Bifunctional Inhibitor Research Articles

Performance of waterborne polyurethane based on N-tert-butyldiethanolamine in corrosion inhibition

The design of bifunctional inhibitors effectively preventing hydrate formation and corrosion is a relevant issue for the oil and gas industry. In this work, we expanded the study of the corrosion inhibition effectiveness for waterborne polyurethanes (WPUs) obtained earlier and shown to be promising inhibitors. The corrosion inhibition ability of WPUs was assessed using weight-loss and electrochemical methods. Commercial corrosion inhibitor Armohib CI-28 was taken as a reference sample. The data obtained showed that the tert-Bu-WPU sample is able to effectively inhibit acid and carbon dioxide corrosion at room temperature; however, with an increase in temperature, its efficiency decreases more intensively than for a commercial inhibitor. In general, waterborne polyurethanes are promising alternatives to commercial reagents due to their multifunctionality.

MD simulation and MM/PBSA identifies phytochemicals as bifunctional inhibitors of SARS-CoV-2

The global spread of SARS-CoV-2 has resulted in millions of fatalities worldwide, making it crucial to identify potent antiviral therapeutics to combat this virus. We employed structure-assisted virtual screening to identify phytochemicals that can target the two proteases which are essential for SARS-CoV-2 replication and transcription, the main protease and papain-like protease. Using virtual screening and molecular dynamics, we discovered new phytochemicals with inhibitory activity against the two proteases. Isoginkgetin, kaempferol-3-robinobioside, methyl amentoflavone, bianthraquinone, podocarpusflavone A, and albanin F were shown to have the best affinity and inhibitory potential among the compounds, and can be explored clinically for use as inhibitors of novel coronavirus SARS-CoV-2. Communicated by Ramaswamy H. Sarma

Trends in kinase drug discovery: targets, indications and inhibitor design.

The FDA approval of imatinib in 2001 was a breakthrough in molecularly targeted cancer therapy and heralded the emergence of kinase inhibitors as a key drug class in the oncology area and beyond. Twenty years on, this article analyses the landscape of approved and investigational therapies that target kinases and trends within it, including the most popular targets of kinase inhibitors and their expanding range of indications. There are currently 71 small-molecule kinase inhibitors (SMKIs) approved by the FDA and an additional 16 SMKIs approved by other regulatory agencies. Although oncology is still the predominant area for their application, there have been important approvals for indications such as rheumatoid arthritis, and one-third of the SMKIs in clinical development address disorders beyond oncology. Information on clinical trials of SMKIs reveals that approximately 110 novel kinases are currently being explored as targets, which together with the approximately 45 targets of approved kinase inhibitors represent only about 30% of the human kinome, indicating that there are still substantial unexplored opportunities for this drug class. We also discuss trends in kinase inhibitor design, including the development of allosteric and covalent inhibitors, bifunctional inhibitors and chemical degraders.

Dual PD-L1 and TGF-b blockade in patients with recurrent respiratory papillomatosis

BackgroundRecurrent respiratory papillomatosis (RRP) is a human papillomavirus (HPV) driven neoplastic disorder of the upper aerodigestive tract that causes significant morbidity and can lead to fatal airway obstruction. Prior clinical...

Discovery of novel pyrazolopyrimidine derivatives as potent mTOR/HDAC bi-functional inhibitors via pharmacophore-merging strategy

The mTOR and HDAC dual suppression is meaningful for counteracting drug resistance resulted from kinase mutation and bypass mechanisms. Herein, we communicate our recent discovery of a novel structural series of mTOR/HDAC bi-functional inhibitors featuring the pyrazolopyrimidine core via pharmacophore-merging strategy. More than half of them exerted potent dual-target inhibitory activities. In particular, compound 50 exhibited IC50 values of 0.49 and 0.91 nM against mTOR and HDAC1, respectively, along with remarkably enhanced anti-proliferative activity (IC50 = 1.74 μM) against MV4-11 cell line than mTOR inhibitor MLN-0128 (IC50 = 5.84 μM) and HDAC inhibitor SAHA (IC50 = 8.44 μM). Its intracellular intervention of both mTOR signaling and HDAC was validated by the Western blot analysis. Moreover, as the first disclosed mTOR/HDAC dual inhibitor with selectivity for some specific HDAC subtypes, it has the potential to alleviate the adverse effects resulted from pan-HDAC inhibition. Attributed to its favorable in vitro performance, compound 50 is valuable for further functional investigation as a polypharmacological anti-cancer agent.

Abstract 1460: The design and biological characterization of PTP4A-targeted chemodegraders

Abstract The protein tyrosine phosphatase 4A (PTP4A) family members, PTP4A1, PTP4A2 or PTP4A3, are overexpressed in many cancers, and this overexpression is associated with a distinct disadvantage to overall patient survival. Genetic knockdown or deletion of PTP4A diminishes cancer cell migration, survival and tumorigenesis. We previously demonstrated that the small molecule JMS-053 or KVX-053 (7-iminothieno[3,2-c]pyridine-4,6(5H,7H)-dione) functions as a selective, allosteric, and reversible pan-PTP4A, inhibitor. KVX-053 decreased ovarian cancer cell line spheroid viability, migration and in vivo tumor growth. We now report a conjugate of KVX-053 to an adamantyl moiety in an effort to design intracellular PTP4A chemodegraders. In addition to the linker length, we also modified the functional group attachments to the KVX-053 pharmacophore and the adamantly moiety. Significantly, several of these analogs retained potent in vitroinhibition of PTP4A3 enzymatic activity (IC50=100-750 nM), suggesting they could be dual-purpose PTP4A3 inhibitors, targeting both the catalytic activity and reducing intracellular protein concentration. Some of these KVX-053 analogs, including EJR-876-35 and EJR-887-35, exhibited enhanced cytotoxicity against human ovarian cancer, triple negative breast cancer or leukemia cell lines compared to the parent chemotype, KVX-053. Human ovarian cancer cells incubated with 1 micromolar EJR-887-35 exhibited a pronounced loss of PTP4A protein within 6 hours and the loss was sustained for at least 18 hours. These results support the further investigation of chemodegraders as specific first-in-class bifunctional PTP4A inhibitors directed against human cancers. Citation Format: Duncan J. Hart, Ettore J. Rastelli, Anna J. Mendelson, Christopher T. Letai, John Robert Cornelison, Elizabeth R. Sharlow, Peter Wipf, John S. Lazo. The design and biological characterization of PTP4A-targeted chemodegraders [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1460.

Design, synthesis, and biological evaluation of novel dual inhibitors targeting lysine specific demethylase 1 (LSD1) and histone deacetylases (HDAC) for treatment of gastric cancer.

LSD1 and HDAC are physical and functional related to each other in various human cancers and simultaneous pharmacological inhibition of LSD1 and HDAC exerts synergistic anti-cancer effects. In this work, a series of novel LSD1/HDAC bifunctional inhibitors with a styrylpyridine skeleton were designed and synthesized based on our previously reported LSD1 inhibitors. The representative compounds 5d and 5m showed potent activity against LSD1 and HDAC at both molecular and cellular level and displayed high selectivity against MAO-A/B. Moreover, compounds 5d and 5m demonstrated potent antiproliferative activities against MGC-803 and HCT-116 cancer cell lines. Notably, compound 5m showed superior invitro anticancer potency against a panel of gastric cancer cell lines than ORY-1001 and SP-2509 with IC50 values ranging from 0.23 to 1.56μM. Compounds 5d and 5m significantly modulated the expression of Bcl-2, Bax, Vimentin, ZO-1 and E-cadherin, induced apoptosis, reduced colony formation and suppressed migration in MGC-803 cancer cells. In addition, preliminary absorption, distribution, metabolism, excretion (ADME) studies revealed that compounds 5d and 5m showed acceptable metabolic stability in human liver microsomes with minimal inhibition of cytochrome P450s (CYPs). Those results indicated that compound 5m could be a promising lead compound for further development as a therapeutic agent in gastric cancers via LSD1 and HDAC dual inhibition.

A Novel Natural Autoantibody Targeted Complement Inhibitor Protects against Lung Transplant Ischemia Reperfusion Injury

Purpose Chronic obstructive pulmonary disease is characterized by chronic inflammation and severe lung parenchyma damage that is in part driven by autoimmunity. Lung specific autoreactive antibodies (AAb) are indicative of disease progression and severity. The purpose of this study was to elucidate how pre-existing AAb contribute to ischemia reperfusion injury (IRI) and graft rejection following lung transplant (LTx). We hypothesize that pre-existing AAb bind cryptic antigens exposed during IRI which exacerbates lung graft injury in a complement (C)-dependent pathway. Methods We generated a clinically relevant cigarette smoke (CS)-induced mouse model that exhibits increased serum AAb compared to non-smoke exposed age-matched (NS) controls. We analyzed the impact of a full pre-existing AAb repertoire by creating an orthotopic syngeneic left lung LTx model in which we transplanted the left lungs from age-matched donor mice into NS and CS mice. Furthermore, we developed a novel bifunctional inhibitor that blocks IgM binding and inhibits complement. Results CS exposure significantly increased graft injury and immune infiltration 48 hours after LTx. Syngeneic LTx into Rag−/- mice reconstituted with serum from NS and CS mice demonstrated that AAb present in CS are responsible for the observed graft injury. Immunofluorescent staining showed that IgM/IgG binding was increased in CS recipients and colocalized with C3d deposition. These data suggested that AAb-mediated graft injury may occur via the C pathway. To elucidate the role of C in AAb-mediated graft injury, we treated CS LTx recipients with a novel bifunctional C inhibitor, C2scFv-Crry, that blocks IgM binding and C activation. C2scFv-Crry treatment following LTx dramatically reduced acute graft injury and immune infiltration, and significantly decreased de novo AAb production compared to CS control LTx mice. Conclusion Ultimately, these data reveal that CS induces pre-existing AAb production that exacerbate IRI following LTx in a C-dependent manner. Furthermore, we demonstrate the efficacy of a novel C inhibitor in reducing IRI and acute graft injury.

Anticancer Therapy with HDAC Inhibitors: Mechanism-Based Combination Strategies and Future Perspectives.

Simple SummaryBeyond mutations, epigenetic changes have been described as drivers for cancer as well. While leaving the overall DNA structure intact, they can be responsible for tumor malignancy by mediating the transcriptional upregulation of oncogenes. This provides the basis for “epigenetic therapies” in cancer. Histone deacetylases (HDACs) are major players in epigenetic reprogramming. HDAC inhibitors (HDACis), either with broad-spectrum activity on various HDAC isoforms or with specific subtype specificity, have shown promising anticancer efficacies. The tremendous number of genes potentially affected creates the possibility for the parallel targeting of multiple disease-relevant pathways. Here, we give a comprehensive overview of various preclinical and clinical studies on HDACis. A particular focus is placed on the detailed description of promising strategies based on the combination of HDACis with other drugs. This also includes the development of new bifunctional inhibitors as well as novel approaches for HDAC degradation, rather than inhibition, via PROteolysis-TArgeting Chimeras (PROTACs).The increasing knowledge of molecular drivers of tumorigenesis has fueled targeted cancer therapies based on specific inhibitors. Beyond “classic” oncogene inhibitors, epigenetic therapy is an emerging field. Epigenetic alterations can occur at any time during cancer progression, altering the structure of the chromatin, the accessibility for transcription factors and thus the transcription of genes. They rely on post-translational histone modifications, particularly the acetylation of histone lysine residues, and are determined by the inverse action of histone acetyltransferases (HATs) and histone deacetylases (HDACs). Importantly, HDACs are often aberrantly overexpressed, predominantly leading to the transcriptional repression of tumor suppressor genes. Thus, histone deacetylase inhibitors (HDACis) are powerful drugs, with some already approved for certain hematological cancers. Albeit HDACis show activity in solid tumors as well, further refinement and the development of novel drugs are needed. This review describes the capability of HDACis to influence various pathways and, based on this knowledge, gives a comprehensive overview of various preclinical and clinical studies on solid tumors. A particular focus is placed on strategies for achieving higher efficacy by combination therapies, including phosphoinositide 3-kinase (PI3K)-EGFR inhibitors and hormone- or immunotherapy. This also includes new bifunctional inhibitors as well as novel approaches for HDAC degradation via PROteolysis-TArgeting Chimeras (PROTACs).

Gallic Acid: A Naturally Occuring Bifunctional Inhibitor of Amyloid and Metal Induced Aggregation with Possible Implication in Metal Based Therapy

Metal ions play a vital role in the aggregation of proteins by interfering with their correct folding, thereby affecting protein homeostasis and cell viability, leading to neurodegenerative diseases like Alzheimer's and Parkinson's. Development of therapeutics against protein misfolding diseases has become one of the widely studied areas of research. Till date, all advances in neurodegenerative diseases’ therapeutics help symptomatically but do not prevent the root cause of the disease, i.e., the aggregation of protein involved in the diseases.

ВИДІЛЕННЯ ІНГІБІТОРА ТРИПСИНУ НАСІННЯ ЛЮЦЕРНИ З ДОПОМОГОЮ АФФІННОЇ ХРОМАТОГРАФІЇ

A protein inhibitor of trypsin of the cultivar Eva alfalfa seeds was isolated and characterized. It has significant antiproteolytic activity and is promising for the creation of compositions that are designed to correct nutrition in various conditions, accompanied by increased activation of proteolytic enzymes. The stages of purification of the trypsin inhibitor from alfalfa seeds included: extraction of 0.05 M borate buffer (pH 7.6), fractionation of the protein component of the extract with ammonium sulfate, followed by dialysis of the fraction between 75% and 100% saturation and affinity chromatography on a biospecific sorbent trypsin - sepharose 4B. Calculations showed that from 100 g of alfalfa seeds of the cultivar Eva, 67.14 mg of trypsin inhibitor was obtained, the inhibitory activity of which is 27.6 IU / mg protein. Experimental data show that the obtained inhibitor reduces trypsin activity by 63.05% with a weight ratio of inhibitor: enzyme of 1: 1. It is known from literature that a soybean trypsin inhibitor reduces trypsin activity by 30%. The isolated trypsin inhibitor has significant inhibitory activity, the value of which is higher than the inhibitory activity of the plant trypsin inhibitor from soybeans. Affinity chromatography allowed us to obtain a pure, homogeneous trypsin inhibitor, which has significant antiproteolytic activity, which can be compared with the antiproteolytic activity of known plant trypsin inhibitors. From the obtained experimental data, it follows that both, the obtained inhibitor and the inhibitor, which is part of a commercial preparation, effectively reduce trypsin activity, slightly inhibit chymotrypsin activity, and do not affect α-amylase and protease activity. The above data indicate that the trypsin inhibitor of alfalfa seeds of the cultivar Eva is not a bifunctional inhibitor, since it does not affect the activity of amilolytic enzymes. The isolated inhibitor belongs to proteins with a high degree of hydrophobicity. The composition of amino acids, the side chains of which can take part in the formation of hydrogen bonds, is 25% of the total number of amino acid residues of the alfalfa seed trypsin inhibitor. For STI, this value is 23%.

HIV-1 Env-Dependent Cell Killing by Bifunctional Small-Molecule/Peptide Conjugates.

A strategy has been established for the synthesis of a family of bifunctional HIV-1 inhibitor covalent conjugates with the potential to bind simultaneously to both the gp120 and gp41 subunits of the HIV-1 envelope glycoprotein trimeric complex (Env). One component of the conjugates is derived from BNM-III-170, a small-molecule CD4 mimic that binds to gp120. The second component, comprised of the peptide DKWASLWNW ("Trp3"), was derived from the N-terminus of the HIV-1 gp41 Membrane Proximal External Region (MPER) and found previously to bind to the gp41 subunit of Env. The resulting bifunctional conjugates were shown to inhibit virus cell infection with low micromolar potency and to induce lysis of the HIV-1 virion. Crucially, virolysis was found to be dependent on the covalent linkage of the BNM-III-170 and Trp3 domains, as coadministration of a mixture of the un-cross-linked components proved to be nonlytic. However, a significant magnitude of lytic activity was observed in Env-negative and other control pseudoviruses, suggesting parallel mechanisms of action of the conjugates involving Env interaction and direct membrane disruption. Computational modeling suggested strong membrane-binding activity of BNM-III-170, which may underly the nonspecific virolytic effects of the conjugates. To investigate the scope of the membrane effect, cell-based cytotoxicity and membrane permeability assays were performed employing flow cytometry. Here, we observed a dose-dependent and specific cytotoxic effect on HIV-1 Env-expressing cells by the small-molecule bifunctional inhibitor. Most importantly, Env-negative cells were not susceptible to the cytotoxic effect upon exposure to this construct at concentrations where cell-killing effects were observed for Env-positive cells. Computational structural modeling supports a mechanism in which the bifunctional inhibitors bind to the gp120 and gp41 subunits in tandem in open-state Env trimers and induce relative motion of the gp120 subunits consistent with models of Env inactivation. This observation supports the idea that the cell-killing effect of the small-molecule bifunctional inhibitor is due to specific Env conformational triggering. This work lays important groundwork to advance a small-molecule bifunctional inhibitor approach for eliminating Env-expressing infected cells and the eradication of HIV-1.

Covalent Inhibition of Bacterial Urease by Bifunctional Catechol-Based Phosphonates and Phosphinates.

In this study, a new class of bifunctional inhibitors of bacterial ureases, important molecular targets for antimicrobial therapies, was developed. The structures of the inhibitors consist of a combination of a phosphonate or (2-carboxyethyl)phosphinate functionality with a catechol-based fragment, which are designed for complexation of the catalytic nickel ions and covalent bonding with the thiol group of Cys322, respectively. Compounds with three types of frameworks, including β-3,4-dihydroxyphenyl-, α-3,4-dihydroxybenzyl-, and α-3,4-dihydroxybenzylidene-substituted derivatives, exhibited complex and varying structure-dependent kinetics of inhibition. Among irreversible binders, methyl β-(3,4-dihydroxyphenyl)-β-(2-carboxyethyl)phosphorylpropionate was observed to be a remarkably reactive inhibitor of Sporosarcina pasteurii urease (kinact/KI = 10 420 s-1 M-1). The high potential of this group of compounds was also confirmed in Proteus mirabilis whole-cell-based inhibition assays. Some compounds followed slow-binding and reversible kinetics, e.g., methyl β-(3,4-dihydroxyphenyl)-β-phosphonopropionate, with Ki* = 0.13 μM, and an atypical low dissociation rate (residence time τ = 205 min).

Design, synthesis and biological evaluation of novel c-Met/HDAC dual inhibitors

In this work three novel series of c-Met/HDAC bifunctional inhibitors were designed and synthesized by merging pharmacophores of c-Met and HDAC inhibitors. The most potent compound 11j inhibited c-Met kinase and HDAC1 with IC50 values of 21.44 and 45.22 nM, respectively. In addition, 11j showed efficient antiproliferative activities against both MCF-7 and A549 cells with greater potency than the reference drug SAHA and Cabozantinib. This work may lay the foundation for developing novel dual c-Met/HDAC inhibitors as potential anticancer therapeutics.

Catch and Anchor Approach To Combat Both Toxicity and Longevity of Botulinum Toxin A.

Botulinum neurotoxins have remarkable persistence (∼weeks to months in cells), outlasting the small-molecule inhibitors designed to target them. To address this disconnect, inhibitors bearing two pharmacophores-a zinc binding group and a Cys-reactive warhead-were designed to leverage both affinity and reactivity. A series of first-generation bifunctional inhibitors was achieved through structure-based inhibitor design. Through X-ray crystallography, engagement of both the catalytic Zn2+ and Cys165 was confirmed. A second-generation series improved on affinity by incorporating known reversible inhibitor pharmacophores; the mechanism was confirmed by exhaustive dialysis, mass spectrometry, and in vitro evaluation against the C165S mutant. Finally, a third-generation inhibitor was shown to have good cellular activity and low toxicity. In addition to our findings, an alternative method of modeling time-dependent inhibition that simplifies assay setup and allows comparison of inhibition models is discussed.

Design, Synthesis, and Biological Evaluation of Dual c-Met/HDAC Inhibitors Bearing 2-Aminopyrimidine Scaffold

AbstractA series of c-Met/histone deacetylase (HDAC) bifunctional inhibitors was designed and synthesized by merging pharmacophores of c-Met and HDAC inhibitors. Among them, the most potent compound, 2o, inhibited c-Met kinase and HDACs, with IC50 values of 9.0 and 31.6 nM, respectively, and showed efficient antiproliferative activities against both A549 and HCT-116 cancer cell lines with greater potency than an equimolar mixture of the respective inhibitors of the two enzymes: crizotinib and vorinostat (SAHA). Our study provided an efficient strategy for the discovery of multitargeted antitumor drugs.

Discovery of Novel c-Mesenchymal-Epithelia transition factor and histone deacetylase dual inhibitors

Clinically, a single agent that simultaneously inhibits multiple targets has been widely used in cancer treatment to overcome complicated dose design and anti-cancer resistance. Inspired by the synergistic effects between c-Met and HDAC in tumor development, a novel series of c-Met/HDAC bifunctional inhibitors was designed and synthesized by merging the pharmacophores of HDAC inhibitor into a c-Met inhibitor. All the target compounds were evaluated for their biological activity, the most potent compound, 14x, exhibited strong inhibition against HDAC1 with an IC50 of 18.49 nM and remarkable inhibitory activity against c-Met with an IC50 of 5.40 nM, respectively. In addition, 14x efficiently inhibited the proliferation of HCT-116, MCF-7 and A549 cell lines with IC50 values of 0.22 μM, 1.59 μM and 0.22 μM, respectively, which were superior to the reference compounds Cabozantinib and SAHA. Futhermore, 14x induced apoptosis and cause cell cycle arrest in G2/M phase. Docking experiments on c-Met and HDAC enzymes revealed the key interactions between 14x with the target protein. These results indicated that 14x was a potent dual c-Met/HDAC inhibitor and deserved for further investigation.

Chemical strategies to overcome resistance against targeted anticancer therapeutics.

Emergence of resistance is a major factor limiting the efficacy of molecularly targeted anticancer drugs. Understanding the specific mutations, or other genetic or cellular changes, that confer drug resistance can help in the development of therapeutic strategies with improved efficacies. Here, we outline recent progress in understanding chemotype-specific mechanisms of resistance and present chemical strategies, such as designing drugs with distinct binding modes or using proteolysis targeting chimeras, to overcome resistance. We also discuss how targeting multiple binding sites with bifunctional inhibitors or identifying collateral sensitivity profiles can be exploited to limit the emergence of resistance. Finally, we highlight how incorporating analyses of resistance early in drug development can help with the design and evaluation of therapeutics that can have long-term benefits for patients.

Bifunctional Inhibitors from Capsicum chinense Seeds with Antimicrobial Activity and Specific Mechanism of Action Against Phytopathogenic Fungi.

Antimicrobial peptides (AMPs) are found in the defense system in virtually all life forms, being present in many, if not all, plant species. The present work evaluated the antimicrobial, enzymatic activity and mechanism of action of the PEF2 fraction from Capsicum chinense Jack. seeds against phytopathogenic fungi. Peptides were extracted from C. chinense seeds and subjected to reverse-phase chromatography on an HPLC system using a C18 column coupled to a C8 guard column, then the obtained PEF2 fraction was rechromatographed using a C2/C18 column. Two fractions, named PEF2A and PEF2B, were obtained. The fractions were tested for antimicrobial activity on Colletotrichum gloeosporioides, Colletotrichum lindemuthianum, Fusarium oxysporum and Fusarium solani. Trypsin inhibition assays, reverse zymographic detection of protease inhibition and α-amylase activity assays were also performed. The mechanism of action by which PEF2 acts on filamentous fungi was studied through analysis of membrane permeability and production of reactive oxygen species (ROS). Additionally, we investigated mitochondrial functionality and caspase activation in fungal cells. It is possible to observe that PEF2 significantly inhibited trypsin activity and T. molitor larval α-amylase activity. The PEF2 fraction was able to inhibit the growth of C. gloeosporioides, C. lindemuthianum and F. oxysporum. PEF2A inhibited the growth of C. lindemuthianum (75%) and F. solani (43%). PEF2B inhibited C. lindemuthianum growth (66%) and F. solani (94%). PEF2 permeabilized F. solani cell membranes and induced ROS in F. oxysporum and F. solani. PEF2 could dissipate mitochondrial membrane potential but did not cause the activation of caspases in all studied fungi. The results may contribute to the biotechnological application of these AMPs in the control of pathogenic microorganisms in plants of agronomic importance.

Design, Synthesis, and Biological Evaluation of Dual c-Met/HDAC Inhibitors Bearing 2-Aminopyrimidine Scaffold

AbstractA series of c-Met/histone deacetylase (HDAC) bifunctional inhibitors was designed and synthesized by merging pharmacophores of c-Met and HDAC inhibitors. Among them, the most potent compound, 2o, inhibited c-Met kinase and HDACs, with IC50 values of 9.0 and 31.6 nM, respectively, and showed efficient antiproliferative activities against both A549 and HCT-116 cancer cell lines with greater potency than an equimolar mixture of the respective inhibitors of the two enzymes: crizotinib and vorinostat (SAHA). Our study provided an efficient strategy for the discovery of multitargeted antitumor drugs.