Cancer-Leading Proteases: Structures, Functions, and Inhibition

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Cancer-Leading
Proteases:
Structures, Functions, and Inhibition
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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
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