Isocitrate dehydrogenase (IDH) is an enzyme that catalyses the oxidative decarboxylation of isocitrate, producing α-ketoglutarate (α-KG) relative to the hydroxylation of substrates. However, IDH mutants can further reduce α-KG to 2-hydroxyglutarate (2-HG) which competitively inhibits α-KG dependent enzymes, leading to the downregulation of normal hydroxylation pathways. Good IDH mutant inhibitors can effectively reduce the level of 2-HG and therefore disturb cellular malignant transformation. In this review, we introduce the biological functions of IDH, describe the tumorigenesis mechanisms of IDH variants, and review the structure-based drug discovery of clinical inhibitors during 2012-2024. We also find successful applications of covalent strategy in the development of irreversible IDH inhibitors. Biological screening methods are also collected in this paper, which may help researchers to rapidly construct workflows for drug discovery and development.

The emergence of multi-drug resistance (MDR) presents a significant impediment to the efficacy of cancer treatment. Aberrant expression of ABC (ATP-binding cassette) transporters is acknowledged as one of the underlying factors contributing to MDR. P-glycoprotein (P-gp, MDR1, ABCB1), breast cancer resistance protein (BCRP, ABCG2), and MDR-associated protein 1 (MRP1, ABCC1) are members of the ABC transporter, and their over-expression usually occurs in drug-resistant tumor cells. In this work, the structure-activity relationships of the biaryl amide skeleton were systematically investigated via structural optimization step by step, which led to the identification of an exceptionally potent resistance reversal agent, D2. Compound D2 effectively reversed MDR to paclitaxel and cisplatin in A2780/T, A2780/CDDP and A549/T cell lines. It could directly bind to P-gp and downregulate the expression of both P-gp and MRP1. The treatment with D2 increased the intracellular accumulation of Rh123 and inhibited P-gp-mediated drug efflux of Rh123 in A2780/T cells. Therefore, compound D2 exhibits promising potential in overcoming multidrug resistance (MDR) induced by P-gp in cancer.

A series of semisynthetic noscapine-urea congeners (7a-7h) as potential tubulin-binding agents are being developed by integrating a urea pharmacophore at the C-9 position of the noscapine scaffold. Their binding affinity to tubulin was predicted through molecular docking, molecular dynamics (MD) simulations, and the MM-PBSA approach. These molecules were subsequently chemically synthesized and assessed using breast cancer cell lines (MCF-7 and MDA-MB-231) and normal human embryonic kidney cells (HEK). Both the docking score and the predicted binding free energy (ΔG) revealed that urea congeners had a stronger affinity towards tubulin than noscapine and effectively inhibited the proliferation of all cancer cell types without affecting normal healthy cells. The results indicated that compound 7g exhibited the most promise and was chosen for further studies. Moreover, MDA-MB-231 cells treated with 7g at its IC concentration showed morphological changes such as membrane blebbing, fragmented nuclei, and the presence of apoptotic bodies. Apoptosis induction was further confirmed by flow cytometry. Moreover, the tubulin binding assay revealed a greater binding affinity with an equilibrium dissociation constant (KD) of 42 ± 2.4 μM for compound 7g. The number of MCF-7 cells engrafted as breast tumors in nude mice was found to be reduced significantly without any adverse effects. Noscapine is already in clinical trials, but the urea noscapine congener offers an advantage because of its increased potency without impacting the nontoxic profile of noscapine.

Given the vulnerability of colorectal cancer (CRC) patients could not obtain a sustained benefit from chemotherapy, combination therapy is frequently employed as a treatment strategy. Targeting PARP1 blockade exhibit specific toxicity towards tumor cells with BRCA1 or BRCA2 mutations through synthetic lethality. This study focuses on developing a series of potent PROTACs targeting PARP1 in order to enhance the sensitivity of CRC cells with BRCA1 or BRCA2 mutations to chemotherapy. Compound C6, obtained based on precise structural optimization of the linker, has been shown to effectively degrade PARP1 with a DC value of 58.14 nM. Furthermore, C6 significantly increased the cytotoxic efficacy of SN-38, an active metabolite of Irinotecan, in BRCA-mutated CRC cells, achieving a favorable combination index (CI) of 0.487. In conclusion, this research underscores the potential benefits of employing a combination therapy that utilizes PAPRP1 degrader C6 alongside Irinotecan for CRC patients harboring BRCA mutations in CRC.

Platinum drugs are the most widely used chemotherapeutics to treat various tumors. Their primary mode of action is supposed to be inducing apoptosis of cancer cells via covalent binding to DNA. This mechanism has shackled the design of new platinum drugs for many years. Mounting evidence shows that many platinum complexes form non-covalent adducts with DNA or interact with proteins to exhibit significant antitumor activity, thus implying some distinct mechanisms from that of traditional platinum drugs. These unconventional examples indicate that covalent DNA binding is not the precondition for the antitumor activity of platinum complexes, and diversified reactions or interactions with biomolecules, organelles, signal pathways, or immune system could lead to the antitumor activity of platinum complexes. The atypical mechanisms break the classical DNA-only paradigm and structure-activity relationships, thus opening a wide avenue for the design of innovative platinum anticancer drugs.

Protein arginine methyltransferase 7 (PRMT7), a type III methyltransferase responsible solely for arginine mono-methylation, plays a critical role in numerous physiological and pathological processes. Recent studies have highlighted its aberrant expression or mutation in various cancers, implicating it in tumorigenesis, cancer progression, and drug resistance. Consequently, PRMT7 has emerged as a promising target for cancer diagnosis and therapeutic intervention. In this review, we present an overview of the molecular structure of PRMT7, discuss its roles and mechanisms in different cancer types, and analyze the binding modes and structure-activity relationships of reported PRMT7 inhibitors. Furthermore, we identify the challenges encountered in functional exploration and drug development targeting PRMT7, propose potential solutions to these challenges, and outline future directions for the development of PRMT7 inhibitors to inform future drug discovery efforts.

Peptidomimetics of Suppressors of cytokine signaling 1 (SOCS1) protein demonstrated valid therapeutic potentials as anti-inflammatory agents. Indeed, SOCS1 has a small kinase inhibitory region (KIR) primarily involved in the inhibition of the JAnus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) pathway Herein, on the basis of previous investigations on a potent mimetic of KIR-SOCS1, named PS5, we designed and evaluated the SAR (Structure Activity Relationship) features of two xylene-based macrocycles analogues of PS5. These novel compounds bear thiol-xylene linkages with mono- and bi-cyclic scaffolds: they were in vitro functionally investigated toward JAK2 catalytic domain, as ligands with microscale thermophoresis (MST) and as inhibitors through LC-MS analyses. To evaluate structural properties Circular Dichroism (CD) and Nuclear Magnetic Resonance (NMR) spectroscopies were employed along with serum stability assays. Results indicated that a monocycle scaffold is well-tolerated by PS5 sequence enhancing the affinity toward the kinase with a K in the low micromolar range and providing consistent inhibitory effects of the catalytic activity, which were evaluated for the first time in the case of SOCS1 mimetics. Conformationally, the presence of xylene scaffold affects the flexibility of the compounds and their stabilities to proteases degradation. This study contributes to the understanding of the factors necessary for accurately mimicking the inhibitory mechanism of SOCS1 protein towards JAK2 and to the translation of proteomimetics into drugs.

Metabolic dysfunction-associated steatohepatitis (MASH) has become a serious threat to human health, which exhibited an increasing prevalence globally. Recently, the farnesoid X receptor (FXR) has been identified as a promising strategy for the treatment of MASH by regulating multiple pathogenesis. In this study, a new series of FXR agonists bearing piperidine scaffold was designed to reduce the high lipophilicity of the existing FXR agonists. After comprehensive multiparameter optimization, LZ-007 was discovered as a highly potent FXR agonist with suitable stability in liver microsomes of multiple species. LZ-007 exhibited highly oral bioavailability and targeted tissue exposure in the liver and ileum, while the plasma exposure is low, which might minimize the systemic side effects. Moreover, LZ-007 was significantly up-regulated the expressions of FXR and its downstream genes in the liver and ileum. In MASH model, LZ-007 exerted potent anti-MASH effects by regulating the multiple signal pathways related to lipid metabolism, oxidative stress, inflammation and fibrosis. In a 30-day toxicity study, no apparent adverse effects were observed in LZ-007 treated groups, even at the high doses of 250 and 500 mg/kg. With the positive pharmacodynamics and safety profiles, LZ-007 is worthy of further evaluation as a new anti-MASH agent.

The global population affected by Hepatitis B virus (HBV) is approximately 296 million, but few drugs have been able to completely eradicate HBV and the range of effective treatments remains limited. Recent advancements in molecular biology and artificial intelligence, as well as a comprehensive understanding of the molecular structure of HBV, have greatly aided the rational development of anti-HBV agents. Such advancements have facilitated an increasing array of candidate drugs transitioning into clinical trials, however, no novel target-based compounds have been approved for clinical application. To expedite the progression of anti-HBV drug development, establishing a reliable and robust in vitro HBV infection system is of great importance. However, owing to the host and tissue specificity of HBV, identifying a stable and dependable cell culture system for screening all anti-HBV agents poses significant challenges. In this review, we summarize recent advances in screening methods for small-molecule inhibitors that target key stages of the HBV replication cycle from a medicinal chemistry perspective.

Natural coumarins and isocoumarins show significant therapeutic potential against cancer in preclinical studies by targeting multiple pathways and processes. These compounds influence several critical cellular processes, such as apoptosis, autophagy, and cell cycle regulation, which are pivotal in cancer development and progression. Their capability to target multiple signalling pathways provides a strategic advantage over single-target therapies, which are often limited by drug resistance. Notably, coumarins have the potential to inhibit angiogenesis, the process through which tumours develop new blood vessels, thereby potentially restricting tumour growth and metastasis. Additionally, coumarins may enhance anticancer effects by modulating immune responses and reducing inflammation, thus offering a dual approach to combating cancer. They also show promise in addressing multidrug resistance, a significant challenge in cancer therapy, by targeting drug efflux proteins and potentially improving the efficacy of existing treatments. While preclinical studies are promising, further research is required to elucidate the pharmacokinetics, toxicity, and potential side effects of coumarins in humans. Continued clinical evaluation will be crucial to confirm their effectiveness in cancer patients. Nonetheless, their ability to target multiple pathways positions coumarin based molecules as potential candidates for future anti-cancer drug development.

Bisepoxylignans have been reported to possess a variety of biological functions, especially in anti-inflammatory aspects. However, the bis-tetrahydrofuran scaffold restricts the type and position of substituents, which further limits the further optimization of their biological activity and druggability. Here, a series of novel derivative s of bisepoxylignans bearing 7H-pyrrolo[2,3-d]pyrimidin-4-amine and 1H-pyrazolo[3,4-d]pyrimidin-4-amine scaffolds were designed and synthesized by a scaffold hopping strategy. Biological evaluation demonstrated that compound 7x exhibited the most potent anti-inflammatory activity, both in vitro and in vivo. Additionally, 7x displayed an excellent oral safety profile at a dose of 500 mg/kg. The anti-inflammatory effect of 7x is potentially mediated by the inhibition of the TLR4/NF-κB pathway and the promotion of M1 to M2 microglial phenotypic conversion. Taken together, 7x could be a promising lead compound for the development of novel therapeutic agents for the treatment of inflammatory diseases.

Heme, abundant in the mitochondria of cancer cells, is a key target for the anticancer activity of artemisinin (ART). Current strategies to enhance the anticancer activity of ART focus solely on its delivery to heme-enriched subcellular localizations while overlooking the decisive effects of ART-heme interactions. Here, we propose an ingenious strategy that synergizes mitochondria-targeted drug delivery and linker-mediated drug conformation modulation, thereby significantly enhancing the anticancer activity of ART. By strategically conjugating artemisinin (ART) with the mitochondria-targeting rhein (R) using different linkers, we aimed to precisely adjust the conformation of the conjugates. Comprehensive computational analysis revealed that the conjugate with the optimal linker length (C) displayed a favorable conformation that facilitated cell permeability and exhibited the highest binding affinity to heme and Fe ions. Moreover, it exhibited superior tumor suppression capabilities both in vitro and in vivo, overcoming the uncertainty of in vivo application caused by the rapid clearance of the conventional mitochondria-targeted cation TPP, and even inducing immunogenic cell death associated with immunotherapy. This novel strategy opens up a new avenue for the development of drug conjugate systems.

Doxorubicin (DOX)-induced cardiomyopathy (DIC) greatly limits its clinical application of the anticancer drug. Therefore, there is an immediate necessity to undertake intervention studies to minimize DIC, encompassing the screening of regulatory compounds and delving into the underlying regulatory mechanisms. A growing body of research suggests that ferroptosis is an essential process in the development of DIC. Here, we demonstrated that DOX causes elevated iron levels in cardiomyocytes and mouse hearts, and leads to ferroptosis and cardiac insufficiency. Next, we performed high-throughput screening of a library of herbal small molecule compounds for novel compounds that inhibit ferroptosis, using Fe levels as a screening index for DIC prevention and treatment drugs. We found that Praeruptorin A (PA) was able to reduce Fe concentration in cardiomyocytes, inhibit ferroptosis, and alleviate DIC and cardiac dysfunction in mice. Concurrently, PA exhibits a synergistic effect with DOX in suppressing the proliferation of carcinoma of breast MCF-7 cell in nude mice. Mechanistically, we found that PA inhibited the expression of divalent metal transporter protein 1 (DMT1), suppressed Fe overload in cardiomyocytes, and inhibited ferroptosis, thereby alleviating DIC. Our study demonstrated the feasibility of high-throughput screening targeting the Fe concentration, and elucidated the role and mechanism of PA in alleviating DIC, which provides a new possibility.

Small molecules that possess the ability to regulate the interactions between Son of Sevenless 1 (SOS1) and Kristen rat sarcoma (KRAS) offer immense potential in the realm of cancer therapy. In this study, we present a novel series of SOS1 inhibitors featuring a tricyclic quinazoline scaffold. Notably, we have identified compound 8d, which demonstrates the highest potency with an IC value of 5.1 nM for disrupting the KRAS:SOS1 interaction. Compound 8d exhibits a promising pharmacokinetic profile and achieves a remarkable 70.5 % inhibition of tumor growth in pancreas tumor xenograft models. Furthermore, molecular dynamic simulations have unveiled that the tricyclic quinazoline derivatives exhibit extensive interaction with Tyr884, a crucial residue for the recognition between SOS1 and KRAS. Our findings provide fresh insights into the design of future SOS1 inhibitors, paving the way for innovative therapeutic strategies.

The growing prevalence of microbial infections, and antimicrobial resistance (AMR) stemming from the overuse and misuse of antibiotics, call for novel therapeutic agents, particularly ones targeting resistant microbial strains. Scientists are striving to develop innovative agents to tackle the rising microbial infections and abate the risk of AMR. Pyrazole, a five-membered heterocyclic compound belonging to the azole family, is a versatile scaffold and serves as a core structure in many drugs with antimicrobial and other therapeutic effects. In this review, we have updated pyrazole-based antibacterial and antifungal agents mainly developed between 2016 and 2024, by combining with diverse pharmacophores such as coumarin, thiazole, oxadiazole, isoxazole, indole, etc. Meanwhile, the various strategies (molecular hybridization, bioisosterism, scaffold hopping, multicomponent reactions, and catalyst-free synthesis) for integrating different functional groups with the pyrazole ring are discussed. Additionally, structure-activity relationships of these pyrazole derivatives, i.e., how structural modifications impact their selectivity and therapeutic potential against bacterial and fungal strains, are highlighted. This review provides insights into designing next-generation antimicrobials to combat AMR, and offers valuable perspectives to the scientists working on heterocyclic compounds with diverse bioactivities.

Factor XIa (FXIa) has emerged as a novel anticoagulant target with a reduced risk of bleeding. However, due to the nearly identical residues it shares with its closest homologue, plasma kallikrein (PKa), only a few selective FXIa inhibitors have been reported. Herein, we describe the discovery of novel triazole-based pyridone derivatives as potent and selective FXIa inhibitors. Structural optimization identified triazole-based benzoic acids as optimal P2' fragments. The representative compound (S)-10h (IC = 0.38 nM for FXIa) was approximately 3-fold more potent than asundexian for FXIa, along with up to 150-fold selectivity over PKa (13-fold for asundexian) and up to 100,000-fold selectivity over FXa and thrombin (5000-fold for asundexian). Extensive molecular dynamics simulations and free energy calculations revealed that electrostatic interactions with varied residues near the binding site, particularly the loop at the bottom of the S2' pocket (IP-loop), are critical factors contributing to the improved selectivity over PKa. Calculations of electrostatic potential (ESP) surfaces illustrated that FXIa forms a more positive ESP than PKa, thrombin, and FXa, which attracts the carboxylic acid group of the designed compounds, enhancing both potency and selectivity. Moreover, compound (S)-10h demonstrated potent in vitro anticoagulant activity with an EC value of 0.55 μM for aPTT, without interfering with PT up to 100 μM. Thus, compound (S)-10h represents a promising lead for further optimization as a novel anticoagulant agent.

Kinesin spindle protein (KSP) plays a crucial role during mitosis, making it an attractive target for cancer treatment. Herein, we report the design, synthesis, and evaluation of the first series of KSP degraders by using the utilization of the proteolysis-targeting chimera (PROTAC) technology. Compound 21 was identified as a potent KSP degrader with a DC (concentration causing 50 % of protein degradation) value of 114.8 nM and a D (maximum degradation) of 90 % in the HCT-116 cells. Compound 21 showed strong antiproliferative activity against HCT-116 cells with an IC values of 10 nM. Mechanistic investigations revealed that 21 causes the cell arrest at the G2/M phase and subsequent cell apoptosis. In addition, 21 demonstrated more significant inhibition of tumor growth in an HCT-116 xenograft model compared to its parent compound 1. Our findings suggest that 21 may become the promising leads for further development.

The FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutation is a key target for acute myeloid leukemia (AML) treatment. The second-generation inhibitors such as Gilteritinib still present off-target effects and associated side effects. Therefore, identifying novel FLT3-ITD inhibitors has become a promising strategy for AML treatment. In this study, a 4D-QSAR model was developed based on Gilteritinib and its analogues, and it was found that introducing hydrophobic bulky groups at the piperazine or piperidine of Gilteritinib would enhance the binding affinity to FLT3-ITD. So, three series of targeted compounds (A1-A5, B1-B5 and C1-C5) were designed and synthesized. The antiproliferative activity against MOLM-13 cells was evaluated in vitro. Compound A1 (IC = 25.65 nM), with a cubane group at the piperazine position; Compounds B2 (IC = 63.38 nM) and C2 (IC = 54.96 nM), with a norbornene group at the piperidine position, showed the strongest inhibition in their series. Their IC values were comparable to that of the positive control Gilteritinib (IC = 22.37 nM). FLT3-ITD was confirmed as the degradation target through a kinase inhibition assay, where the IC values were 2.12 nM (Compound A1), 1.29 nM (Compound B2), and 3.06 nM (Compound C2), which were comparable to that of Gilteritinib (IC = 0.43 nM). Additionally, molecular docking and molecular dynamics (MD) simulations showed that Compounds A1, B2, and C2 had similar binding modes to that of Gilteritinib with more stable affinities. Overall, these results demonstrated that Compounds A1, B2, and C2 were promising inhibitors for targeting AML with FLT3-ITD mutation.

Pancreatic ductal adenocarcinoma (PDAC) is a clinically challenging cancer because of the difficulty in diagnosis and its resistance to chemotherapy. Focal adhesion kinase (FAK) is found overexpressed in PDAC, and targeting FAK has been proved to impede the progress of PDAC. However, most of FAK inhibitors were reported to bind with FAK in a DFG-in conformation, leading to a limited anti-tumor effect in clinical studies. Herein, to develop FAK inhibitors targeting the inactive DFG-out conformation, a series of large aromatic rings were selected to improve the interaction with Phe565 of the DFG motif. Compound 26 was designed to effectively inhibit FAK and the proliferation of PANC-1 cells with IC of 50.94 nM and 0.15 μM, respectively. Besides, compound 26 was proved to strongly suppress the proliferation, colony formation, migration, and invasion in FAK-overexpressing PDAC cells. This inhibitor was confirmed to induce the apoptosis and G2/M arrest in PANC-1 cells through the suppression of FAK/PI3K/Akt signal pathway. Meanwhile, compound 26 was found to simultaneously inhibit FAK with DFG-out conformation and JAK3/Aurora B (IC of 9.99 nM and 0.49 nM, respectively). In vivo, compound 26 effectively inhibited the tumorigenesis and metastasis of PDAC with desirable biosafety. Overall, these results suggested that compound 26 was a promising candidate for the treatment of PDAC.

Honokiol is a natural product with an interesting array of biological effects, including significant anti-tumor properties. However, full exploration of its therapeutic potential is hampered by its modest pharmacokinetic profile and by the lack of synthetic methods that allow to obtain specifically designed derivatives with improved properties. In addition, the specific molecular targets of honokiol remain poorly understood, a fact that limits the search of alternative hits for subsequent optimization programs. In this work we describe an optimized series of synthetic routes that allow to access to a variety of honokiol derivatives, including a set of minimalist photoaffinity probes to map potential protein targets in live cells. Chemical proteomic studies of the most potent probe revealed a defined set of proteins as the cellular targets of honokiol. Significantly, up to the 62 % of the identified proteins have described roles in cancer, highlighting their potential relationship with the antitumor effects of honokiol. Furthermore, several of the top hits have been validated as direct binding partners of honokiol by cellular thermal shift assay (CETSA). In sum, the work described herein provides the first landscape of the cellular targets of honokiol in living cells and contributes to define the specific molecular pathways affected by this natural product.