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Clinical Cancer Research : An Official... Dec 2013To investigate the antitumor effects of targeting Src and tubulin in mucinous ovarian carcinoma.
PURPOSE
To investigate the antitumor effects of targeting Src and tubulin in mucinous ovarian carcinoma.
EXPERIMENTAL DESIGN
The in vitro and in vivo effects and molecular mechanisms of KX-01, which inhibits Src pathway and tubulin polymerization, were examined in mucinous ovarian cancer models.
RESULTS
In vitro studies using RMUG-S and RMUG-L cell lines showed that KX-01 inhibited cell proliferation, induced apoptosis, arrested the cell cycle at the G2-M phase, and enhanced the cytotoxicity of oxaliplatin in the KX-01-sensitive cell line, RMUG-S. In vivo studies showed that KX-01 significantly decreased tumor burden in RMUG-S and RMUG-L mouse models relative to untreated controls, and the effects were greater when KX-01 was combined with oxaliplatin. KX-01 alone and in combination with oxaliplatin significantly inhibited tumor growth by reducing cell proliferation and inducing apoptosis in vivo. PTEN knock-in experiments in RMUG-L cells showed improved response to KX-01. Reverse phase protein array analysis showed that in addition to blocking downstream molecules of Src family kinases, KX-01 also activated acute stress-inducing molecules.
CONCLUSION
Our results showed that targeting both the Src pathway and tubulin with KX-01 significantly inhibited tumor growth in preclinical mucinous ovarian cancer models, suggesting that this may be a promising therapeutic approach for patients with mucinous ovarian carcinoma.
Topics: Acetamides; Adenocarcinoma, Mucinous; Animals; Antineoplastic Agents; Apoptosis; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Synergism; Female; Humans; Inhibitory Concentration 50; Mice; Mice, Nude; Microtubules; Morpholines; Organoplatinum Compounds; Ovarian Neoplasms; Oxaliplatin; PTEN Phosphohydrolase; Protein Multimerization; Pyridines; Tubulin Modulators; Tumor Burden; Xenograft Model Antitumor Assays; src-Family Kinases
PubMed: 24100628
DOI: 10.1158/1078-0432.CCR-13-1305 -
JAAD Case Reports Oct 2022
PubMed: 36090193
DOI: 10.1016/j.jdcr.2022.07.035 -
Frontiers in Pharmacology 2021Structural changes of small-molecule drugs may bring interesting biological properties, especially in the field of kinase inhibitors. We sought to study tirbanibulin, a...
Structural changes of small-molecule drugs may bring interesting biological properties, especially in the field of kinase inhibitors. We sought to study tirbanibulin, a first-in-class dual Src kinase (non-ATP competitive)/tubulin inhibitor because there was not enough reporting about its structure-activity relationships (SARs). In particular, the present research is based on the replacement of the outer ring of the biphenyl system of 2-[(1,1'-biphenyl)-4-yl]--benzylacetamide, the identified pharmacophore of KX chemotype, with a heterocyclic ring. The newly synthesized compounds showed a range of activities in cell-based anticancer assays, agreeing with a clear SAR profile. The most potent compound, ()--benzyl-4-[4-(4-methoxybenzylidene)-2-methyl-5-oxo-4,5-dihydro-1-imidazol-1-yl]phenylacetamide (KIM-161), demonstrated cytotoxic IC values at 294 and 362 nM against HCT116 colon cancer and HL60 leukemia cell lines, respectively. Profiling of this compound (aqueous solubility, liver microsomal stability, cytochrome P450 inhibition, reactivity with reduced glutathione, and plasma protein binding) confirmed its adequate drug-like properties. Mechanistic studies revealed that this compound does not depend on tubulin or Src kinase inhibition as a factor in forcing HL60 to exit its cell cycle and undergo apoptosis. Instead, KIM-161 downregulated several other kinases such as members of BRK, FLT, and JAK families. It also strongly suppresses signals of ERK1/2, GSK-3α/β, HSP27, and STAT2, while it downregulated AMPKα1 phosphorylation within the HL60 cells. Collectively, these results suggest that phenylacetamide-1-imidazol-5-one (KIM-161) could be a promising lead compound for further clinical anticancer drug development.
PubMed: 35069208
DOI: 10.3389/fphar.2021.794325 -
Cell Reports Jun 2021To identify therapeutic targets for KRAS mutant pancreatic cancer, we conduct a druggable genome small interfering RNA (siRNA) screen and determine that suppression of...
To identify therapeutic targets for KRAS mutant pancreatic cancer, we conduct a druggable genome small interfering RNA (siRNA) screen and determine that suppression of BCAR1 sensitizes pancreatic cancer cells to ERK inhibition. Integrative analysis of genome-scale CRISPR-Cas9 screens also identify BCAR1 as a top synthetic lethal interactor with mutant KRAS. BCAR1 encodes the SRC substrate p130Cas. We determine that SRC-inhibitor-mediated suppression of p130Cas phosphorylation impairs MYC transcription through a DOCK1-RAC1-β-catenin-dependent mechanism. Additionally, genetic suppression of TUBB3, encoding the βIII-tubulin subunit of microtubules, or pharmacological inhibition of microtubule function decreases levels of MYC protein in a calpain-dependent manner and potently sensitizes pancreatic cancer cells to ERK inhibition. Accordingly, the combination of a dual SRC/tubulin inhibitor with an ERK inhibitor cooperates to reduce MYC protein and synergistically suppress the growth of KRAS mutant pancreatic cancer. Thus, we demonstrate that mechanistically diverse combinations with ERK inhibition suppress MYC to impair pancreatic cancer proliferation.
Topics: Acetamides; Apoptosis; Calpain; Cell Line, Tumor; Cell Proliferation; Crk-Associated Substrate Protein; Down-Regulation; Drug Synergism; Extracellular Signal-Regulated MAP Kinases; Gene Expression Regulation, Neoplastic; Half-Life; Humans; Microtubules; Morpholines; Mutation; Organoids; Pancreatic Neoplasms; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-myc; Proto-Oncogene Proteins p21(ras); Pyridines; Transcription, Genetic; Tubulin; Xenograft Model Antitumor Assays; src-Family Kinases
PubMed: 34192548
DOI: 10.1016/j.celrep.2021.109291 -
Journal of Immunology Research 2022Cuproptosis is a newly discovered copper-independent cell death modality, and limited evidence suggests the critical implications in human cancers. Nonetheless, the...
OBJECTIVE
Cuproptosis is a newly discovered copper-independent cell death modality, and limited evidence suggests the critical implications in human cancers. Nonetheless, the clinical impacts of cuproptosis-relevant lncRNAs in lung adenocarcinoma (LUAD) remain largely ill-defined. The present study was aimed at defining a cuproptosis-relevant lncRNA signature for LUAD and discuss the clinical utility.
METHODS
We collected transcriptome expression profiling, clinical information, somatic mutation, and copy number variations from TCGA-LUAD cohort retrospectively. The genetic alterations of cuproptosis genes were systematically assessed across LUAD, and cuproptosis-relevant lncRNAs were screened for defining a LASSO prognostic model. Genomic alterations, immunological and stemness features, and therapeutic sensitivity were studied with a series of computational approaches.
RESULTS
Cuproptosis genes displayed aberrant expression and widespread genomic alterations across LUAD, potentially modulated by m6A/m5C/m1A RNA modification mechanisms. We defined a cuproptosis-relevant lncRNA signature, with a reliable efficacy in predicting clinical outcomes. High-risk subset displayed higher somatic mutations, CNVs, TMB, SNV neoantigens, aneuploidy score, CTA score, homologous recombination defects, and intratumor heterogeneity, cytolytic activity, CD8+ T effector, and antigen processing machinery, proving that this subset might benefit from immunotherapy. Increased stemness indexes and activity of oncogenic pathways might contribute to undesirable prognostic outcomes for high-risk subset. Additionally, high-risk patients generally exhibited higher response to chemotherapeutic agents (cisplatin, etc.). We also predicted several small molecule compounds (GSK461364, KX2-391, etc.) for treating this subset.
CONCLUSION
Accordingly, this cuproptosis-relevant lncRNA signature offers an efficient approach to identify and characterize diverse prognosis, genomic alterations, and treatment outcomes in LUAD, thus potentially assisting personalized therapy.
Topics: Humans; Adenocarcinoma; Biomarkers, Tumor; Cisplatin; Copper; DNA Copy Number Variations; Gene Expression Regulation, Neoplastic; Genomics; Lung; Lung Neoplasms; Retrospective Studies; RNA, Long Noncoding; ROC Curve; Apoptosis
PubMed: 36281357
DOI: 10.1155/2022/2756611 -
Cancer Medicine Dec 2013Recurrence of prostate cancer (CaP) after androgen-deprivation therapy continues to have the greatest impact on patient survival. Castration-recurrent (CR)-CaP is likely...
Recurrence of prostate cancer (CaP) after androgen-deprivation therapy continues to have the greatest impact on patient survival. Castration-recurrent (CR)-CaP is likely driven by the activation of androgen receptor (AR) through multiple mechanisms including induction of AR coregulators, AR mutants or splice variants, and AR posttranslational modification such as phosphorylation by Src-family and Ack1 tyrosine kinases. Here, we address whether Src is required for the CR growth of human CWR22 CaP xenografts. The shRNA-mediated Src knockdown or treatment with the Src inhibitors, dasatinib or KXO1, reduced CaP recurrence over controls and increased time-to-recurrence following castration. Moreover, CR-CaP [Src-shRNA] tumors that recurred had similar Src protein and activation levels as those of parental cells, strengthening the notion that Src activity is required for progression to CR-CaP. In contrast, the ability of dasatinib or KXO1 to inhibit Src kinase activity in vitro did not correlate with their ability to inhibit serum-driven in vitro proliferation of CR and androgen-dependent stable cell lines derived from CWR22 tumors (CWR22Rv1 and CWR22PC, respectively), suggesting that the in vitro proliferation of these CaP lines is Src independent. Taken together, these findings strongly suggest that Src is a potent and specific therapeutic target for CR-CaP progression.
Topics: Acetamides; Animals; Antineoplastic Agents; Cell Line, Tumor; Dasatinib; HEK293 Cells; Humans; Male; Mice; Mice, Nude; Morpholines; Neoplasm Recurrence, Local; Orchiectomy; Prostatic Neoplasms; Protein Kinase Inhibitors; Pyridines; Pyrimidines; RNA, Small Interfering; Thiazoles; Xenograft Model Antitumor Assays; src-Family Kinases
PubMed: 24403252
DOI: 10.1002/cam4.144 -
Molecular Cancer Research : MCR Nov 2017Unlike breast cancer that is positive for estrogen receptor-α (ERα), there are no targeted therapies for triple-negative breast cancer (TNBC). ERα is silenced in TNBC...
Unlike breast cancer that is positive for estrogen receptor-α (ERα), there are no targeted therapies for triple-negative breast cancer (TNBC). ERα is silenced in TNBC through epigenetic changes including DNA methylation and histone acetylation. Restoring ERα expression in TNBC may sensitize patients to endocrine therapy. Expression of c-Src and ERα are inversely correlated in breast cancer suggesting that c-Src inhibition may lead to reexpression of ERα in TNBC. KX-01 is a peptide substrate-targeted Src/pretubulin inhibitor in clinical trials for solid tumors. KX-01 (1 mg/kg body weight-twice daily) inhibited growth of tamoxifen-resistant MDA-MB-231 and MDA-MB-157 TNBC xenografts in nude mice that was correlated with Src kinase inhibition. KX-01 also increased ERα mRNA and protein, as well as increased the ERα targets progesterone receptor (PR), pS2 (TFF1), cyclin D1 (CCND1), and c-myc (MYC) in MDA-MB-231 and MDA-MB-468, but not MDA-MB-157 xenografts. MDA-MB-231 and MDA-MB-468 tumors exhibited reduction in mesenchymal markers (vimentin, β-catenin) and increase in epithelial marker (E-cadherin) suggesting mesenchymal-to-epithelial transition (MET). KX-01 sensitized MDA-MB-231 and MDA-MB-468 tumors to tamoxifen growth inhibition and tamoxifen repression of the ERα targets pS2, cyclin D1, and c-myc. Chromatin immunoprecipitation (ChIP) of the ERα promoter in KX-01-treated tumors demonstrated enrichment of active transcription marks (acetyl-H3, acetyl-H3Lys9), dissociation of HDAC1, and recruitment of RNA polymerase II. Methylation-specific PCR and bisulfite sequencing demonstrated no alteration in ERα promoter methylation by KX-01. These data demonstrate that in addition to Src kinase inhibition, peptidomimetic KX-01 restores ERα expression in TNBC through changes in histone acetylation that sensitize tumors to tamoxifen. Src kinase/pretubulin inhibitor KX-01 restores functional ERα expression in ERα breast tumors, a novel treatment strategy to treat triple-negative breast cancer. .
Topics: Acetamides; Animals; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Synergism; Epithelial-Mesenchymal Transition; Estrogen Receptor alpha; Female; Gene Expression Regulation, Neoplastic; Humans; Mice; Morpholines; Pyridines; Tamoxifen; Treatment Outcome; Triple Negative Breast Neoplasms; Xenograft Model Antitumor Assays
PubMed: 28751463
DOI: 10.1158/1541-7786.MCR-16-0297-T -
Cancer Research and Treatment Jul 2017KX-01 is a novel dual inhibitor of Src and tubulin. Unlike previous Src inhibitors that failed to show clinical benefit during treatment of breast cancer, KX-01 can...
PURPOSE
KX-01 is a novel dual inhibitor of Src and tubulin. Unlike previous Src inhibitors that failed to show clinical benefit during treatment of breast cancer, KX-01 can potentially overcome the therapeutic limitations of current Src inhibitors through inhibition of both Src and tubulin. The present study further evaluates the activity and mechanism of KX-01 and .
MATERIALS AND METHODS
The antitumor effect of KX-01 in triple negative breast cancer (TNBC) cell lines was determined by MTT assay. Wound healing and immunofluorescence assays were performed to evaluate the action mechanisms of KX-01. Changes in the cell cycle and molecular changes induced by KX-01 were also evaluated. A MDA-MB-231 mouse xenograft model was used to demonstrate the effects.
RESULTS
KX-01 effectively inhibited the growth of breast cancer cell lines. The expression of phospho-Src and proliferative-signaling molecules were down-regulated in KX-01-sensitive TNBC cell lines. In addition, migration inhibition was observed by wound healing assay. KX-01-induced G2/M cell cycle arrest and increased the aneuploid cell population in KX-01-sensitive cell lines. Multi-nucleated cells were significantly increased after KX-01 treatment. Furthermore, KX-01 effectively delayed tumor growth in a MDA-MB-231 mouse xenograft model.
CONCLUSION
KX-01 effectively inhibited cell growth and migration of TNBC cells. Moreover, this study demonstrated that KX-01 showed antitumor effects through the inhibition of Src signaling and the induction of mitotic catastrophe. The antitumor effects of KX-01 were also demonstrated using a mouse xenograft model.
Topics: Acetamides; Aneuploidy; Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Movement; Cell Proliferation; Disease Models, Animal; Female; G2 Phase Cell Cycle Checkpoints; Humans; Mitosis; Morpholines; Phosphorylation; Protein Kinase Inhibitors; Pyridines; Triple Negative Breast Neoplasms; Tumor Burden; Xenograft Model Antitumor Assays; src-Family Kinases
PubMed: 27737538
DOI: 10.4143/crt.2016.168 -
Acta Dermato-venereologica Oct 2023
Topics: Humans; Keratosis, Actinic; Ointments; Retrospective Studies; Treatment Outcome; Upper Extremity
PubMed: 37876333
DOI: 10.2340/actadv.v103.15296 -
European Journal of Medicinal Chemistry Oct 2011KX2-391 (KX-01/Kinex Pharmaceuticals), N-benzyl-2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetamide, is a highly selective Src substrate binding site inhibitor. To...
KX2-391 (KX-01/Kinex Pharmaceuticals), N-benzyl-2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetamide, is a highly selective Src substrate binding site inhibitor. To understand better the role of pyridine ring and N-benzylsubstitution in KX2-391 and establish the structure-activity relationship, a number of N-benzyl substituted (((2-morpholinoethoxy)phenyl)thiazol-4-yl)acetamide derivatives containing thiazole instead of pyridine were synthesized and evaluated for Src kinase inhibitory activities. The unsubstituted N-benzyl derivative (8a) showed the inhibition of c-Src kinase with GI(50) values of 1.34 μM and 2.30 μM in NIH3T3/c-Src527F and SYF/c-Src527F cells, respectively. All the synthesized compounds were evaluated for inhibition of cell proliferation of human colon carcinoma (HT-29), breast carcinoma (BT-20), and leukemia (CCRF-CEM) cells. 4-Fluorobenzylthiazolyl derivative 8b exhibited 64-71% inhibition in the cell proliferation of BT-20 and CCRF cells at concentration of 50 μM.
Topics: Acetamides; Animals; Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Colonic Neoplasms; Female; Humans; Inhibitory Concentration 50; Leukemia; Mice; Morpholines; NIH 3T3 Cells; Protein Kinase Inhibitors; Pyridines; Structure-Activity Relationship; Thiazoles; src-Family Kinases
PubMed: 21852023
DOI: 10.1016/j.ejmech.2011.07.050