Abstract
Human Pim1 (proviral integration site for Moloney murine leukemia virus) kinase is a 313-amino acid serine-threonine kinase that possesses several biological functions in cell survival, proliferation and differentiation, and its overexpression has been observed in a number of human cancers. Indeed, this kinase is a proto-oncogene that has been implicated in early transformation and tumor progression, especially in hematopoietic malignancies and prostate carcinoma where it is a marker of a poor prognosis. For these reasons, Pim1 is emerging as an important target in drug discovery, and many Pim1 inhibitors have been reported in the last three years. The challenge of this research is to obtain compounds that specifically inhibit only Pim1 and not Pim2 and Pim3, the other members of the Pim family, with the aim of providing selective inhibitors as potential therapeutic agents and also of studying the different roles of the three enzymes. In this review Pim1 functions and Pim1 role in human cancer are summarized, but the primary focus of the article is on the Pim1 threedimensional structure that was deeply analyzed by a detailed inspection of the available crystallographic data and all complexes of small molecule inhibitors reported in the literature to this point. Finally, the use of molecular modeling techniques for the identification and optimization of Pim1 inhibitors is extensively discussed. This data collection, which to the best of our knowledge was not previously reviewed in such detail, could offer a useful tool for medicinal chemists working in the field of small molecule kinase inhibitors.
Keywords: Pim1, serine-threonine kinase, inhibitors, cancer, X-ray, structure-based drug design, C-TAK1, IL-3-mediated antiapoptotic pathway, MAPK, Ser329, GFI1, FRAT1, RUNX2, VEGF-A/Flk1 pathway, DLBCL, erythroleukemias, chronic myeloid leukemia, U937, HOXA9, Prostate Cancer, BCRP1, squamous cell carcinoma, OSCC, KSHV, AMP-PNP, Glu121, NMR, staurosporine, Lys67
Current Pharmaceutical Design
Title: Using Insights into Pim1 Structure to Design New Anticancer Drugs
Volume: 16 Issue: 35
Author(s): Silvia Schenone, Cristina Tintori and Maurizio Botta
Affiliation:
Keywords: Pim1, serine-threonine kinase, inhibitors, cancer, X-ray, structure-based drug design, C-TAK1, IL-3-mediated antiapoptotic pathway, MAPK, Ser329, GFI1, FRAT1, RUNX2, VEGF-A/Flk1 pathway, DLBCL, erythroleukemias, chronic myeloid leukemia, U937, HOXA9, Prostate Cancer, BCRP1, squamous cell carcinoma, OSCC, KSHV, AMP-PNP, Glu121, NMR, staurosporine, Lys67
Abstract: Human Pim1 (proviral integration site for Moloney murine leukemia virus) kinase is a 313-amino acid serine-threonine kinase that possesses several biological functions in cell survival, proliferation and differentiation, and its overexpression has been observed in a number of human cancers. Indeed, this kinase is a proto-oncogene that has been implicated in early transformation and tumor progression, especially in hematopoietic malignancies and prostate carcinoma where it is a marker of a poor prognosis. For these reasons, Pim1 is emerging as an important target in drug discovery, and many Pim1 inhibitors have been reported in the last three years. The challenge of this research is to obtain compounds that specifically inhibit only Pim1 and not Pim2 and Pim3, the other members of the Pim family, with the aim of providing selective inhibitors as potential therapeutic agents and also of studying the different roles of the three enzymes. In this review Pim1 functions and Pim1 role in human cancer are summarized, but the primary focus of the article is on the Pim1 threedimensional structure that was deeply analyzed by a detailed inspection of the available crystallographic data and all complexes of small molecule inhibitors reported in the literature to this point. Finally, the use of molecular modeling techniques for the identification and optimization of Pim1 inhibitors is extensively discussed. This data collection, which to the best of our knowledge was not previously reviewed in such detail, could offer a useful tool for medicinal chemists working in the field of small molecule kinase inhibitors.
Export Options
About this article
Cite this article as:
Schenone Silvia, Tintori Cristina and Botta Maurizio, Using Insights into Pim1 Structure to Design New Anticancer Drugs, Current Pharmaceutical Design 2010; 16 (35) . https://dx.doi.org/10.2174/138161210794454996
DOI https://dx.doi.org/10.2174/138161210794454996 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
Call for Papers in Thematic Issues
"Tuberculosis Prevention, Diagnosis and Drug Discovery"
The Nobel Prize-winning discoveries of Mycobacterium tuberculosis and streptomycin have enabled an appropriate diagnosis and an effective treatment of tuberculosis (TB). Since then, many newer diagnosis methods and drugs have been saving millions of lives. Despite advances in the past, TB is still a leading cause of infectious disease mortality ...read more
Blood-based biomarkers in large-scale screening for neurodegenerative diseases
Disease biomarkers are necessary tools that can be employ in several clinical context of use (COU), ranging from the (early) diagnosis, prognosis, prediction, to monitor of disease state and/or drug efficacy. Regarding neurodegenerative diseases, in particular Alzheimer’s disease (AD), a battery of well-validated biomarkers are available, such as cerebrospinal fluid ...read more
Current Pharmaceutical challenges in the treatment and diagnosis of neurological dysfunctions
Neurological dysfunctions (MND, ALS, MS, PD, AD, HD, ALS, Autism, OCD etc..) present significant challenges in both diagnosis and treatment, often necessitating innovative approaches and therapeutic interventions. This thematic issue aims to explore the current pharmaceutical landscape surrounding neurological disorders, shedding light on the challenges faced by researchers, clinicians, and ...read more
Diabetes mellitus: advances in diagnosis and treatment driving by precision medicine
Diabetes mellitus (DM) is a chronic degenerative metabolic disease with ever increasing prevalence worldwide which is now an epidemic disease affecting 500 million people worldwide. Insufficient insulin secretion from pancreatic β cells unable to maintain blood glucose homeostasis is the main feature of this disease. Multifactorial and complex nature of ...read more
![](/images/wayfinder.jpg)
- 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
- Announcements
Related Articles
-
Kidney Diseases and Chemokines
Current Drug Targets Hypoxia-inducible Factor (HIF) in Hormone Signaling During Health and Disease
Cardiovascular & Hematological Agents in Medicinal Chemistry Beyond Oncolytic Virotherapy: Replication-Competent Retrovirus Vectors for Selective and Stable Transduction of Tumors
Current Gene Therapy Radiopharmaceuticals for Oncology Drug Development: A Pharmaceutical Industry Perspective
Current Pharmaceutical Design The Role of Mammalian Target of Rapamycin (mTOR) Inhibitors in the Treatment of Solid Tumors
Current Cancer Therapy Reviews Specialisation of the Tropomyosin Composition of Actin Filaments Provides New Potential Targets for Chemotherapy
Current Cancer Drug Targets Disorders of Protein Biogenesis and Stability
Protein & Peptide Letters EXTraordinary Bones: Functional and Genetic Analysis of the EXT Gene Family
Current Genomics Mammalian Target of Rapamycin (mTOR) Inhibitors as Anti-Cancer Agents
Current Cancer Drug Targets siRNA Modifications and Sub-Cellular Localization: A Question of Intracellular Transport?
Current Pharmaceutical Design Iontophoresis: Drug Delivery System by Applying an Electrical Potential Across the Skin
Drug Delivery Letters Carbonic Anhydrase Inhibitors and the Management of Cancer
Current Topics in Medicinal Chemistry Editorial
Current Medical Imaging Natural Thiazoline-Based Cyclodepsipeptides from Marine Cyanobacteria: Chemistry, Bioefficiency and Clinical Aspects
Current Medicinal Chemistry Preclinical and Clinical Studies on Bryostatins, A Class of Marine-Derived Protein Kinase C Modulators: A Mini-Review
Current Topics in Medicinal Chemistry Advances of AKT Pathway in Human Oncogenesis and as a Target for Anti-Cancer Drug Discovery
Current Cancer Drug Targets Potential Neuroprotective Effect of Cannabinoids in COVID-19 Patients
Current Topics in Medicinal Chemistry Lipid-Induced Modulation of Protective Signalling Pathways in Cardiovascular Disease: The Role of High Density Lipoproteins
Current Signal Transduction Therapy Bioactive Components and Pharmacological Action of Wikstroemia indica (L.) C. A. Mey and Its Clinical Application
Current Pharmaceutical Biotechnology Serum miRNAs Signature Plays an Important Role in Keloid Disease
Current Molecular Medicine