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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5459_Библиотеки_им_академика_М_И_Перельмана
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CAMK Calcium/calmodulin-dependent protein kinase
CAT Computerized axial tomography
CAR-T Chimeric antigen receptor T cells
CBC Complete blood count
CDC Center for Disease Control
CDK Cyclin-dependent kinase
CT Computed tomography
CLL Chronic lymphocytic leukemia
CTCL Cutaneous T cell lymphoma
CTLA-4 Cytotoxic T lymphocyte-associated antigen-4
CK1 Casein kinase 1
CML Chronic myelogenous leukemia
CAT Computerized axial tomography (scan)
CMML Chronic myelomonocytic leukemia
CNS Central nervous system
CHF Congestive heart failure
cAMP cyclic AMP
COPD Chronic obstructive pulmonary disease
CPK Creatine phosphokinase
CPR Cardiopulmonary resuscitation
CRC Colorectal cancer
CRF Chronic renal failure
CR Complete remission
CXR Chest X-ray
DM Diabetes mellitus
DNA Deoxyribonucleic acid
DLBCL Diffuse large B-cell lymphoma
DLCL Diffuse large-cell lymphoma
DNAPK DNA-dependent protein kinase
EBV Epstein-Barr virus
EGFR Epidermal growth factor receptor
ERK Extracellular signal-regulated kinase
ECG/EKG Electrocardiogram
FDA U.S.Food and Drug Administration
FGFR Fibroblast growth factor receptor
FL Follicular lymphoma
FSH Follicle-stimulating hormone
FLT3 fms-related tyrosine kinase 3
GERD Gastroesophageal reux disease
GIST Gastrointestinal stromal tumor
GBM Glioblastoma multiforme
GI Gastrointestinal
GFR Glomerular ltration rate
GPCR G protein-coupled receptor
GSK3 Glycogen synthase kinase 3
Common Abbreviations and Acronyms
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HAV Hepatitis A virus
HBV Hepatitis B virus
HER1 Human epidermal growth factor receptor 1
HPC Hepatitis C virus
HIV Human immunodeciency virus
HCC Hepato-cellular carcinoma
HCL Hairy cell leukemia
HL Hodgkin lymphoma
HPV Human papillomavirus
HDL High-density lipoprotein
HGB Hemoglobin
HCK Hematopoietic cell kinase
HCL Hairy cell leukemia
HL Hodgkin’s lymphoma
HRT Hormone replacement therapy
HSP Heat shock protein
HTS High-throughput screening
IC
50
Concentration required to obtain 50% inhibition
IBD Inammatory bowel disease
IBS Irritable bowel syndrome
ICD Implantable cardioverter debrillator
ICU Intensive care unit
IDDM Insulin-dependent diabetes mellitus
IM Intramuscular
IP Intraperitoneal
IT Intrathecal
IV Intravenous
IL Interleukin
IUD Intrauterine device
IVP Intravenous pyelogram
IgH Immunoglobulin heavy chain
iMiD Immunomodulatory drugs
IKK IκB kinase
ILK Integrin-linked kinase
IRS Insulin receptor signaling protein
JAK Janus kinase
JNK c-Jun N-terminal kinase
JIP JNK-interacting protein
JBD JNK-binding domain
kDa kilodalton
KD Kinase domain
LDL Low-density lipoprotein
LBD Ligand-binding domain
LE Ligand efciency
LFT Liver function tests
Common Abbreviations and Acronyms
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LCH Langerhans cell histiocytosis
LDH Lactic dehydrogenase
LMM Lentigo Maligna Melanoma
LN Lymph node
LP Lumbar puncture
LRRK1/2 Leucine-rich repeat kinase 1/2
MAPK Mitogen-activated protein kinase
MAP2K Mitogen-activated protein kinase kinase
MAP3K Mitogen-activated protein kinase kinase kinase
MAP4K Mitogen-activated protein kinase kinase kinase kinase
MAPKAPK Mitogen-activated protein kinase-activated protein kinase
MKP1 Mitogen-activated protein kinase phosphatase 1
MET Mesenchymal epithelial transition factor
MEK MAPK/ERK kinase
MRI Magnetic resonance imaging
MDS Myelodysplastic syndromes
MCL Mantle cell lymphoma
MM Multiple myeloma
MDR Multi-drug resistant
MI Myocardial infarction (heart attack)
MMR Measles, mumps, and rubella
MRI Magnetic resonance imaging (scan)
MRT Malignant rhabdoid tumor
MRSA Methicillin-resistant Staphylococcus aureus
MS Multiple sclerosis
MTD Maximum tolerated dose
mTOR mammalian target of rapamycin
mTORC1 mammalian target of rapamycin complex 1
mTORC2 mammalian target of rapamycin complex 2
NIDDM Non-insulin-dependent diabetes mellitus
NKDA No known drug allergies
NSAID Non-steroidal anti-inammatory drug
NSCLC Non-small cell lung cancer
NHL Non-Hodgkin lymphoma
NPC Nasopharyngeal carcinoma
NRSTS Non-rhabdomyosarcoma soft tissue sarcoma
NF Neurobromatosis
NFκB Nuclear factor κB
NLK Nemo-like kinase
NMR Nuclear magnetic resonance
NTRK Neurotrophic tyrosine receptor kinase
OCD Obsessive-compulsive disorder
ORR Overall response rate
OS Overall survival
PAD Peripheral arterial disease
Common Abbreviations and Acronyms
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PAT Paroxysmal atrial tachycardia
PAP Papanicolaou (a test for cervical cancer)
PD Parkinson’s disease
PET Positron emission tomography
PFT Pulmonary function test
PID Pelvic inammatory disease
PI-3K Phosphoinositide 3-kinase
PMS Premenstrual syndrome
PPD Puried protein derivative
PT Prothrombin time
PTH Parathyroid hormone
PTSD Post-traumatic stress syndrome
PTT Partial thromboplastin time
PTEN Phosphatase and tensin homolog
PSA Prostate-specic antigen
PARP Poly ADP ribose polymerase
PD1 Programmed cell death protein-1
PD-L1 Programmed death-ligand 1
PO Per os (by mouth)
PUD Peptic ulcer disease
PVC Premature ventricular contraction
PFS Progression-free survival
PD-1 Programmed cell death protein-1
PR Partial remission
PDGFR Platelet-derived growth factor receptor
PDK1 Phosphoinositide-3-dependent kinase 1
PET Positron emission tomography
PH Pleckstrin homology (PIP3 binding) domain
Ph+ Philadelphia chromosome positive
PIP2 Phosphatidylinositol (4,5)-bisphosphate
PIP3 Phosphatidylinositol (3,4,5)-trisphosphate
PK Pharmacokinetics
PKA/B/C Protein kinase A/B/C
PTB Phospho-tyrosine binding domain
RA Rheumatoid arthritis
RCT Randomized control trial
RNA Ribonucleic acid
RBC Red blood cell/red blood count
RSV Respiratory syncytial virus
RCC Renal cell carcinoma
RANK Receptor activator of nuclear factor-kappa B
RET Rearranged during transfection
RTK Receptor tyrosine kinase
RGC Receptor guanylyl cyclase
SAD Seasonal affective disorder
Common Abbreviations and Acronyms
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SIDS Sudden infant death syndrome
SLE Systemic lupus erythematosus
SC Subcutaneous
SCC Squamous cell carcinoma
SCC Small cell carcinoma
SCLC Small cell lung cancer
SLL Small lymphocytic leukemia
STD Sexually transmitted disease
SCNSL Secondary central nervous system lymphoma
SH1 src homology 1 domain (kinase domain)
SH2 src homology 2 domain
SH3 src homology 3 domain
STAT Signal transducer and activator of transcription
SYK Spleen tyrosine kinase
TB Tuberculosis
TAH Total abdominal hysterectomy
TIA Transient ischemic attack (stroke)
TIBC Total iron binding capacity
TCC Transitional cell carcinoma
TFG-β Transforming growth factor beta
TMJ Temporomandibular joint
TNF-α Tumor necrosis factor alpha
TNBC Triple-negative breast cancer
TBI Total body irradiation
TCP Thrombocytopenia
TKL Tyrosine kinase-like kinase
TK Tyrosine kinase
TYK2 tyrosine kinase 2
TSH Thyroid-stimulating hormone
TURP Transurethral resection of prostate gland
US Ultrasound (scan)
URI Upper respiratory infection
UTI Urinary tract infection
UVR Ultraviolet radiation
VEF Ventricular ejection fraction
VEGFR Vascular endothelial growth factor receptor
VHL Von Hippel Lindau
WBC White blood cell count
WCC White cell count
WM Waldenstrom’s macroglobulinemia
WT Wild type
XRT Radiotherapy (external)
YST Yolk sac tumor
Common Abbreviations and Acronyms
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1© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024
S. K. De, Drug Design and Discovery,
https://doi.org/10.1007/978-3-031-75682-5_1
Chapter 1
An Overview ofProtein Kinase Inhibitors
Abstract Protein kinases become one of the most successful drug targets for the
treatment of various diseases. Protein kinase catalyzes the transfer of the
γ-phosphoryl group of the ATP to specic protein substrates which is an important
cellular signal communication and maintenance of homeostasis. Most kinases share
a common protein kinase domain. Some kinase inhibitors bind to the ATP site and
some inhibitors bind to the allosteric site. There are 82 kinase inhibitors in the mar-
ket. Here chemical structures of approved kinase inhibitors, their binding modes,
medical uses, and names of drug developers are described. Humans have four typi-
cal MAP kinases such as extracellular signal-regulated kinases (ERKs), c-Jun
N-terminal kinases (JNKs), p38 MAP kinases, and nemo-like kinase (NLK), and
their structure and activation, cellular signaling, and pathological implications are
highlighted.
Keywords Roles of kinase activation · FDA-approved kinase inhibitors ·
Mitogen-activated kinases · Structure · Function
1.1 Introduction
The protein kinase family is the second largest enzyme family (after proteases) and
the fth largest gene family in humans. Protein kinases are the second largest group
of drug targets after G-protein-coupled receptors (GPCR) and they account for an
estimated 20–30% drug development pipeline. The human genome has almost 518
kinase genes and 106 pseudogenes. Among 518 known kinases, 478 are typical and
40 are atypical kinases [1–16]. Protein kinases comprise 2% of the mammalian
genome and catalyze the transfer of the γ-phosphoryl group of the ATP to specic
protein substrates (Fig.1.1). This covalent post-translational modication is a cru-
cial component of normal cellular communication and maintenance of homeostasis.
The signals can initiate inside or outside the cells and pass through a series of steps
with multiple enzymes and messengers. Reversible protein phosphorylation and
dephosphorylation are the most prominent post-transcriptional modications to
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2
N
N
N
N
NH
2
O
OHOH
OPO
O-
O
P
O
O
OP
O
O
O
N
N
N
N
NH
2
O
OHOH
OPO
O-
O
P
O
O
O
N
H
OH
O
ATP
N
H
O
O PO
O
O
ADP
serine
proteinsubstrate
kinase
+
+
phosphoserine
Fig. 1.1 Protein phosphorylation and dephosphorylation and protein kinase-catalyzed transfer of
a γ-phosphoryl group from ATP onto serine hydroxyl group of a protein substrate (showing with
red color)
proteins discovered by Edmond Fisher and Edwin Krebs (Fig.1.1), who shared the
Nobel Prize in 1992.
Protein kinases are enzymes that add inorganic phosphate to proteins and protein
phosphatases are enzymes that remove inorganic phosphate from protein. The
amino acids in proteins mostly phosphorylated are serine, threonine, and tyrosine
and less common amino acid phosphorylated is histidine. There are 82 small mol-
ecule protein kinase inhibitors and 4 antibody kinase inhibitors FDA-approved for
treating cancers and other diseases (see Tables 1.1 and 1.2). There are signicant
numbers of small molecule kinase inhibitors in various phases of clinical trials.
1 An Overview ofProtein Kinase Inhibitors
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Table 1.1 FDA-approved kinase inhibitors and their applications, binding mode, and PDB code
Drug name Target kinase
Protein substrate
Phosphorylation site
Binding
mode Medical use
PDB Code and
Refs.
Abemaciclib CDK Serine/threonine Type I Breast cancer 5L2S [17]
Abrocitinib JAK Tyrosine Type 1 Atopic dermatitis 6BBU [18]
Acalabrutinib BTK Tyrosine Covalent CLL/MCL 8FD9 [19]
Afatinib EGFR
HER2
Tyrosine Covalent Non-small cell lung carcinoma
(NSCLC)
4G5J [20]
Alectinib ALK Tyrosine Type I NSCLC 3AOX [21]
Alpelisib PI3K Inositol/serine/threonine Type I Breast cancer 4JPS [22]
Apatinib VEGFR2 Tyrosine Type I Gastric carcinoma ND
Axitinib PDGFR Tyrosine Type II Renal cell carcinoma (RCC) 4AG8 [23]
Avapritinib PDGFR Tyrosine NR Gastrointestinal stromal tumors NR
Baricitinib JAK Tyrosine NR Rheumatoid arthritis, alopecia areata 6VN8 [24]
Binimetinib B-RAF/MEK Serine/threonine Type III Melanoma 7M0U [25]
Brigatinib ALK/EGFR Tyrosine Type I NSCLC 6MX8 [26]
Bosutinib Bcr-Abl/Src Tyrosine Type II CML 3UE4 [27]
Cabozantinib FLT3/VEGFR/c-MET Tyrosine Type II RCC/medullary thyroid cancer 4MXC [28]
Capmatinib c-MET Tyrosine NR NSCLC NR
Ceritinib ALK Tyrosine Type I NSCLC 4MKC [29]
Cobimetinib MEK Serine/Threonine/
Tyrosine
Type III Melanoma 4AN2 [30]
Copanlisib PI-3K Inositol/Serine/
Threonine
Type I Follicular lymphoma (FL) 5G2N [31]
Crizotinib ALK Tyrosine Type I NSCLC 3ZBF [32]
Dasatinib ABL/KIT Tyrosine Type I CML/ALL 3G6D [33]
(continued)
1.1 Introduction
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Table 1.1 (continued)
Drug name Target kinase
Protein substrate
Phosphorylation site
Binding
mode Medical use
PDB Code and
Refs.
Dabrafenib BRAF Serine/Threonine Type I 1/2 Melanoma 5CSW [34]
Dacomitinib EGFR Tyrosine Covalent NSCLC 4I23 [35]
Deucravacitinib TYK2 Tyrosine Type III Psoriasis NR
Duvelisib PI-3K Inositol/Serine/
Threonine
NR CLL/SLL/FL NR
Encorafenib MAPK/BRAF Serine/Threonine Type I Melanoma NR
Entrectinib TRK Tyrosine Type I NSCLC 5FTO [36]
Erdatinib FGFR Tyrosine Type I Urothelial carcinoma 5EW8 [37]
Erlotinib EGFR Tyrosine Type I NSCLC/pancreaticcancer 4HJO [38]
Everolimus mTOR Serine/Threonine Renal cell carcinoma 6L3A [39]
Fedratinib JAK2 Tyrosine Type I Myelobrosis 6VNE [24]
Fostamatinib SYK Tyrosine Type I Autoimmune/thrombocyto-penia 4O75 [40]
Futibatinib FGFR Tyrosine Covalent Cholangiocarcinoma 6MZW [41]
Getinib EGFR Tyrosine Type I NSCLC 5Y7Z [42]
Gilteritinib FLT3 Tyrosine Type I AML 6JQR [43]
Ibrutinib BTK Tyrosine Covalent MCL/ CLL/SLL 5P9J [44]
Idelalisib PI-3K Inositol/Serine/
Threonine
Type I CLL/SLL 4XE0 [45]
Imatinib ABL/KIT Tyrosine Type II CLL/ALL 2HYY [46]
Ingratinib FGFR Tyrosine Type I Cholangiocarcinoma 3TT0 [47]
Lapatinib EGFR/HER2 Tyrosine Type I 1/2 Breast cancer 3BBT [48]
Larotrectinib TRK Tyrosine Type I Solid tumors with NTRK fusion NR
Leniolisib PI3Kδ Inositol/Serine/
Threonine
Type I APDS 5O83 [49]
Lenvatinib FGFR/KIT Tyrosine Type I Thyroid cancer 3WZD [50]
1 An Overview ofProtein Kinase Inhibitors
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Drug name Target kinase
Protein substrate
Phosphorylation site
Binding
mode Medical use
PDB Code and
Refs.
Lorlatinib ALK Tyrosine Type I NSCLC 4UXL [51]
Midostaurin FLT3/KIT Tyrosine Type I NSCLC 4NCT [52]
Mobocertinib EGFR Tyrosine Covalent NSCLC 7A6K [53]
Neratinib EGFR Tyrosine Covalent 2JIV [54]
Netarsudil ROCK Serine/Threonine Type I Glaucoma NR
Nilotinib ABL/KIT Tyrosine Type II CML 3CS9 [55]
Nintedanib Src/Lck/PDGFR/
VEGFR
Tyrosine Type I Idiopathic pulmonary brosis/NSCLC 3C7Q [56]
Osimertinib EGFR Tyrosine Covalent NSCLC 6JXT [57]
Pacritinib JAK2/FLT3 Tyrosine Type I Myelobrosis 5LBZ [58]
Palbociclib CDK Serine/Threonine Type I Breast cancer 5L2I [17]
Pazopanib VEGFR/KIT Tyrosine Type I Renal cancer NR
Pemigatinib FGFR Tyrosine Type I Cholangiocarcinoma 7WCL [59]
Pexidartinib KIT/FLT3 Tyrosine Type II Tenosynovial giant cell tumor 4R7H [60]
Pirtobrutinib BTK Tyrosine Type I MCL 8FLL [61]
Ponatinib ABL/FLT3 Tyrosine Type II CML/ALL 3OXZ [62]
Pralsetinib RET Tyrosine Type I NSCLC 7JU5 [63]
Radotinib ABL Tyrosine Type II CML NR
Rapamycin mTOR Serine/Threonine NR RCC/kidney transplantation 7SQ9 [64]
Regorafenib VEGFR/KIT Tyrosine Type II Colorectal cancer NR
Ribociclib CDK4/6 Tyrosine/Serine Type I Breast cancer 5L2T [17]
Ripretinib PDGFR/KIT Tyrosine Type II Gastrointestinal stromal tumor 6MOB [65]
Ritlecitinib JAK3 Tyrosine Covalent Severe alopecia NR
Ruxolitinib JAK Tyrosine Type I Myelobrosis 6VGL [24]
(continued)
1.1 Introduction
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