Discovery of Novel Dual Extracellular Regulated Protein Kinases (ERK) and Phosphoinositide 3-Kinase (PI3K) Inhibitors as a Promising Strategy for Cancer Therapy

Concomitant inhibition of MAPK and PI3K signaling pathways has been recognized as a promising strategy for cancer therapy, which effectively overcomes the drug resistance of MAPK signaling pathway-related inhibitors. Herein, we report the scaffold-hopping generation of a series of 1H-pyrazolo[3,4-d]pyrimidine dual ERK/PI3K inhibitors. Compound 32d was the most promising candidate, with potent inhibitory activities against both ERK2 and PI3Kα which displays superior anti-proliferative profiles against HCT116 and HEC1B cancer cells. Meanwhile, compound 32d possessed acceptable pharmacokinetic profiles and showed more efficacious anti-tumor activity than GDDC-0980 and the corresponding drug combination (BVD-523 + GDDC-0980) in HCT-116 xenograft model, with a tumor growth inhibitory rate of 51% without causing observable toxic effects. All the results indicated that 32d was a highly effective anticancer compound and provided a promising basis for further optimization towards dual ERK/PI3K inhibitors.

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Discovery of Novel Dual Poly(ADP-ribose)polymerase and Phosphoinositide 3-Kinase Inhibitors as a Promising Strategy for Cancer Therapy

Journal of Medicinal Chemistry ◽

10.1021/acs.jmedchem.9b00622 ◽

2019 ◽

Vol 63 (1) ◽

pp. 122-139 ◽

Cited By ~ 4

Author(s):

Junwei Wang ◽

Hui Li ◽

Guangchao He ◽

Zhaoxing Chu ◽

Kewen Peng ◽

...

Keyword(s):

Cancer Therapy ◽

Kinase Inhibitors ◽

Promising Strategy ◽

Phosphoinositide 3 Kinase

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Synthesis and Anti-Tumor Activity Evaluation of Novel 7-Fluoro-4-(1- Piperazinyl) Quinolines

Letters in Drug Design & Discovery ◽

10.2174/1570180815666180820131036 ◽

2019 ◽

Vol 16 (6) ◽

pp. 663-669

Author(s):

Dan Liu ◽

Aiqi Xue ◽

Zhixin Liu ◽

Yi Zhang ◽

Penghui Peng ◽

...

Keyword(s):

Spectral Analysis ◽

Cancer Therapy ◽

Carcinoma Cell ◽

A549 Cells ◽

Quinoline Derivatives ◽

Human Carcinoma ◽

Carcinoma Cell Lines ◽

Human Carcinoma Cell ◽

Anti Tumor Activity

Background: Three series of new 7-fluoro-4-(1-piperazinyl) quinolines (I1~I6, II1~II2 and IV1~IV4) were synthesized. Their anti-tumor activity was evaluated in vitro against three human carcinoma cell lines, namely SGC-7901 cells, BEL-7402 cells and A549 cells expressing high levels of EGFR by Methyl Thiazolyl Terazolium (MTT) assay. Methods: Three series of quinoline derivatives were synthesized, characterized and evaluated for their in vitro anti-tumor activities. Results and Discussion: Structures of the newly synthesized compounds were confirmed by spectral analysis. The preliminary bioassay indicated that compounds I1, I10 and II1 exhibited better anti-tumor activity than the rest of the target compounds and gefitinib against A549 cell based assay, which demonstrated that compounds I1, I10 and II1 are potential agents for cancer therapy. Results suggested that the substitutes on piperazinyl influenced anti-tumor activities remarkably. Conclusion: These results are useful for discovering more potent novel anti-tumor compounds and further studies are ongoing.

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Enhancement of gold-nanocluster-mediated chemotherapeutic efficiency of cisplatin in lung cancer

Journal of Materials Chemistry B ◽

10.1039/d1tb00276g ◽

2021 ◽

Author(s):

Mei Jiang ◽

Yuchen Lin ◽

Xiaocui Fang ◽

Mingpeng Liu ◽

Lilusi Ma ◽

...

Keyword(s):

Lung Cancer ◽

Cancer Therapy ◽

Delivery System ◽

Gold Nanoclusters ◽

Cationic Peptide ◽

Gold Nanocluster ◽

Lung Cancer Therapy ◽

Anti Tumor Activity

A novel delivery system for cisplatin based on electrostatics-mediated assemblies of gold nanoclusters and PEGylated cationic peptide was constructed. The constructed cisplatin@GC-pKs showed much enhanced anti-tumor activity for lung cancer therapy.

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Semi-Synthesis of Harringtonolide Derivatives and Their Antiproliferative Activity

Molecules ◽

10.3390/molecules26051380 ◽

2021 ◽

Vol 26 (5) ◽

pp. 1380

Author(s):

Xiutao Wu ◽

Lijie Gong ◽

Chen Chen ◽

Ye Tao ◽

Wuxi Zhou ◽

...

Keyword(s):

Antiproliferative Activity ◽

Normal Cell ◽

Selectivity Index ◽

Cytotoxic Activities ◽

Structure Activity ◽

Growth Inhibitory ◽

Growth Inhibitory Activity ◽

Hct 116 ◽

Systematic Structure

Harringtonolide (HO), a natural product isolated from Cephalotaxus harringtonia, exhibits potent antiproliferative activity. However, little information has been reported on the systematic structure−activity relationship (SAR) of HO derivatives. Modifications on tropone, lactone, and allyl positions of HO (1) were carried out to provide 17 derivatives (2–13, 11a–11f). The in vitro antiproliferative activity against four cancer cell lines (HCT-116, A375, A549, and Huh-7) and one normal cell line (L-02) was tested. Amongst these novel derivatives, compound 6 exhibited comparable cell growth inhibitory activity to HO and displayed better selectivity index (SI = 56.5) between Huh-7 and L-02 cells. The SAR results revealed that the tropone and lactone moieties are essential for the cytotoxic activities, which provided useful suggestions for further structural optimization of HO.

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Expression of KLRG1 and CD127 defines distinct CD8+ subsets that differentially impact patient outcome in follicular lymphoma

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-002662 ◽

2021 ◽

Vol 9 (7) ◽

pp. e002662

Author(s):

Hongyan Wu ◽

Xinyi Tang ◽

Hyo Jin Kim ◽

Shahrzad Jalali ◽

Joshua C Pritchett ◽

...

Keyword(s):

T Cells ◽

Follicular Lymphoma ◽

Memory Cell ◽

Skewed Distribution ◽

T Lymphocyte Subsets ◽

Free Survival ◽

Pi3k Inhibitors ◽

Lymphoid Malignancies ◽

Phosphoinositide 3 Kinase ◽

With Memory

BackgroundCD8+ T-lymphocyte subsets defined by killer lectin-like receptor G1 (KLRG1) and CD127 expression have been reported to have an important role in infection, but their role in the setting of lymphoid malignancies, specifically follicular lymphoma (FL), has not been studied.MethodsTo characterize the phenotype of KLRG1/CD127-defined CD8+ subsets, surface and intracellular markers were measured by flow cytometry and Cytometry by time of flight (CyTOF), and the transcriptional profile of these cells was determined by CITE-Seq (Cellular Indexing of Transcriptomes and Epitopes by Sequencing). The functional capacity of each subset was determined, as was their impact on overall survival (OS) and event-free survival (EFS) of patients with FL.ResultsWe found that intratumoral CD8+ cells in FL are skewed toward effector cell subsets, particularly KLRG+CD127- and KLRG1-CD127- cells over memory cell subsets, such as KLRG1-CD127+ and KLRG1+CD127+ cells. While effector subsets exhibited increased capacity to produce cytokines/granules when compared with memory subsets, their proliferative capacity and viability were found to be substantially inferior. Clinically, a skewed distribution of intratumoral CD8+ T cells favoring effector subtypes was associated with an inferior outcome in patients with FL. Increased numbers of CD127+KLRG1- and CD127+KLRG1+ were significantly associated with a favorable OS and EFS, while CD127-KLRG1- correlated with a poor EFS and OS in patients with FL. Furthermore, we demonstrated that interleukin (IL)-15 promotes CD127-KLRG1+ cell development in the presence of dendritic cells via a phosphoinositide 3-kinase (PI3K)-dependent mechanism, and treatment of CD8+ T cells with a PI3K inhibitor downregulated the transcription factors responsible for CD127-KLRG1+ differentiation.ConclusionsTaken together, these results reveal not only a biological and prognostic role for KLRG1/CD127-defined CD8+ subsets in FL but also a potential role for PI3K inhibitors to manipulate the differentiation of CD8+ T cells, thereby promoting a more effective antitumor immune response.

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Signaling Pathways Regulating TC21-induced Tumorigenesis

Journal of Biological Chemistry ◽

10.1074/jbc.m703037200 ◽

2007 ◽

Vol 282 (38) ◽

pp. 27713-27720 ◽

Cited By ~ 26

Author(s):

Mete Erdogan ◽

Ambra Pozzi ◽

Neil Bhowmick ◽

Harold L Moses ◽

Roy Zent

Keyword(s):

P38 Mapk ◽

Cancer Progression ◽

Transforming Growth Factor ◽

Cellular Transformation ◽

Tumor Formation ◽

Transformed Cells ◽

Growth Inhibitory ◽

Phosphoinositide 3 Kinase

TC21(R-Ras2), a Ras-related GTPase with transforming potential similar to H-, K- and N-Ras, is implicated in the pathogenesis of human cancers. Transforming growth factor β (TGF-β), a cytokine that plays a significant role in modulating tumorigenesis, normally prevents uncontrolled cell proliferation but paradoxically induces proliferation in H-Ras-transformed cancer cells. Although TC21 activates some pathways that mediate cellular transformation by the classical Ras proteins, the mechanisms through which TC21 induces tumor formation and how TGF-β regulates TC21 transformed cells is not known. To better understand the role of TC21 in cancer progression, we overexpressed an activated G23V mutant of TC21 in a nontumorigenic murine mammary epithelial (EpH4) cell line. Mutant TC21-expressing cells were significantly more oncogenic than cells expressing activated G12V H-Ras both in vivo and in vitro. TC21-induced transformation and proliferation required activation of p38 MAPK, mTOR (the mammalian target of rapamycin), and phosphoinositide 3-kinase but not Akt/PKB. Transformation by TC21 rendered EpH4 cells insensitive to the growth inhibitory effects of TGF-β, and the soft agar growth of these cells was increased upon TGF-β stimulation. Despite losing responsiveness to TGF-β-mediated growth inhibition, both Smad-dependent and independent pathways remained intact in TC21-transformed cells. Thus, overexpression of active TC21 in EpH4 cells induces tumorigenicity through the phosphoinositide 3-kinase, p38 MAPK, and mTOR pathways, and these cells lose their sensitivity to the normal growth inhibitory role of TGF-β.

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DDRE-30. CELL-PENETRATING PEPTIDE ANTAGONIST OF CCAAT/ENHANCER BINDING PROTEIN ß DISPLAYS POTENT ANTI-GLIOBLASTOMA ACTIVITY

Neuro-Oncology ◽

10.1093/neuonc/noab196.314 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi80-vi81

Author(s):

Jim Rotolo ◽

Lila Ghamsari ◽

Ricardo Ramierez ◽

Mark Koester ◽

Siok Leong ◽

...

Keyword(s):

Gene Expression ◽

Leucine Zipper ◽

Binding Protein ◽

Xenograft Model ◽

Mesenchymal Transition ◽

Enhancer Binding Protein ◽

Ccaat Enhancer Binding Protein ◽

Subcutaneous Xenograft ◽

Peptide Antagonist ◽

Anti Tumor Activity

Abstract CCAAT/Enhancer Binding Protein Beta (C/EBPß) is a transcription factor overexpressed in glioblastoma (GBM). Mechanistically, C/EBPß is a master regulator of mesenchymal transition in GBM, and its increased expression correlates with mesenchymal differentiation and predicts poor clinical outcome. C/EBPß activity requires dimerization with co-factors such as CREB/ATF family members via leucine zipper interactions. ST101 is a novel peptide antagonist of C/EBPß currently being evaluated in a Phase 1/2 clinical study in patients with advanced unresectable and metastatic solid tumors. ST101 binds to the C/EBPß leucine zipper, thereby preventing dimer formation and inhibiting its transcriptional activity, resulting in selective tumor cell cytotoxicity. Here, we describe ST101 non-clinical anti-tumor activity against GBM. In vitro studies in T98G and U251 cells demonstrate ST101 dose-dependent impact of cell viability (EC50 of 2.2 and 1.2 μM, respectively), accompanied by significant impact on C/EBPß-mediated gene expression as determined by qPCR analysis. In contrast, normal human mononuclear and epithelial cells were not sensitive to ST101 (EC50 > 80 μM). In vivo, ST101 displayed significant anti-tumor activity in a U251 GBM subcutaneous xenograft model, resulting in 81.4% tumor growth inhibition (TGI) vs. control and undetectable tumors in 50% of animals. Following ST101 exposure tumors displayed reduced BIRC3 and ID2 gene expression, and significantly increased cleaved caspase 3 immunostaining indicative of cell death induction. In U251 tumors, subtherapeutic ST101 (< 5% TGI) in combination with temozolomide (< 5% TGI) resulted in 52.8% TGI, significantly greater than either single-agent alone. Similarly, in a temozolomide-refractory T98G GBM subcutaneous xenograft model, ST101 (41.6% TGI) in combination with TMZ (< 5% TGI) resulted in significant anti-GBM response (72.4% TGI). These data emphasize the potential of ST101 as a potent peptide therapeutic for GBM.

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