describe the transformation of dabrafenib, an FDA-approved oncogenic BRAF inhibitor, into a selective PKR inhibitor. Dabrafenib was identified by screening as a promising PKR lead with similar potency against BRAF and PKR. Guided by X-ray cocrystal structures, we introduced modifications that removed BRAF while retaining PKR inhibition. This optimization yielded , which shows markedly reduced BRAF activity, improved PKR selectivity (IC > 10,000 nM against BRAF vs IC = 263 nM against PKR ), and minimal activity against related eIF2α kinases in cells. These findings establish as a promising chemical starting point for further PKR inhibitor optimization.
Endoplasmic reticulum aminopeptidase 1 (ERAP1) regulates immune responses by proteolytically processing peptides presented by major histocompatibility class I molecules (MHC-I). ERAP1 can reduce the immunogenicity of can...Endoplasmic reticulum aminopeptidase 1 (ERAP1) regulates immune responses by proteolytically processing peptides presented by major histocompatibility class I molecules (MHC-I). ERAP1 can reduce the immunogenicity of cancer cells by destroying cancer-associated antigenic peptides or contribute to autoimmunity by generating self-antigenic peptides. ERAP1 inhibition has emerged as a tractable approach for cancer immunotherapy and specific classes of autoimmune diseases. We describe the discovery of a potent and selective ERAP1 inhibitor that targets its regulatory allosteric site. The compound has favorable pharmacokinetics, oral bioavailability, can regulate the immunopeptidome of cancer cells, and enhance tumor antigenicity controlling growth. When administered in the murine collagen-induced arthritis model, we observed no exacerbation of autoimmune responses but rather a dose-dependent therapeutic benefit. Our results demonstrate that ERAP1 inhibition is a tractable approach to modulating immune responses, provide mechanistic insight, and are valuable tools for interrogating ERAP1 biology and further drug development.
Artificial intelligence is increasingly applied in early drug discovery to accelerate hit identification and reduce costs. In this study, we implemented an AI-driven design workflow using REINVENT to generate novel anta...Artificial intelligence is increasingly applied in early drug discovery to accelerate hit identification and reduce costs. In this study, we implemented an AI-driven design workflow using REINVENT to generate novel antagonists for the A adenosine receptor, a validated target for neurodegenerative diseases. The approach combined ligand-based and structure-based components with pharmacokinetic considerations, including blood-brain barrier permeability, within a multiparameter optimization scoring function. Two generative runs were performed: the first, with balanced scoring weights, yielded inactive 1,2,4-triazole derivatives, while an alternative filtering pipeline identified a micromolar hit. A second run emphasizing structural constraints and key receptor interactions produced three active compounds with nanomolar affinity and predicted CNS permeability. These findings highlight the critical role of scoring function parametrization and filtering strategies in AI-driven drug design and demonstrate the potential of reinforcement learning to explore chemical space for CNS-targeted ligands.
Antimicrobial peptides (AMPs), distinguished by their broad-spectrum antibacterial activity and low propensity to induce antibiotic resistance, show the promising potential for infectious diseases. However, the direct de...Antimicrobial peptides (AMPs), distinguished by their broad-spectrum antibacterial activity and low propensity to induce antibiotic resistance, show the promising potential for infectious diseases. However, the direct development of AMPs into therapeutics remains challenging due to their poor proteolytic stability and limited in vivo antibacterial activity. This study employed our pioneering solid-phase and side-chain guanidyl-construction (SSG) stapling technique to systematically screen and modify the natural AMP Aurein1.2, resulting in a series of guanidyl-stapled peptides A1 to A9. The optimal guanidyl-stapled peptide A4 exhibited the significantly improved α-helical content and proteolytic stability than the linear counterpart, as well as potent in vitro antibacterial activity and acceptable hemolysis. Importantly, A4 demonstrated markedly enhanced therapeutic performance for the treatment of the infected wound on mice, highlighting its strong potential as the next-generation antimicrobial agent.
In recent years, controllable targeted protein degradation has emerged as an innovative chemical tool and therapeutic strategy for drug discovery. As a spatiotemporally precise alternative to conventional PROTACs, ROS-me...In recent years, controllable targeted protein degradation has emerged as an innovative chemical tool and therapeutic strategy for drug discovery. As a spatiotemporally precise alternative to conventional PROTACs, ROS-mediated controllable targeted protein degradation has attracted growing attention. This Perspective outlines the design principles, mechanisms, and representative advances of photodynamic, photothermal, and sonodynamic ROS degraders. We critically assess their druggability advantages, clinical translation barriers and limitations, while providing forward-looking insights into rational design and therapeutic applications. We aim to provide a medicinal chemistry-focused guidance for the development of next-generation controllable targeted protein degradation platforms.
Liver fibrosis is an urgent clinical condition that lacks effective therapies. In this study, molecular networking-guided fractionation of the medicinal plant yielded a focused jatrophane diterpenoid library (-), featur...Liver fibrosis is an urgent clinical condition that lacks effective therapies. In this study, molecular networking-guided fractionation of the medicinal plant yielded a focused jatrophane diterpenoid library (-), featuring 26 previously undescribed structures. Subsequent antifibrotic screening of this library in TGF-β1-stimulated hepatic stellate cells (HSCs) identified euphylonoid D () as a novel hit, enabling a preliminary structure-activity relationship (SAR) analysis of this class. In a CCl-induced mouse model, significantly alleviated liver fibrosis while exhibiting a favorable safety profile. Mechanistic studies revealed that acts as the first small-molecule inhibitor of Jagged-1 (JAG1), a classic Notch ligand, thereby suppressing Notch signaling, leading to the attenuation of liver fibrosis. These findings not only validate JAG1 as a therapeutic target for liver fibrosis but also highlight as a promising lead for developing novel antifibrotic agents.
GPR3, GPR6, and GPR12 form a subfamily of Class A orphan G protein-coupled receptors (oGPCRs), for which endogenous ligands have not been identified. Despite their high sequence similarity, each receptor exhibits unique...GPR3, GPR6, and GPR12 form a subfamily of Class A orphan G protein-coupled receptors (oGPCRs), for which endogenous ligands have not been identified. Despite their high sequence similarity, each receptor exhibits unique expression profiles in human tissues. Their physiological roles and therapeutic potential are gradually being understood, indicating their critical involvement in various diseases, including central nervous system (CNS) disorders, metabolic diseases, and cancer. Notably, the GPR6 inverse agonist CVN424 is currently in Phase III clinical trials for the treatment of Parkinson's disease (PD). The recent determination of high-resolution structures of GPR3, GPR6, and GPR12 has significantly enhanced their attractiveness as emerging therapeutic targets for drug discovery. Herein, we summarize the current understanding of the structural and functional characteristics of GPR3, GPR6, and GPR12. We further highlight recent progress in relevant ligand discovery and discuss the key challenges and opportunities in developing potent and selective modulators targeting these orphan receptors.
Metabolic alterations, including aerobic glycolysis and oxidative phosphorylation (OXPHOS), drive the progression of FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD)-mutated acute myeloid leukemia (AML)...Metabolic alterations, including aerobic glycolysis and oxidative phosphorylation (OXPHOS), drive the progression of FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD)-mutated acute myeloid leukemia (AML) and have emerged as attractive therapeutic targets. Histone deacetylases (HDACs) play a key role in these metabolic processes by regulating acetylation modifications of histones and nonhistone proteins. Herein, a series of novel benzimidazole derivatives were designed and synthesized based on the target structure. Among them, compound exhibited potent inhibitory activity and selectivity for class I HDACs. Notably, the combination of and the FLT3 inhibitor quizartinib showed significant synergistic antiproliferative effects both in vitro and in vivo. Mechanistic studies showed that this combined strategy could simultaneously inhibit glycolysis and OXPHOS by blocking the PI3K/AKT signaling pathway, ultimately exerting antitumor activity. In summary, this study highlights as a potential metabolic regulator and provides a promising therapeutic strategy for AML.
Parkinson's disease (PD) therapy remains limited by complications of the levodopa regimen, highlighting the need for novel therapeutic strategies to modulate dopaminergic signaling. Melanostatin (MIF-1) has attracted att...Parkinson's disease (PD) therapy remains limited by complications of the levodopa regimen, highlighting the need for novel therapeutic strategies to modulate dopaminergic signaling. Melanostatin (MIF-1) has attracted attention as a privileged scaffold for dopamine D receptor (DR) modulation due to its intrinsic positive allosteric modulatory activity, although improved potency and drug-like properties are required for translation. In this work, nicotinic acid (Nic), a vitamer of vitamin B, was employed as a proline (Pro) bioisostere, generating 12 vitamin B-MIF-1 hybrids. Nicotinoyl-l-leucylglycinamide () emerged as a lead compound, promoting a 5.11-fold enhancement of dopamine potency at 0.01 nM and displaying neuroprotective activity at 50-100 μM in dopaminergic-differentiated SH-SY5Y cells. Additionally, Pro-to-Nic substitution showed no cytotoxicity in HepG2, reduced P-glycoprotein-mediated efflux, and preserved β-turn conformational propensity, supporting improved oral drug-like properties. Collectively, these findings identify as a dual-acting lead and establish Nic as a privileged Pro surrogate for next-generation MIF-1-based PD therapeutics.
Dysregulation of PRMT1, a key epigenetic enzyme, is strongly implicated in breast cancer pathogenesis. However, developing selective PRMT1 inhibitors has been challenging due to the high conservation of the catalytic dom...Dysregulation of PRMT1, a key epigenetic enzyme, is strongly implicated in breast cancer pathogenesis. However, developing selective PRMT1 inhibitors has been challenging due to the high conservation of the catalytic domain across PRMT family members. We herein report (MS3-123), the first small-molecule, nanomolar covalent inhibitor targeting the unique Cys119 within the SAM-binding pocket of PRMT1 (IC = 11.4 nM) with over 17-96-fold selectivity against other type I PRMTs subfamily and >439-fold selectivity against type II PRMT5. selectively engages Cys119, inhibiting PRMT1 activity at both enzymatic and cellular levels. Functionally, suppressed breast cancer cell proliferation, migration, invasion, induced cell cycle arrest and apoptosis, and impaired tumor growth in the MDA-MB-231-xenograft model. Our findings establish as both a valuable chemical probe for PRMT1 research and a promising lead candidate for breast cancer treatment, highlighting the potential of covalent targeting for selective epigenetic drug discovery.
Neovascular glaucoma (NVG) seriously threatens visual, through elevated intraocular pressure (IOP) and intraocular neovascularization. At present, no clinical drug simultaneously lowers IOP and inhibits vascular growth....Neovascular glaucoma (NVG) seriously threatens visual, through elevated intraocular pressure (IOP) and intraocular neovascularization. At present, no clinical drug simultaneously lowers IOP and inhibits vascular growth. Moreover, to address the high invasiveness of intravitreal injection and the high systemic toxicity of oral administration, we ultimately discovered the first VEGFR/PDGFR/CA II dual-functional inhibitor for treating NVG that can be administered through the subconjunctival injection. Compared with positive drugs and , exhibited better inhibitory activity against VEGFR2, PDGFRα/β and CA II enzymes. Moreover, exhibited potent antiproliferative activity in VEGFR2-BAF3 cells and robust inhibition of angiogenesis in HUVECs. Furthermore, also inhibited the formation of corneal neovascularization in rabbits through multiple signaling pathways. In acute and chronic glaucoma model, significantly reduced the IOP of rabbits. Overall, these findings provided compelling evidence that offers new perspectives in the treatment of NVG.
The translocator protein (TSPO) has gained increasing attention in the diagnosis and treatment of brain cancers. Current TSPO-targeting radiotracers, predominantly labeled with C and F, limit the incorporation of emergin...The translocator protein (TSPO) has gained increasing attention in the diagnosis and treatment of brain cancers. Current TSPO-targeting radiotracers, predominantly labeled with C and F, limit the incorporation of emerging radionuclides into theranostic applications. In this study, we designed and synthesized four DOTA-conjugated TSPO-targeting precursors featuring various polyethylene glycol (PEG) linkers, which enabled straightforward and efficient labeling with Ga or Lu. and evaluations demonstrated that compared with [F]FDG, all four Ga-labeled radioligands exhibited specific accumulation in glioblastoma in an orthotopic U87MG tumor-bearing mouse model. Among them, [Ga]TSPO-1 displayed more favorable physicochemical properties, binding affinity, and, notably, the highest uptake in U87MG tumor tissues. Furthermore, [Lu]TSPO-1 significantly inhibited U87MG tumor growth in the mouse model with satisfactory biosafety, implying its potent therapeutic potential for glioblastomas. In summary, this study develops DOTA-conjugated radioligands targeting TSPO and highlights the promise of [Ga/Lu]TSPO-1 for radiotheranostic applications in brain oncology.
In 2024, thirty-nine new small molecule drugs were approved worldwide. A brief introduction to each new drug is followed by the synthetic details that highlight the most scalable routes available at the time of publicati...In 2024, thirty-nine new small molecule drugs were approved worldwide. A brief introduction to each new drug is followed by the synthetic details that highlight the most scalable routes available at the time of publication in patents or primary literature. Structural complexity varies widely across the drugs that are included in the review, as do the methods of synthesis used to access these new drugs.
Weckesser J, Miletić N, Sivashanmugam SA
… +18 more, Ohmayer U, Steger M, Shashikadze B, Gehrtz P, Unzue Lopez A, Wegener A, Dietz TY, Hammann T, Hartung IV, Elson L, Němec V, Schwalm MP, Adhikari B, Wolf E, Krämer A, Müller S, Daub H, Knapp S
Proteolysis-targeting chimeras (PROTACs) have emerged as a novel drug modality, but their development currently relies on a limited number of E3 ligase ligands, primarily targeting CRBN and VHL. Conversely, current valid...Proteolysis-targeting chimeras (PROTACs) have emerged as a novel drug modality, but their development currently relies on a limited number of E3 ligase ligands, primarily targeting CRBN and VHL. Conversely, current validation studies on novel E3 ligase ligands are typically limited to a few highly degradable targets, like BRD4. Here, we used our previously established workflow for E3 ligase ligand validation, employing promiscuous kinase PROTACs, to evaluate the potential of recruiting DCAF1 for PROTAC development. Our study revealed the DCAF1-dependent degradation of a diverse set of kinases, which were validated in orthogonal assays. In a comparative analysis, we identified a significant overlap between the degradable kinome of DCAF1- versus CRBN-recruiting PROTACs, suggesting alternative design strategies for PROTACs using available structurally diverse DCAF1 ligands. Moreover, ubiquitinomics analysis of the PROTAC-induced ubiquitination patterns provided insight into substrate- and isoform-selective degradation. The presented data will establish DCAF1-recruiting PROTACs as a versatile design strategy for future degrader development.
Spleen tyrosine kinase (SYK) is a cytoplasmic nonreceptor kinase involved in immune signaling and homologous recombination (HR) repair of DNA double-strand breaks, and its aberrant activation promotes therapeutic resista...Spleen tyrosine kinase (SYK) is a cytoplasmic nonreceptor kinase involved in immune signaling and homologous recombination (HR) repair of DNA double-strand breaks, and its aberrant activation promotes therapeutic resistance in triple-negative breast cancer (TNBC). We developed a machine learning (ML)-corrected virtual screening strategy that reduces false positives in docking-based screening and identified a benzimidazole lead (L-5). SAR-guided optimization yielded a potent type II SYK inhibitor, (IC = 16 nM), which stabilizes the DFG-out inactive conformation via hinge, αC-helix, and DFG interactions. shows strong antiproliferative, pro-apoptotic, and antimigratory effects in TNBC cells and suppresses tumor growth in an MDA-MB-231 xenograft model without overt toxicity. Mechanistically, increases DNA damage by inhibiting SYK-mediated CtIP phosphorylation and shows synergy with the PARP inhibitor Olaparib. These findings establish as a promising therapeutic candidate and demonstrate the potential of SYK inhibition as a strategy to overcome HR-mediated resistance in TNBC.
The transcriptional upregulation of drug efflux pumps constitutes a primary mechanism of azole resistance acquired by diverse fungal pathogens. This overexpression diminishes intracellular azole accumulation, thereby com...The transcriptional upregulation of drug efflux pumps constitutes a primary mechanism of azole resistance acquired by diverse fungal pathogens. This overexpression diminishes intracellular azole accumulation, thereby compromising drug efficacy and contributing to therapeutic failure. The coadministration of azole antifungals with efflux pump inhibitors presents a promising therapeutic strategy to combat resistant fungal infections. In the search for novel antifungal drugs, we obtained 49 isoxazoline derivatives through structural modification of the isoxazolin-3-one skeleton. Among them, showed potent synergistic activity with fluconazole (FLC) against azole-resistant (FICI = 0.094). In the larvae and mice model, exhibited potent therapeutic efficacy. Interestingly, mechanistic investigations revealed that , when combined with FLC, reduced the expression of , an efflux pump gene, in the multidrug-resistant clinical isolate . Taken together, these results identify as a promising lead candidate for combating azole-resistant infections.
Bagal SK, Diène CRN, Stefanovic-Barrett S
… +18 more, Breed J, Kauffman GW, Bodnarchuk MS, Collie GW, Staniszewska AD, Srivastava A, Irving E, Cassar DJ, Gray S, Hughes C, Kettle JG, Nash S, Northall S, Peter A, Schade M, Stubbs CJ, Smith A, Young L
Son of Sevenless Homologue 1 (SOS1) is a promising oncology target with inhibitors in phase 1/2 clinical studies. A focused HTS triage led to a singular SOS1 series having a pyridyl core. The conformational preference of...Son of Sevenless Homologue 1 (SOS1) is a promising oncology target with inhibitors in phase 1/2 clinical studies. A focused HTS triage led to a singular SOS1 series having a pyridyl core. The conformational preference of the diamide pyridyl core was critical to binding potency, leading to pyrazine and pyridyl being the preferred motifs. Application of structure-based design to build into a buried lipophilic pocket led to a significant 50-fold potency enhancement. Strategic fluorination of aryl rings and substituents generated compounds with favorable dipoles, low P-gp and BCRP efflux, and high rat Kp. Multiple analogues were progressed into PK/PD studies where they were combined with a KRAS inhibitor. Combination treated tumors in mice showed deeper, more sustained reductions in DUSP6 mRNA and phosphorylated ERK compared to KRAS inhibitor alone. Thus, these novel CNS penetrant SOS1 inhibitors have potential to enhance antitumor responses when combined with RAS or MAPK inhibitors.