Abstract
Pim kinases, also known as Serine/Threonine kinases, are intensively studied protein drug targets in cancer research. They play crucial role in the regulation of signal transduction cascades that promote cell survival, proliferation and drug resistance. Pim kinases are overexpressed in several hematopoietic and solid tumors and support in vitro/in vivo malignant cell growth and survival, through cell cycle regulation and inhibition of apoptosis. Pim kinases do not have an identified regulatory domain, as they are constitutively active. They appear to be critical downstream effectors of a number of oncoproteins. When overexpressed, they mediate drug resistance to agents such as Rapamycin. X-ray crystallographic studies reveal that unlike other kinases, Pim kinases have a hinge region, which forms a unique binding pocket for ATP, offering a target for a large number of potent small-molecule Pim kinase inhibitors. Combination therapy of Pim kinase inhibitors with chemotherapeutic and other kinase modulators seems to produce an additive cytotoxic effect in cancer cells. Though clinical trials have been carried out on the first Pim inhibitory agent, SGI-1776, no concept data could be generated due to its early withdrawal. However, it has helped in accelerating the discovery of several novel Pim inhibitors in recent years. Current research on Pim kinase is expected to lead to a new generation of potent Pim kinase inhibitors with appropriate pharmacological profiles suitable for human cancer therapy in the near future. Herein, we review the synthetic route and mechanistical studies of Pim kinase inhibitors which are currently in human trials.
Keywords: Pim kinase inhibitors, clinical trials, haematological malignancies, solid cancers, apoptosis, X-ray crystallographic studies.
Anti-Cancer Agents in Medicinal Chemistry
Title:Potential Pharmacological Inhibitors of Pim Kinase Under Clinical Trials
Volume: 18 Issue: 8
Author(s): Gomathi P. Jeyapal, Moola J.N. Chandrasekar*, Rajendiran Krishnasamy, Jubie Selvaraj, Manal Mohammad and Moola J. Nanjan
Affiliation:
- Department of Pharmaceutical Chemistry, JSS College of Pharmacy (A Constituent College of Jagadguru Sri Shivarathreeswara University, Mysuru), Ootacamund-643001, Tamilnadu,India
Keywords: Pim kinase inhibitors, clinical trials, haematological malignancies, solid cancers, apoptosis, X-ray crystallographic studies.
Abstract: Pim kinases, also known as Serine/Threonine kinases, are intensively studied protein drug targets in cancer research. They play crucial role in the regulation of signal transduction cascades that promote cell survival, proliferation and drug resistance. Pim kinases are overexpressed in several hematopoietic and solid tumors and support in vitro/in vivo malignant cell growth and survival, through cell cycle regulation and inhibition of apoptosis. Pim kinases do not have an identified regulatory domain, as they are constitutively active. They appear to be critical downstream effectors of a number of oncoproteins. When overexpressed, they mediate drug resistance to agents such as Rapamycin. X-ray crystallographic studies reveal that unlike other kinases, Pim kinases have a hinge region, which forms a unique binding pocket for ATP, offering a target for a large number of potent small-molecule Pim kinase inhibitors. Combination therapy of Pim kinase inhibitors with chemotherapeutic and other kinase modulators seems to produce an additive cytotoxic effect in cancer cells. Though clinical trials have been carried out on the first Pim inhibitory agent, SGI-1776, no concept data could be generated due to its early withdrawal. However, it has helped in accelerating the discovery of several novel Pim inhibitors in recent years. Current research on Pim kinase is expected to lead to a new generation of potent Pim kinase inhibitors with appropriate pharmacological profiles suitable for human cancer therapy in the near future. Herein, we review the synthetic route and mechanistical studies of Pim kinase inhibitors which are currently in human trials.
Export Options
About this article
Cite this article as:
Jeyapal P. Gomathi , Chandrasekar J.N. Moola*, Krishnasamy Rajendiran , Selvaraj Jubie , Mohammad Manal and Nanjan J. Moola, Potential Pharmacological Inhibitors of Pim Kinase Under Clinical Trials, Anti-Cancer Agents in Medicinal Chemistry 2018; 18 (8) . https://dx.doi.org/10.2174/1871520618666180131113519
DOI https://dx.doi.org/10.2174/1871520618666180131113519 |
Print ISSN 1871-5206 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5992 |
Call for Papers in Thematic Issues
Induction of cell death in cancer cells by modulating telomerase activity using small molecule drugs
Telomeres are distinctive but short stretches present at the corners of chromosomes and aid in stabilizing chromosomal makeup. Resynthesis of telomeres supported by the activity of reverse transcriptase ribonucleoprotein complex telomerase. There is no any telomerase activity in human somatic cells, but the stem cells and germ cells undergone telomerase ...read more
Role of natural compounds as anti anti-cancer agents
Cancer is considered the leading cause of worldwide mortality, accounting for nearly 10 million deaths in 2022. Cancer outcome can be improved through an appropriate screening and early detection and through an efficient clinical treatment. Chemotherapy remains an important approach in treatment o f several types of cancers, even though ...read more
Signaling and enzymatic modulators in cancer treatment
Cancer accounts for nearly 10 million deaths in 2022 and is considered the leading cause of worldwide mortality. Cancer outcome can be improved through an appropriate screening and early detection and through an efficient clinical treatment. Chemotherapy, radiotherapy and surgery are the most important approach for the treatment of several ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
Related Articles
-
Toxicities of Immunosuppressive Treatment of Autoimmune Neurologic Diseases
Current Neuropharmacology Metastatic Brain Tumors: To Treat or Not to Treat, and with What?
Current Cancer Therapy Reviews Vinorelbine in the Treatment of Non-Small Cell Lung Cancer
Current Medicinal Chemistry PET and SPECT Imaging for the Acceleration of Anti-Cancer Drug Development
Current Drug Targets Metalloprotein Inhibitors for the Treatment of Human Diseases
Current Topics in Medicinal Chemistry Uric Acid and the Kidney: Urate Transport, Stone Disease and Progressive Renal Failure
Current Pharmaceutical Design Structural Findings and Molecular Modeling Approach of a TFPI-Like Inhibitor
Protein & Peptide Letters Pathologic Findings of Autoimmune Pancreatitis and IgG4-Related Disease
Current Immunology Reviews (Discontinued) Extracellular Citrate in Health and Disease
Current Molecular Medicine Tumor Dormancy and the Angiogenic Switch: Possible Implications of Bone Marrow- Derived Cells
Current Pharmaceutical Design Recent Advances in the Development of Multi-Kinase Inhibitors
Mini-Reviews in Medicinal Chemistry Active Metabolites Resulting from Decarboxylation, Reduction and Ester Hydrolysis of Parent Drugs
Current Drug Metabolism PEG-Interferon Alfa-2b for Acute Hepatitis C: A Review
Mini-Reviews in Medicinal Chemistry Anlotinib-Induced Hypertension: Current Concepts and Future Prospects
Current Pharmaceutical Design Immune Modulation by Ionizing Radiation and its Implications for Cancer Immunotherapy
Current Pharmaceutical Design A Review of Therapeutic Effects of Curcumin
Current Pharmaceutical Design Role of Natural Phenolic Compounds in Cancer Chemoprevention via Regulation of the Cell Cycle
Current Pharmaceutical Biotechnology Drug Resistance in Renal Tumors of Childhood
Current Pharmaceutical Biotechnology Classical to Current Approach for Treatment of Psoriasis: A Review
Endocrine, Metabolic & Immune Disorders - Drug Targets Irinotecan for Treatment of Childhood Cancers: A Promising Therapeutic Partner
Current Cancer Therapy Reviews