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6 results on '"Mnk Inhibitors"'

1. An integrated approach for discovery of highly potent and selective Mnk inhibitors: Screening, synthesis and SAR analysis.

Author

Teo, Theodosia, Yang, Yuchao, Yu, Mingfeng, Basnet, Sunita K.C., Gillam, Todd, Hou, Jinqiang, Schmid, Raffaella M., Kumarasiri, Malika, Diab, Sarah, Albrecht, Hugo, Sykes, Matthew J., and Wang, Shudong

Subjects
*DRUG synergism, *DRUG development, *PROTEIN synthesis, *MITOGEN-activated protein kinase phosphatases, *PROTEIN kinase inhibitors, *DRUG synthesis, *STRUCTURE-activity relationship in pharmacology
Abstract

Deregulation of protein synthesis is a common event in cancer. As MAPK-interacting kinases (Mnks) play critical roles in regulation of protein synthesis, they have emerged as novel anti-cancer targets. Mnks phosphorylate eukaryotic initiation factor 4E (eIF4E) and promote eIF4E-mediated oncogenic activity. Given that the kinase activity of Mnks is essential for oncogenesis but is dispensable for normal development, the discovery of potent and selective pharmacological Mnk inhibitors provides pharmacological target validation and offers a new strategy for cancer treatment. Herein, comprehensive in silico screening approaches were deployed, and three thieno[2,3- d ]pyrimidine and pyrazolo[3,4- d ]pyrimidine derivatives were identified as hit compounds. Further chemical modification of thieno[2,3- d ]pyrimidine derivative 3 has given rise to a series of highly potent Mnk2 inhibitors that could be potential leads for the treatment of acute myeloid leukemia. [ABSTRACT FROM AUTHOR]

Published
2015
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2. MAP Kinase-Interacting Kinases—Emerging Targets against Cancer

Author

Mingfeng Yu, Malika Kumarasiri, Theodosia Teo, Sarah Diab, Shudong Wang, Robert W. Milne, Christopher G. Proud, Diab, Sarah, Kumarasiri, Malika, Yu, Mingfeng, Teo, Theodosia, Proud, Chris, Milne, Robert, and Wang, Shudong

Subjects
Eukaryotic Initiation Factor-4E, Mnk, Clinical Biochemistry, Antineoplastic Agents, Protein Serine-Threonine Kinases, Biochemistry, Small Molecule Libraries, 03 medical and health sciences, Structure-Activity Relationship, 0302 clinical medicine, Neoplasms, Drug Discovery, Animals, Humans, Kinome, Molecular Targeted Therapy, Kinase activity, Phosphorylation, Mnk inhibitors, Protein kinase A, Protein Kinase Inhibitors, Molecular Biology, 030304 developmental biology, Pharmacology, 0303 health sciences, biology, Kinase, EIF4E, General Medicine, MAPK, 3. Good health, Cell biology, Protein kinase domain, 030220 oncology & carcinogenesis, Mitogen-activated protein kinase, eIF4E, biology.protein, cancer therapy, Molecular Medicine
Abstract

Mitogen-activated protein kinase (MAPK)-interacting kinases (Mnks) regulate the initiation of translation through phosphorylation of eukaryotic initiation factor 4E (eIF4E). Mnk-mediated eIF4E activation promotes cancer development and progression. While the phosphorylation of eIF4E is necessary for oncogenic transformation, the kinase activity of Mnks seems dispensable for normal development. For this reason, pharmacological inhibition of Mnks could represent an ideal mechanism-based and nontoxic therapeutic strategy for cancer treatment. In this review, we discuss the current understanding of Mnk biological roles, structures, and functions, as well as clinical implications. Importantly, we propose different strategies for identification of highly selective small molecule inhibitors of Mnks, including exploring a structural feature of their kinase domain, DFD motif, which is unique within the human kinome. We also argue that a combined targeting of Mnks and other pathways should be considered given the complexity of cancer. Refereed/Peer-reviewed

Published
2014
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3. Discovery of 5-(2-(Phenylamino)pyrimidin-4-yl)thiazol-2(3H)-one Derivatives as Potent Mnk2 Inhibitors: Synthesis, SAR Analysis and Biological Evaluation

Author

Peng Li, Robert W. Milne, Hugo Albrecht, Mingfeng Yu, Frankie Lam, Sunita K.C. Basnet, Matthew J. Sykes, Theodosia Teo, Malika Kumarasiri, Shudong Wang, Sarah Diab, Diab, Sarah, Teo, Theodosia Hua Swan, Kumarasiri, Malika, Li, Peng, Yu, Mingfeng, Lam, Frankie, Basnet, Sunita KC, Sykes, Matthew J, Albrecht, Hugo, Milne, Robert, and Wang, Shudong

Subjects
Models, Molecular, MAPK/ERK pathway, Antineoplastic Agents, Apoptosis, Protein Serine-Threonine Kinases, Biology, Pharmacology, Biochemistry, Structure-Activity Relationship, Cell Line, Tumor, Drug Discovery, Humans, Mnk inhibitors, General Pharmacology, Toxicology and Pharmaceutics, Protein kinase A, Protein Kinase Inhibitors, Cell Proliferation, Biological evaluation, Aniline Compounds, Dose-Response Relationship, Drug, Molecular Structure, CGP57380, Kinase, Organic Chemistry, EIF4E, Intracellular Signaling Peptides and Proteins, apoptosis, HCT116 Cells, eIF4E phosphorylation, Leukemia, Myeloid, Acute, Thiazoles, Pyrimidines, Drug development, Purines, MCF-7 Cells, anticancer drug discovery, Molecular Medicine, Phosphorylation, Drug Screening Assays, Antitumor
Abstract

Phosphorylation of eIF4E by human mitogen-activated protein kinase (MAPK)-interacting kinases (Mnks) is crucial for human tumourigenesis and development. Targeting Mnks may provide a novel anticancer therapeutic strategy. However, the lack of selective Mnk inhibitors has so far hampered pharmacological target validation and clinical drug development. Herein, we report, for the first time, the discovery of a series of 5-(2-(phenylamino)pyrimidin-4-yl)thiazole-2(3H)-one derivatives as Mnk inhibitors. Several derivatives demonstrate very potent Mnk2 inhibitory activity. The most active and selective compounds were tested against a panel of cancer cell lines, and the results confirm the cell-type-specific effect of these Mnk inhibitors. Detailed cellular mechanistic studies reveal that Mnk inhibitors are capable of reducing the expression level of anti-apoptotic protein Mcl-1, and of promoting apoptosis in MV4-11 acute myeloid leukaemia cells. Refereed/Peer-reviewed

Published
2014

4. Targeting Mnks for cancer therapy

Author

Jin-Qiang Hou, Shudong Wang, Frankie Lam, Christopher G. Proud, Hou, Jinqiang, Lam, Fong Ki, Proud, Chris, and Wang, Shudong

Subjects
MAPK/ERK pathway, Proto-Oncogene Proteins c-akt, Mnk, Reviews, Biology, Protein Serine-Threonine Kinases, targeted cancer therapy, PI3K, Mnk Inhibitors, Protein Structure, Secondary, Serine, Mice, Phosphatidylinositol 3-Kinases, Animals, Humans, Targeted Cancer Therapy, Amino Acid Sequence, Phosphorylation, Protein kinase B, PI3K/AKT/mTOR pathway, mnk, mnk inhibitors, TOR Serine-Threonine Kinases, Akt, EIF4E, Intracellular Signaling Peptides and Proteins, Raf, Pi3K, MAPK, Cell biology, Eukaryotic Initiation Factor-4E, Oncology, structure based drug design, eIF4E, ras Proteins, mTOR, Structure based drug design, raf Kinases, Mitogen-Activated Protein Kinases, Sequence Alignment, Ras
Abstract

Deregulation of protein synthesis is a common event in human cancer and a key player in translational control is eIF4E. Elevated expression levels of eIF4E promote cancer development and progression. Recent findings suggest that eIF4E activity is a key determinant of the PI3K/Akt/mTOR and Ras/Raf/MEK/ERK mediated tumorigenic activity and targeting eIF4E should have a major impact on these pathways in human cancer. The function of eIF4E is modulated through phosphorylation of a conserved serine (Ser209) by Mnk1 and Mnk2 downstream of ERK. While the phosphorylation event is necessary for oncogenic transformation, it seems to be dispensable for normal development. Hence, pharmacologic Mnk inhibitors may provide non-toxic and effective anti-cancer strategy. Strong circumstantial evidence indicates that Mnk inhibition presents attractive therapeutic potential, but the lack of selective Mnk inhibitors has so far confounded pharmacological target validation and clinical development. Refereed/Peer-reviewed

Published
2012

5. Sulfoximine substituted quinazolines for pharmaceutical compositions US 20150005278 (A1): a patent evaluation.

Author

Gopaul K and Koorbanally NA

Subjects
Drug Design, Eukaryotic Initiation Factor-4E metabolism, Humans, Metabolic Diseases drug therapy, Metabolic Diseases physiopathology, Patents as Topic, Quinazolines chemistry, Sulfur Compounds chemistry, Intracellular Signaling Peptides and Proteins antagonists & inhibitors, Protein Serine-Threonine Kinases antagonists & inhibitors, Quinazolines pharmacology
Abstract

Mnk1 and Mnk2 are protein kinases responsible for phosphorylating eIF4E, a eukaryotic initiation factor responsible for initiating translation. Inhibiting Mnk1 and Mnk2 could therefore play a role in treating metabolic diseases such as cancer, diabetes, and hyperlipidemia. A wide range of sulfoximine substituted quinazolines were synthesised and evaluated for their Mnk1 and Mnk2 inhibitory activity. Amongst these compounds, 26 quinazolines showed activity against Mnk1 at <100 nM and 54 showed activity against Mnk2 at 1 nM. The results indicate that this scaffold is much more active against Mnk2 than Mnk1. The synthesised compounds may be future drugs in the treatment of metabolic diseases.

Published
2016
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6. Discovery of 5-(2-(phenylamino)pyrimidin-4-yl)thiazol-2(3H)-one derivatives as potent Mnk2 inhibitors: synthesis, SAR analysis and biological evaluation.

Author

Diab S, Teo T, Kumarasiri M, Li P, Yu M, Lam F, Basnet SK, Sykes MJ, Albrecht H, Milne R, and Wang S

Subjects
Aniline Compounds chemistry, Aniline Compounds pharmacology, Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Apoptosis drug effects, Cell Line, Tumor, Cell Proliferation drug effects, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, HCT116 Cells, Humans, Intracellular Signaling Peptides and Proteins metabolism, Leukemia, Myeloid, Acute drug therapy, MCF-7 Cells, Models, Molecular, Molecular Structure, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors chemistry, Protein Serine-Threonine Kinases metabolism, Purines chemistry, Purines pharmacology, Pyrimidines chemical synthesis, Pyrimidines chemistry, Structure-Activity Relationship, Thiazoles chemical synthesis, Thiazoles chemistry, Antineoplastic Agents pharmacology, Drug Discovery, Intracellular Signaling Peptides and Proteins antagonists & inhibitors, Leukemia, Myeloid, Acute pathology, Protein Kinase Inhibitors pharmacology, Protein Serine-Threonine Kinases antagonists & inhibitors, Pyrimidines pharmacology, Thiazoles pharmacology
Abstract

Phosphorylation of eIF4E by human mitogen-activated protein kinase (MAPK)-interacting kinases (Mnks) is crucial for human tumourigenesis and development. Targeting Mnks may provide a novel anticancer therapeutic strategy. However, the lack of selective Mnk inhibitors has so far hampered pharmacological target validation and clinical drug development. Herein, we report, for the first time, the discovery of a series of 5-(2-(phenylamino)pyrimidin-4-yl)thiazole-2(3H)-one derivatives as Mnk inhibitors. Several derivatives demonstrate very potent Mnk2 inhibitory activity. The most active and selective compounds were tested against a panel of cancer cell lines, and the results confirm the cell-type-specific effect of these Mnk inhibitors. Detailed cellular mechanistic studies reveal that Mnk inhibitors are capable of reducing the expression level of anti-apoptotic protein Mcl-1, and of promoting apoptosis in MV4-11 acute myeloid leukaemia cells., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Published
2014
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