Abstract
The therapeutic potential of targeting p21-Activated Kinases (PAK1 – 6) for the treatment of cancer has recently gained traction in the biotech industry. Many pharmaceutically-viable ATP competitive inhibitors have been through different stages of pre-clinical development with only a single compound evaluated in human trails (PF-3758309). The best studied functional roles of PAK proteins are control of cell adhesion and migration. PAK proteins are known downstream effectors of Ras signaling with PAK expression elevated in cancer (pancreatic, colon, breast, lung and other solid tumors). In addition altered PAK expression is a confirmed driver of this disease, especially in tumors harboring oncogenic Ras. However, there are very few examples of gain-of-function PAK mutations, as a majority of the cancer types have elevated PAK expression due to gene amplification or transcriptional modifications. There is a substantial number of known substrates affected by this aberrant PAK activity. One particular substrate, β-catenin, has garnered interest given its importance in both normal and cancer cell development. These data place PAK proteins between two major signaling pathways in cancer (Ras and β -catenin), making therapeutic targeting of PAKs an intriguing approach for the treatment of a broad array of oncological malignancies.
Keywords: Inhibitors, oncology, p21-activated kinase, Ras, Wnt; β-catenin.
Anti-Cancer Agents in Medicinal Chemistry
Title:Therapeutic Potential of Targeting PAK Signaling
Volume: 16 Issue: 1
Author(s): William Senapedis, Marsha Crochiere, Erkan Baloglu and Yosef Landesman
Affiliation:
Keywords: Inhibitors, oncology, p21-activated kinase, Ras, Wnt; β-catenin.
Abstract: The therapeutic potential of targeting p21-Activated Kinases (PAK1 – 6) for the treatment of cancer has recently gained traction in the biotech industry. Many pharmaceutically-viable ATP competitive inhibitors have been through different stages of pre-clinical development with only a single compound evaluated in human trails (PF-3758309). The best studied functional roles of PAK proteins are control of cell adhesion and migration. PAK proteins are known downstream effectors of Ras signaling with PAK expression elevated in cancer (pancreatic, colon, breast, lung and other solid tumors). In addition altered PAK expression is a confirmed driver of this disease, especially in tumors harboring oncogenic Ras. However, there are very few examples of gain-of-function PAK mutations, as a majority of the cancer types have elevated PAK expression due to gene amplification or transcriptional modifications. There is a substantial number of known substrates affected by this aberrant PAK activity. One particular substrate, β-catenin, has garnered interest given its importance in both normal and cancer cell development. These data place PAK proteins between two major signaling pathways in cancer (Ras and β -catenin), making therapeutic targeting of PAKs an intriguing approach for the treatment of a broad array of oncological malignancies.
Export Options
About this article
Cite this article as:
Senapedis William, Crochiere Marsha, Baloglu Erkan and Landesman Yosef, Therapeutic Potential of Targeting PAK Signaling, Anti-Cancer Agents in Medicinal Chemistry 2016; 16 (1) . https://dx.doi.org/10.2174/1871520615666150617111414
DOI https://dx.doi.org/10.2174/1871520615666150617111414 |
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
-
Substance P: Structure, Function, and Therapeutics
Current Topics in Medicinal Chemistry Paclitaxel Formulations: Challenges and Novel Delivery Options
Current Drug Delivery Carcinogenicity and Chronic Rodent Toxicity of the Selective Progesterone Receptor Modulator Ulipristal Acetate
Current Drug Safety Renal Development: A Complex Process Dependent on Inductive Interaction
Current Pediatric Reviews Oral Precancerous Lesions Show Increased Levels of Glutathione Compared to Cancerous Tissue
Current Nutrition & Food Science Copper-62 Labeled ReCCMSH Peptide Analogs for Melanoma PET Imaging
Current Radiopharmaceuticals Urotensin-II Receptor: A Double Identity Receptor Involved in Vasoconstriction and in the Development of Digestive Tract Cancers and other Tumors
Current Cancer Drug Targets Targeting the Nucleotide Metabolism Proteins of the NUDIX Family and SAMHD1 in Cancer
Current Medicinal Chemistry Enzymes To Die For: Exploiting Nucleotide Metabolizing Enzymes for Cancer Gene Therapy
Current Gene Therapy Expression, Regulation, and Role of an Oligopeptide Transporter: PEPT1 in Tumors
Current Medicinal Chemistry Cervical Cancer Diagnosis: Insights into Biochemical Biomarkers and Imaging Techniques
Combinatorial Chemistry & High Throughput Screening Prophylaxis of Cancer
Current Cancer Therapy Reviews Emerging Roles of MicroRNA-22 in Human Disease and Normal Physiology
Current Molecular Medicine EMT Blockage Strategies: Targeting Akt Dependent Mechanisms for Breast Cancer Metastatic Behaviour Modulation
Current Gene Therapy Function of miRNA in Controlling Drug Resistance of Human Cancers
Current Drug Targets Antibody-Targeted Immunoliposomes for Cancer Treatment
Mini-Reviews in Medicinal Chemistry Mechanism-based Modulator Discovery for Sirtuin-catalyzed Deacetylation Reaction
Mini-Reviews in Medicinal Chemistry Thinking Outside the ‘Block’: Alternative Polymer Compositions for Micellar Drug Delivery
Current Topics in Medicinal Chemistry Structure-Activity Evaluation of N-benzyl-5-substituted Indole-3-imine Derivatives and their Amine Congeners as Bovine Testicular Hyaluronidase (BTH) Inhibitor
Letters in Drug Design & Discovery PET with Non-Standard Nuclides
Current Topics in Medicinal Chemistry