Cancer-Leading Proteases: Structures, Functions, and Inhibition

Description

Cancer-Leading Proteases: Structures, Functions, and Inhibition presents a detailed discussion on the role of proteases as drug targets and how they have been utilized to develop anticancer drugs. Proteases possess outstanding diversity in their functions. Because of their unique properties, proteases are a major focus of attention for the pharmaceutical industry as potential drug targets or as diagnostic and prognostic biomarkers. This book covers the structure and functions of proteases and the chemical and biological rationale of drug design relating to how these proteases can be exploited to find useful chemotherapeutics to fight cancers. In addition, the book encompasses the experimental and theoretical aspects of anticancer drug design based on proteases. It is a useful resource for pharmaceutical scientists, medicinal chemists, biochemists, microbiologists, and cancer researchers working on proteases. Cover Cancer-Leading Proteases: Structures, Functions, and Inhibition Copyright Contributors About the Editor Preface 1 Cancer-leading proteases: An introduction Introduction Different classes of proteases Cysteine proteases Serine proteases Aspartic proteases Threonine proteases Matrix metalloproteases Mechanism of cancerous roles of proteases Protease specificity Protease inhibitors Anticancer activity of proteases Conclusions References Further reading 2 Potential roles of protease inhibitors in anticancer therapy Introduction Role of proteases in cancer development and metastasis Caspases and apoptosis Cathepsin B Urokinase-type plasminogen activator Matrix metalloproteinases (MMPs) Classification of proteases and their specific role in cancer Optimal pH in which they are active The catalyzed reaction Chemical nature of the catalytic site Cysteine proteases Serine proteases Aspartate proteases Threonine proteases Matrix metalloproteinases (MMPs) Glutamic proteases Importance of inhibitors of proteases in cancer Inhibitors of proteases Classification of protease inhibitors by mechanism of action Reversible class Irreversible class Engineering class Classification of protease inhibitors by target Aspartic proteases Cysteine proteases Matrix metalloproteinases Serine proteases Threonine proteases Plant products as protease inhibitors Bowman-Birk inhibitors Potato I and II or potato carboxypeptidase inhibitors (PCIs) Serpins Food crop HIV protease inhibitors Conclusions References Further reading 3 Studies on cysteine proteases and their inhibitors for anticancer drug design Introduction The role of cysteine proteases in tumor growth and progession Caspases and calpains Cysteine cathepsins Cathepsin substrate (E-cadherin) Cathepsin B Cathepsin S Inhibitors of cysteine proteases Endogenous inhibitors From natural sources Reversible and irreversible inhibitors Metalloinhibitors Conclusions References Further reading 4 Ubiquitin-specific proteases as targets for anticancer drug therapies Introduction Roles of ubiquitin-specific proteases Cell cycle regulation Chromatin remodeling DNA damage repair and p53 signaling Regulation of RNA maturation and protein synthesis Other cancer-related signaling pathways Alterations of USPs in human cancer Targeting USPs in cancer Concluding remarks Acknowledgments Conflicts of interest References 5 Aspartic proteases: Potential drug targets for anticancer drug development Introduction Aspartate proteases Distribution and occurrence Classification of aspartate proteases Structure of aspartate proteases Zymogen and its activation Active site Flap Catalytic mechanism Substrate specificity Physiological role of aspartate proteases Aspartate proteases involved in cancer Cathepsin D γ-Secretase β-Secretase-1 (BACE-1) Pepsinogen C Napsin A Aspartic protease inhibitors HIV-1 protease inhibitors as anticancer agents Cathepsin D inhibitors as anticancer agents Endothelin-converting enzyme inhibitors as anticancer agents γ-Secretase inhibitor as anticancer agents β-Secretase inhibitors as anticancer agents Conclusions References 6 Inhibitors of HIV protease in cancer therapy Introduction Protease inhibitors First generation HIV protease inhibitors Second-generation HIV protease inhibitors Lopinavir Atazanavir Darunavir Tipranavir Fosamprenavir HIV protease inhibitors and metalloproteases (MMPs) Conclusions References 7 Serine proteases in ovarian cancer Introduction Role of proteases in cancer Roles of serine proteases in cancer Urokinase plasminogen activator Kallikreins HTRA1 (PRSS11 or IGFBP-5) Type II transmembrane serine proteases (TTSPs) Hepsin Matriptase-2 Prostasin Biomarkers and protease inhibitors in cancer treatment Serpin E1 (plasminogen activator inhibitor-1, PAI-1) Serpin B5 Serpin F1 SPINK1 (Kazal type 1) Fibroblast activation protein Serine proteases: A potential target for anticancer drugs Conclusions References Further reading 8 Serine proteases leading to prostate cancer: Structures, functions, and development of anticancer drugs Introduction Proteases and PCa progression Plasminogen activation system Structure of uPA Function of uPA Human kallikreins in prostate cancer Prostate-specific antigen (hK3/KLK3) Structure of PSA Function of PSA Kallikrein 2 Structure of kallikrein 2 Function of kallikrein 2 Type II transmembrane serine protease (TTSP) TMPRSS2 Structure of TMPRSS2 Function of TMPRSS2 Matriptase (MT-SP1, TADG-15, epithin, ST14) Matriptase activation Structure of matriptase Function of matriptase Hepsin Function of hepsin Structure of hepsin Other serine proteases Targeting serine proteases for cancer therapy Protease-targeted drug discovery against prostate cancer Conclusions Acknowledgments References 9 HCV NS3 serine protease as a drug target for the development of drugs against hepatocellular carcinoma (liver cancer) Introduction HCV genomic organization and progression of HCV to HCC HCV NS3 protease: Structural perspective HCV NS3 protease zinc-binding site HCV NS3 protease substrate binding site HCV NS3/4A interaction complex and mechanistic role of NS4A in the activation of HCV NS3 protease HCV NS3/4A protease inhibitors and the molecular basis of binding with NS3/4A protease Reversible covalent inhibitors Noncovalent inhibitors Emergence of drug resistance against HCV NS3/4A protease inhibitors Conclusions Additional information References 10 Collagenases and gelatinases and their inhibitors as anticancer agents Introduction Structures of MMPs Structures of collagenases Structures of gelatinases Roles of collagenases and gelatinases in human diseases Collagenases Collagenases in cancers Gelatinases Gelatinases in cancer Inhibitors of collagenases and gelatinases as anticancer agents Conclusions Acknowledgments References 11 c-Met as a potential therapeutic target in triple negative breast cancer Introduction c-MET structure and functions c-Met signaling c-Met and adaptor protein c-Met-CD44 links cytoskeleton HGF-independent c-Met-activation c-Met-receptor endocytosis c-Met and biological signaling pathways MAPK (mitogen-activated protein kinase) cascade PI3K-Akt pathway NF- κ B pathway PTK2 pathway STAT pathway Wnt/ β -catenin pathway c-Met in cancer c-Met in breast cancer c-Met in triple negative breast cancer (TNBC) Inhibitors of c-Met protein Conclusions References Further reading 12 Rhomboid proteases leading to cancer: Structures, functions, and inhibition Introduction Rhomboid proteases Rhomboid-related proteins/secretases (RHBL-1, 2, 3, 4) Rhomboid-related protein-2 (RHBL-2) Rhomboid-related protein-4/rhomboid domain containing protein-1 (RHBL-4) Rhomboid-related protein-1 (RHBL-1) Rhomboid-related protein-3/ventrhoid transmembrane protein (RHBL-3) Presenilins-associated rhomboid-like protein (PARL) Derlin-1 iRhoms Inhibitors of rhomboid proteases Conclusions Acknowledgment References 13 KRAS: Structure, function, and development of anticancer drugs Introduction RAS superfamily: Highly conserved structure and function Structure Function Signaling KRAS activation and role of effectors Oligomers Role in disease and mutations Role in disease Mutations Pancreatic cancer Lung cancer Colorectal cancer Mutations in RASopathies KRAS targeted drug development Direct targeting of RAS Targeting membrane-KRAS interactions Synthetic lethal interactions Inhibiting RAS-regulated metabolic processes in cancer cells Immunotherapy Recent advances in direct targeting of KRAS G12C Challenges in developing therapies to target KRAS Conclusions References 14 Tumor-suppressive proteases revisited: Role in inhibiting tumor progression and metastasis Introduction Extracellular proteases with tumor-suppressive activity Matrix metalloproteinases Neprilysin Cysteine cathepsins Kallikreins Prostasin serine protease Testisin Dipeptidyl peptidase 4 ADAMTSs Intracellular proteases Caspases Deubiquitylases Autophagins Conclusion and future prospective References Further reading 15 Vitamin D as therapeutic agent acting against cancers caused by proteases Introduction Functions of vitamin D Nuclear functions Vitamin D and the gastrointestinal tract Vitamin D and liver Effect of vitamin D on the bone Effect of vitamin D on the kidney Effect of vitamin D on the brain Vitamin D and immunity Vitamin D and hypertension Effect of vitamin D on obesity Effect of vitamin D on reproduction Vitamin D in cancer management and therapy Anticancer mechanism of vitamin D Antiinflammatory effect of vitamin D Antioxidant effect of vitamin D Vitamin D effect on lymphangioleiomyomatosis (LAM) Vitamin D repair DNA damage Vitamin D regulate cell proliferation and differentiation Vitamin D induces cancer cell death Vitamin D and protease inhibition Role of vitamin D in cancer prevention Vitamin D and breast cancer Vitamin D and colon cancer Vitamin D and prostate cancer Vitamin D and other types of cancer Conclusions References Further reading 16 Molecular imaging of proteases in cancer Introduction Proteases Matrix metalloproteases (MMPs) Cysteine proteases Cathepsins Caspases Bleomycin hydrolase (Blmh) Serine proteases Threonine proteases Aspartate proteases Molecular imaging strategies Modalities for MMPs Optical imaging (OIM) for MMPs Bioluminescence imaging (BLI) for MMPs PET and SPECT imaging of MMPs Magnetic resonance imaging (MRI) for MMPs Imaging modalities for cathepsins Quenched fluorescent activity-based imaging of cathepsins Magnetic resonance imaging (MRI) for cathepsins Imaging modalities for caspases Molecular imaging of urokinase plasminogen activator (uPA) system Optical imaging for uPA Magnetic resonance imaging for uPA SPECT and PET imaging for uPA Conclusions References Further reading Index A B C D E F G H I J K L M N O P Q R S T U V W X Z Back Cover