Discovery of N,N'-diarylurea molecules with activity against multidrug-resistant Staphylococcus aureus.

The emergence and global spread of methicillin-resistant Staphylococcus aureus (MRSA) pose a serious threat to public health, underscoring the urgent need for novel antibacterial interventions. Here, we screened 18 newly synthesized N,N'-diarylurea derivatives to identify compounds with activity against MRSA. Our investigations led to the discovery of a small molecule, SCB-24, which exhibited promising antimicrobial activity against MRSA USA300. Notably, SCB-24 demonstrated high activity even in the presence of 10% fetal bovine serum and showed excellent selectivity for bacterial over mammalian cells. SCB-24 also showed potent activity against various MRSA strains, including those resistant to second- and third-line antibiotics. Importantly, the efficacy of SCB-24 was inferior to that of vancomycin in MRSA-infected Galleria mellonella larvae. Overall, our findings suggest that SCB-24 has great potential as a new therapeutic for multidrug-resistant S. aureus infections.

Multipathway regulation induced by 4-(phenylsulfonyl)morpholine derivatives against triple-negative breast cancer.

Phenotypic drug discovery (PDD) is an effective drug discovery approach by observation of therapeutic effects on disease phenotypes, especially in complex disease systems. Triple-negative breast cancer (TNBC) is composed of several complex disease features, including high tumor heterogeneity, high invasive and metastatic potential, and a lack of effective therapeutic targets. Therefore, identifying effective and novel agents through PDD is a current trend in TNBC drug development. In this study, 23 novel small molecules were synthesized using 4-(phenylsulfonyl)morpholine as a pharmacophore. Among these derivatives, GL24 (4m) exhibited the lowest half-maximal inhibitory concentration value (0.90 µM) in MDA-MB-231 cells. To investigate the tumor-suppressive mechanisms of GL24, transcriptomic analyses were used to detect the perturbation for gene expression upon GL24 treatment. Followed by gene ontology (GO) analysis, gene set enrichment analysis (GSEA), and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, multiple ER stress-dependent tumor suppressive signals were identified, such as unfolded protein response (UPR), p53 pathway, G2/M checkpoint, and E2F targets. Most of the identified pathways triggered by GL24 eventually led to cell-cycle arrest and then to apoptosis. In summary, we developed a novel 4-(phenylsulfonyl)morpholine derivative GL24 with a strong potential for inhibiting TNBC cell growth through ER stress-dependent tumor suppressive signals.

Large-scale data analysis for robotic yeast one-hybrid platforms and multi-disciplinary studies using GateMultiplex.

BACKGROUND: Yeast one-hybrid (Y1H) is a common technique for identifying DNA-protein interactions, and robotic platforms have been developed for high-throughput analyses to unravel the gene regulatory networks in many organisms. Use of these high-throughput techniques has led to the generation of increasingly large datasets, and several software packages have been developed to analyze such data. We previously established the currently most efficient Y1H system, meiosis-directed Y1H; however, the available software tools were not designed for processing the additional parameters suggested by meiosis-directed Y1H to avoid false positives and required programming skills for operation. RESULTS: We developed a new tool named GateMultiplex with high computing performance using C++. GateMultiplex incorporated a graphical user interface (GUI), which allows the operation without any programming skills. Flexible parameter options were designed for multiple experimental purposes to enable the application of GateMultiplex even beyond Y1H platforms. We further demonstrated the data analysis from other three fields using GateMultiplex, the identification of lead compounds in preclinical cancer drug discovery, the crop line selection in precision agriculture, and the ocean pollution detection from deep-sea fishery. CONCLUSIONS: The user-friendly GUI, fast C++ computing speed, flexible parameter setting, and applicability of GateMultiplex facilitate the feasibility of large-scale data analysis in life science fields.

Novel imidazopyridine suppresses STAT3 activation by targeting SHP-1.

The unregulated activation of STAT3 has been demonstrated to occur in many cancers and enhances tumour growth, migration, and invasion. Stimulation by cytokines, growth factors, and hormones triggers this activation by phosphorylating STAT3 at tyrosine 705. Novel imidazopyridine compounds were synthesized to evaluate the inhibition of STAT3 at Y705. Among the tested compounds, 16 reduced the level of phospho-STAT3, inhibited the downstream signalling cascade and subsequently attenuated the survival of hepatocellular carcinoma (HCC) cells. Further assays showed that the reduction effects of compound 16 on tyrosine 705 of STAT3 were attributed to up-regulation of protein tyrosine phosphatase SHP-1.

Alteration of SHP-1/p-STAT3 Signaling: A Potential Target for Anticancer Therapy.

The Src homology 2 (SH2) domain-containing protein tyrosine phosphatase 1 (SHP-1), a non-receptor protein tyrosine phosphatase, has been reported as a negative regulator of phosphorylated signal transducer and activator of transcription 3 (STAT3) and linked to tumor development. In this present review, we will discuss the importance and function of SHP-1/p-STAT3 signaling in nonmalignant conditions as well as malignancies, its cross-talk with other pathways, the current clinical development and the potential role of inhibitors of this pathway in anticancer therapy and clinical relevance of SHP-1/p-STAT3 in cancers. Lastly, we will summarize and highlight work involving novel drugs/compounds targeting SHP-1/p-STAT3 signaling and combined strategies that were/are discovered in our and our colleagues' laboratories.

Design and Synthesis of Malonamide Derivatives as Antibiotics against Methicillin-Resistant Staphylococcus aureus.

Methicillin-resistant Staphylococcus aureus (MRSA) is a serious threat to humans. Most existing antimicrobial drugs, including the ß-lactam and quinoxiline classes, are not effective against MRSA. In this study, we synthesized 24 derivatives of malonamide, a new class of antibacterial agents and potentiators of classic antimicrobials. A derivative that increases bacterial killing and biofilm eradication with low cell toxicity was created.

In vitro and in vivo activity of a novel sorafenib derivative SC5005 against MRSA.

OBJECTIVES: The emergence of MRSA strains resistant to most antibiotics is a serious threat to public health. Based on our discovery that the tyrosine kinase inhibitor sorafenib exhibits inhibitory activity against Staphylococcus species, the objective of this study is to exploit this unique antibacterial activity of sorafenib to develop novel antibacterial agents against MRSA. METHODS: A sorafenib-based focused compound library was synthesized by substituting the pyridinyl and phenyl groups with different functional groups. The resulting sorafenib derivatives were screened for growth-suppressive activities against Staphylococcus aureus and Staphylococcus epidermidis following CLSI guidelines and for cytotoxicity towards human cells using MTT cell viability assays. Compounds with high selectivity for bacterial inhibition over cytotoxicity were further evaluated by time-kill assay and Caenorhabditis elegans and mice survival assays to evaluate their efficacy in vitro and in vivo. RESULTS: The screening of sorafenib derivatives led to the identification of compound SC5005 as a lead compound with high potency in killing different clinical strains of MRSA with an MIC90 of 0.5 mg/L and with low cytotoxicity, as demonstrated by IC50-to-MIC ratios of up to 40. In addition, SC5005 showed a significant protective effect in MSSA- or MRSA-infected C. elegans. Intraperitoneal administration of SC5005 at 10 mg/kg significantly improved the survival of MRSA-infected C57BL/6 mice. CONCLUSIONS: In light of its high potency in suppressing MRSA in both in vitro and in vivo models, SC5005 represents a potential lead agent for continued preclinical development as a therapeutic intervention against MRSA.

RFX-1-dependent activation of SHP-1 inhibits STAT3 signaling in hepatocellular carcinoma cells.

Regulatory factor X-1 (RFX-1) is a transcription factor that has been linked to negative regulation of tumor progression; however, its biological function and signaling cascades are unknown. Here, we performed several studies to elucidate the roles of RFX-1 in the regulation of SHP-1 in hepatocellular carcinoma (HCC) cells. Overexpression of RFX-1 resulted in the activation of SHP-1 and repressed colony formation of HCC cells. In addition, by a mouse xenograft model, we demonstrated that RFX-1 overexpression also inhibited the tumor growth of HCC cells in vivo, suggesting that RFX-1 is of potential interest for small-molecule-targeted therapy. We also found that SC-2001, a bipyrrole molecule, induced apoptosis in HCC cells through activating RFX-1 expression. SC-2001 induced RFX-1 translocation from the cytosol to nucleus, bound to the SHP-1 promoter, and activated SHP-1 transcription. In a xenograft model, knockdown of RFX-1 reversed the antitumor effect of SC-2001. Notably, SC-2001 is much more potent than sorafenib, a clinically approved drug for HCC, in in vitro and in vivo assays. Our study confirmed that RFX-1 acts as a tumor suppressor in HCC and might be a new target for HCC therapy. The findings of this study also provide a new lead compound for targeted therapy via the activation of the RFX-1/SHP-1 pathway.

Tamoxifen induces apoptosis through cancerous inhibitor of protein phosphatase 2A-dependent phospho-Akt inactivation in estrogen receptor-negative human breast cancer cells.

INTRODUCTION: Tamoxifen, a selective estrogen receptor (ER) modulator, may affect cancer cell survival through mechanisms other than ER antagonism. In the present study, we tested the efficacy of tamoxifen in a panel of ER-negative breast cancer cell lines and examined the drug mechanism. METHODS: In total, five ER-negative breast cancer cell lines (HCC-1937, MDA-MB-231, MDA-MB-468, MDA-MB-453 and SK-BR-3) were used for in vitro studies. Cellular apoptosis was examined by flow cytometry and Western blot analysis. Signal transduction pathways in cells were assessed by Western blot analysis. The in vivo efficacy of tamoxifen was tested in xenograft nude mice. RESULTS: Tamoxifen induced significant apoptosis in MDA-MB-231, MDA-MB-468, MDA-MB-453 and SK-BR-3 cells, but not in HCC-1937 cells. Tamoxifen-induced apoptosis was associated with inhibition of cancerous inhibitor of protein phosphatase 2A (CIP2A) and phospho-Akt (p-Akt) in a dose-dependent manner. Ectopic expression of either CIP2A or Akt protected MDA-MB-231 cells from tamoxifen-induced apoptosis. In addition, tamoxifen increased protein phosphatase 2A (PP2A) activity, and tamoxifen-induced apoptosis was attenuated by the PP2A antagonist okadaic acid in the sensitive cell lines, but not in resistant HCC-1937 cells. Moreover, silencing CIP2A by small interfering RNA sensitized HCC-1937 cells to tamoxifen-induced apoptosis. Furthermore, tamoxifen regulated CIP2A protein expression by downregulating CIP2A mRNA. Importantly, tamoxifen inhibited the in vivo growth of MDA-MB-468 xenograft tumors in association with CIP2A downregulation, whereas tamoxifen had no significant effect on CIP2A expression and anti-tumor growth in HCC-1937 tumors. CONCLUSIONS: Inhibition of CIP2A determines the effects of tamoxifen-induced apoptosis in ER-negative breast cancer cells. Our data suggest a novel "off-target" mechanism of tamoxifen and suggest that CIP2A/PP2A/p-Akt signaling may be a feasible anti-cancer pathway.

Obatoclax analog SC-2001 inhibits STAT3 phosphorylation through enhancing SHP-1 expression and induces apoptosis in human breast cancer cells.

Interfering oncogenic STAT3 signaling is a promising anti-cancer strategy. We examined the efficacy and drug mechanism of an obatoclax analog SC-2001, a novel STAT3 inhibitor, in human breast cancer cells. Human breast cancer cell lines were used for in vitro studies. Apoptosis was examined by both flow cytometry and western blot. Signaling pathways were assessed by western blot. In vivo efficacy of SC-2001 was tested in xenograft nude mice. SC-2001 inhibited cell growth and induced apoptosis in association with downregulation of p-STAT3 (Tyr 705) in breast cancer cells. STAT3-regulated proteins, including Mcl-1, survivin, and cyclin D1, were repressed by SC-2001. Over-expression of STAT3 in MDA-MB-468 cells protected cells from SC-2001-induced apoptosis. Moreover, SC-2001 enhanced the expression of protein tyrosine phosphatase SHP-1, a negative regulator of STAT3. Furthermore, the enhanced SHP-1 expression, in conjunction with increased SHP-1 phosphatase activity, was mediated by upregulated transcription by RFX-1. Chromatin immunoprecipitation assay revealed that SC-2001 increased the binding capacity of RFX-1 to the SHP-1 promoter. Knockdown of either RFX-1 or SHP-1 reduced SC-2001-induced apoptosis, whereas ectopic expression of RFX-1 increased SHP-1 expression and enhanced the apoptotic effect of SC-2001. Importantly, SC-2001 suppressed tumor growth in association with enhanced RFX-1 and SHP-1 expression and p-STAT3 downregulation in MDA-MB-468 xenograft tumors. SC-2001 induced apoptosis in breast cancer cells, an effect that was mediated by RFX-1 upregulated SHP-1 expression and SHP-1-dependent STAT3 inactivation. Our study indicates targeting STAT3 signaling pathway may be a useful approach for the development of targeted agents for anti-breast cancer.

Discovery of new dibenzodiazepine derivatives as antibacterials against intracellular bacteria.

The emergence and spread of multidrug-resistant bacteria underscore the critical need for novel antibacterial interventions. In our screening of 12 synthesized thienobenzodiazepines, pyridobenzodiazepines, and dibenzodiazepines, we successfully identified a small molecule compound SW33. Notably, SW33 demonstrated potent inhibitory activity against intracellular multidrug-resistant and fluoroquinolone-resistant strains of S. typhimurium in both macrophages and epithelial cells. Furthermore, SW33 was also effective against intramacrophagic Salmonella typhi, Yersinia enterocolitica, and Listeria monocytogenes. These significant findings suggest that SW33 possesses broad-spectrum activity against intracellular bacteria.

Targeting TGFß receptor-mediated snail and twist: WSG, a polysaccharide from Ganoderma lucidum, and it-based dissolvable microneedle patch suppress melanoma cells.

Cutaneous melanoma is a lethal skin cancer variant with pronounced aggressiveness and metastatic potential. However, few targeted medications inhibit the progression of melanoma. Ganoderma lucidum, which is a type of mushroom, is widely used as a non-toxic alternative adjunct therapy for cancer patients. This study determines the effect of WSG, which is a water-soluble glucan that is derived from G. lucidum, on melanoma cells. The results show that WSG inhibits cell viability and the mobility of melanoma cells. WSG induces changes in the expression of epithelial-to-mesenchymal transition (EMT)-related markers. WSG also downregulates EMT-related transcription factors, Snail and Twist. Signal transduction assays show that WSG reduces the protein levels in transforming growth factor ß receptors (TGFßRs) and consequently inhibits the phosphorylation of intracellular signaling molecules, such as FAK, ERK1/2 and Smad2. An In vivo study shows that WSG suppresses melanoma growth in B16F10-bearing mice. To enhance transdermal drug delivery and prevent oxidation, two highly biocompatible compounds, polyvinyl alcohol (PVA) and polyvinylpyrrolidone (PVP), are used to synthesize a dissolvable microneedle patch that is loaded with WSG (MN-WSG). A functional assay shows that MN-WSG has an effect that is comparable to that of WSG alone. These results show that WSG has significant potential as a therapeutic agent for melanoma treatment. MN-WSG may allow groundbreaking therapeutic approaches and offers a novel method for delivering this potent compound effectively.

Novel sorafenib analogues induce apoptosis through SHP-1 dependent STAT3 inactivation in human breast cancer cells.

INTRODUCTION: Signal transducers and activators of transcription 3 (STAT3) signaling is constitutively activated in various cancers including breast cancer and has emerged as a novel potential anti-cancer target. STAT3 has been demonstrated to be a target of sorafenib, and a protein tyrosine phosphatase Src homology 2-domain containing tyrosine phosphatase 1 (SHP-1) has been demonstrated to downregulate p-STAT3 via its phosphatase activity. Here, we tested the efficacy of two sorafenib analogues, SC-1 and SC-43, in breast cancer cells and examined the drug mechanism. METHODS: Breast cancer cell lines were used for in vitro studies. Cell viability was examined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Apoptosis was examined by flow cytometry and western blot. Signal transduction pathways in cells were assessed by western blot. In vivo efficacy of sorafenib, SC-1 and SC-43 was tested in xenografted nude mice. RESULTS: SC-1 and SC-43 induced more potent apoptosis than sorafenib, in association with downregulation of p-STAT3 and its downstream proteins cyclin D1 and survivin in a dose-dependent manner in breast cancer cell lines (HCC-1937, MDA-MB-468, MDA-MB-231, MDA-MB-453, SK-BR3, MCF-7). Overexpression of STAT3 in MDA-MB-468 cells protected the cells from apoptosis induced by sorafenib, SC-1 and SC-43. Moreover, SC-1 and SC-43 upregulated SHP-1 activity to a greater extent than sorafenib as measured by in vitro phosphatase assays. Knockdown of SHP-1 by siRNA reduced apoptosis induced by SC-1 and SC-43. Importantly, SC-1 and SC-43 showed more efficacious antitumor activity and p-STAT3 downregulation than sorafenib in MDA-MB-468 xenograft tumors. CONCLUSIONS: Novel sorafenib analogues SC-1 and SC-43 induce apoptosis through SHP-1 dependent STAT3 inactivation and demonstrate greater potency than sorafenib in human breast cancer cells.

Single-cell transcriptomics unveils xylem cell development and evolution.

BACKGROUND: Xylem, the most abundant tissue on Earth, is responsible for lateral growth in plants. Typical xylem has a radial system composed of ray parenchyma cells and an axial system of fusiform cells. In most angiosperms, fusiform cells comprise vessel elements for water transportation and libriform fibers for mechanical support, while both functions are performed by tracheids in other vascular plants such as gymnosperms. Little is known about the developmental programs and evolutionary relationships of these xylem cell types. RESULTS: Through both single-cell and laser capture microdissection transcriptomic profiling, we determine the developmental lineages of ray and fusiform cells in stem-differentiating xylem across four divergent woody angiosperms. Based on cross-species analyses of single-cell clusters and overlapping trajectories, we reveal highly conserved ray, yet variable fusiform, lineages across angiosperms. Core eudicots Populus trichocarpa and Eucalyptus grandis share nearly identical fusiform lineages, whereas the more basal angiosperm Liriodendron chinense has a fusiform lineage distinct from that in core eudicots. The tracheids in the basal eudicot Trochodendron aralioides, an evolutionarily reversed trait, exhibit strong transcriptomic similarity to vessel elements rather than libriform fibers. CONCLUSIONS: This evo-devo framework provides a comprehensive understanding of the formation of xylem cell lineages across multiple plant species spanning over a hundred million years of evolutionary history.

Development of erlotinib derivatives as CIP2A-ablating agents independent of EGFR activity.

Cancerous inhibitor of PP2A (CIP2A) is a novel human oncoprotein that inhibits PP2A, contributing to tumor aggressiveness in various cancers. Several studies have shown that downregulation of CIP2A by small molecules reduces PP2A-dependent phosphorylation of Akt and induces cell death. Here, a series of mono- and di-substituted quinazoline and pyrimidine derivatives based on the skeleton of erlotinib (an EGFR inhibitor) were synthesized and their bioactivities against hepatocellular carcinoma were evaluated. The di-substituted quinazoline and pyrimidine derivatives were more potent inhibitors of cancer-cell proliferation than the mono-substituted derivatives. In particular, compound 1 with chloride at position 2 of quinazoline was as potent as erlotinib in inducing cell death but no inhibition for EGFR activity. Further assays confirmed a correlation between cell death, and CIP2A and Akt inhibition by these derivatives. Among all the derivatives, compounds 19 and 22 showed the most potent antiproliferative activities and the strongest inhibition of CIP2A and p-Akt expression.

A novel AMPK activator shows therapeutic potential in hepatocellular carcinoma by suppressing HIF1α-mediated aerobic glycolysis.

Hepatocellular carcinoma (HCC) is characterized by rapid growth, early vascular invasion, and high metastasis. Currently available US Food and Drug Administration (FDA)-approved drugs show low therapeutic efficacy, limiting HCC treatment to chemotherapy. We designed and synthesized a novel small molecule, SCT-1015, that allosterically activated adenosine monophosphate-activated protein kinase (AMPK) to suppress the aerobic glycolysis in HCC. SCT-1015 was shown to bind the AMPK α and ß-subunit interface, thereby exposing the kinase α domain to the upstream kinases, resulting in the increased AMPK activity. SCT-1015 dramatically reduced HCC cell growth in vitro and tumor growth in vivo. We further found that AMPK formed protein complexes with hypoxia-inducible factor 1-alpha (HIF1α) and that SCT-1015-activated AMPK promoted hydroxylation of HIF1α (402P and 564P), resulting in HIF1α degradation by the ubiquitin-proteasome system. With declined HIF1α abundance, many glycolysis-related enzymes were downregulated, suppressing aerobic glycolysis, and promoting oxidative phosphorylation. These results indicated that SCT-1015 channeled HCC cells into an unfavorable metabolic status. Overall, we reported SCT-1015 as a direct activator of AMPK signaling that held therapeutic potential in HCC.

Concomitant inactivation of the epidermal growth factor receptor, phosphatidylinositol 3-kinase/Akt and Janus tyrosine kinase 2/signal transducer and activator of transcription 3 signalling pathways in cardiotoxin III-treated A549 cells.

1. Cardiotoxin (CTX) III, a basic polypeptide with 60 amino acid residues isolated from Naja naja atra venom, has potential anticancer therapeutic activity. The aim of the present study was to investigate the apoptotic effect (and the underlying mechanism of action) of CTX III in human adenocarcinoma A549 cells. 2. It was found that CTX III induces apoptosis in A549 cells, as indicated by an increase in the sub-G(1) population, phosphatidylserine externalization, loss of mitochondrial membrane potential (Psi(m)) with cytochrome c release and activation of caspases 9 and 3. These actions were correlated with upregulation of Bax and Bad and downregulation of various anti-apoptotic proteins, including Bcl-2, Bcl-X(L), Mcl-1, X-linked inhibitor of apoptosis protein (XIAP) and p-Bad in CTX III-treated cells. 3. The signal transduction pathways involved in the effects of CTX III in A549 cells were evaluated using 5 micromol/L AG1478, an inhibitor of the epidermal growth factor receptor (EGFR), and exposing cells to the drug for 8 h. The results indicated that CTX III suppresses phosphorylation of EGFR and activation of phosphatidylinositol 3-kinase (PI3-K)/Akt and Janus tyrosine kinase (JAK) 2/signal transducer and activator of transcription (STAT) 3, all of which are downstream molecules in the EGFR signalling pathway. 4. Exposure of cells for 8 h to the PI3-K inhibitor wortmannin (10 micromol/L) blocked JAK2 and STAT3 activation, whereas exposure of cells to the JAK2 inhibitor AG490 (5 micromol/L) decreased levels of phosphorylated (p-) JAK2 and p-STAT3 without affecting PI3-K/Akt activation. These observations suggest that PI3-K is an upstream activator of JAK2/STAT3. Furthermore, 5 micromol/L AG490 and 10 micromol/L wortmannin treatment of A549 cells for 8 h resulted in upregulation of Bax and Bad and downregulation of Bcl-2, Bcl-X(L), XIAP and p-Bad. 5. Together, the results of the present study indicate that CTX III induces apoptosis in A549 cells by inactivating the EGFR, PI3-K/Akt and JAK2/STAT3 signalling pathways.

Inactivation of epidermal growth factor receptor and downstream pathways in oral squamous cell carcinoma Ca9-22 cells by cardiotoxin III from Naja naja atra.

Cardiotoxin III (1), a basic polypeptide with 60 amino acid residues isolated from Naja naja atra venom, has potential therapeutic activity in cancer. Treatment with 1 reduced phosphorylation of EGFR and Akt, as well as ERK in Ca9-22 cells. Moreover, 1-treatment inhibited constitutive activation of STAT3 and STAT5 in a time-dependent manner. Up-regulation of Bax and down-regulation of anti-apoptotic proteins including Bcl-2, Bcl-X(L), and myeloid cell leukemia-1(Mcl-1) were also found in cells treated with 1. In addition, 1-treatment disrupted mitochondrial membrane potential (DeltaPsim) and resulted in release of mitochondrial cytochrome c and activation of both caspases-9 and -3. AG1478, a specific pharmacological inhibitor of EGFR activation, mimics the cytotoxic effects of 1. Taken together, these results showed that 1 causes significant induction of apoptosis in Ca9-22 cells via abolition of the EGFR-mediated survival pathway of these cells. Thus, cardiotoxin III appears to be a potential therapeutic agent for killing oral squamous carcinoma Ca9-22 cells.

Novel indoloquinoline derivative, IQDMA, inhibits STAT5 signaling associated with apoptosis in K562 cells.

N'-(11H-indolo[3,2-c]quinolin-6-yl)-N,N-dimethylethane-1,2-diamine (IQDMA), an indoloquinoline derivative, synthesized in our laboratory, has been demonstrated to be an effective antitumor agent in human leukemia cells. In the present study, treatment with IQDMA inhibited phosphorylation of epidermal growth factor receptor (EGFR), Src, Bcr-Abl, and Janus-activated kinase (JAK2) in a time-dependent manner. IQDMA also degraded JAK2 protein. Moreover, signal transducer and activator of transcription 5 (STAT5) signaling were also blocked by IQDMA. However, IQDMA did not inhibit other oncogenic and tumor survival pathways such as those mediated by Akt and extracellular signal-regulated kinase 1/2. Furthermore, IQDMA upregulated the expression of p21 and p27 and downregulated the expression of cyclin D1, myeloid cell leukemia-1(Mcl-1), Bcl-X(L), and vascular endothelial growth factor (VEGF). Taken together, these results indicate that IQDMA causes significant induction of apoptosis in K562 cells via downregulation of EGFR, Src, Bcr-Abl, JAK2, and STAT5 signaling and modulation of p21, p27, cyclin D1, Mcl-1, Bcl-X(L), and VEGF proteins. Thus, IQDMA appears to be a potential therapeutic agent for treating leukemia K562 cells.