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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5979_Библиотеки_им_академика_М_И_Перельмана
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16
Table 1.2 (continued)
Year Drug structure and generic name (trade name) MW Company
2018
N
NH
2
O
O
N
N
N
NC
Lorlatinib (Lorbrena)
406 Pzer
2018
N
N
N
N
F
F
NH
O
N
HO
Larotrectinib (Vitrakvi)
428 Bayer
2018
N
H
N
O
NH
2
O
O
Netarsudil (Rhopressa)
453 Aerie Pharm
2019
N
H
N
N
N
N
N
H
O
F
3
C
Upadacitinib (Rinvoq)
380 AbbVie
2019
N
HN
N
H
OHN
O
N
N
F
F
Entrectinib (Rozlytrek)
561 Genentech
2019
N
NN
N
N
N
H
MeOOMe
Erdatinib (Balversa)
446 Janssen
(continued)
1 An Overview ofProtein Kinase Inhibitors
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Table 1.2 (continued)
Year Drug structure and generic name (trade name) MW Company
2019
N
N
NH
N
H
O
N
S
H
N
O
O
Fedratinib (Inrebic)
515 Impact Biomedicines
2019
N
N
H
Cl
N
H
NN
CF
3
Pexidartinib (Turalio)
417 Daiichi Sankyo
2019
NH
N
N
O
N
O
O
NH
2
Zanubrutinib (Brukinsa)
472 BeiGene USA Inc
2020
H
2
N
N
N
FN
N
N
N
N
N
N
Avapritinib (Ayvakit)
499 Blueprint Medicines
Corporation
2020
N
N
N
N
N
F
O
N
H
Capmatinib (Tabrecta)
412 Novartis
(continued)
1.1 Introduction
https://t.me/med1917
18
Table 1.2 (continued)
Year Drug structure and generic name (trade name) MW Company
2020
N
NO
N
NH
N
O
F
F
OMe
Me
O
Pemigatinib (Pemazyre)
487 Incyte Corporation
2020
N
N
H
N
N
HN
O
O
NN
N
F
Pralsetinib (Gavreto)
534 Blueprint Medicines
2020
N
N
CN
O
HO
N
N
N
N
MeO
Selpercatinib (Retevmo)
526 Eli Lilly
2020
N
N
H
N
O
HO
O
F
H
N
Cl
Br
Selumetinib (Koselugo)
458 AstraZeneca
2020
NN
NH
O
N
H
N
O
N
N
N
Tucatinib (Tukysa)
481 Seattle Genetics
(continued)
1 An Overview ofProtein Kinase Inhibitors
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Table 1.2 (continued)
Year Drug structure and generic name (trade name) MW Company
2020
N
NON
H
Br F
N
H
N
H
O
Ripretinib (Qinlock)
510 Deciphera
Pharmaceuticals
2021
N
N
H
N
O
O
F
F
Cl
OH
N
HN
Asciminib (Scemblix)
450 Novartis
2021
N
N
H
N
ON
N
NH
HO
O
O
N
Mobocertinib (Exkvity)
585 Ariad
2021
O
N
OMe
OM
e
N
H
N
H
O
NO
Tivozanib (Fotivda)
454 AVEO
Oncology
2021
N
N
N
NH
O
HN
N
N
N
Trilaciclib (Cosela)
446 G1 Therapeutics
2021
N
H
N
ONN
N
H
N
N
Cl
Cl
OMe
Me
O
Ingratinib (Truseltiq)
560 Novartis
(continued)
1.1 Introduction
https://t.me/med1917
20
Table 1.2 (continued)
Year Drug structure and generic name (trade name) MW Company
2021
O
O
F
F
N
N
N
N
H
2
N
F
O
Umbralisib (Ukoniq)
571 TG Therapeutics
2021
N
N
N
N
O
CN
O
N
Tepotinib (Tepmetko)
492 EMD Serono
2021
N
N
HN
N
NH
O
N
H
O
Belumosudil (Rezurock)
452 Kadmon pharma
2022
N
N
N
H
N
H
N
S
O
O
Abrocitinib (Cibinqo)
323 Pzer
2022
N
N
N
H
O
O
N
O
Pacritinib (Vonjo)
472 CTO Biopharma
(continued)
1 An Overview ofProtein Kinase Inhibitors
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Table 1.2 (continued)
Year Drug structure and generic name (trade name) MW Company
2022
N
NN
H
ON
H
D
3
C
OHN
MeO
N
N
N
Deucravacitinib (Sotyktu)
425 BMS
2022
N
N
N
N
NH
2
MeO
OMe
N
O
Futibatinib (Lytgobi)
418 Taiho
2023
N
N
N
O
NH
O
HN
F
Repotrectinib (Augtyro)
355 TP
Therapeutics
2023
N
H
O
F
OM
e
N
N
CF
3
NH
2
O
NH
2
Pirtobrutinib (Jaypirca)
479 Eli Lily
2023
N
N
N
H
NH
N
O
Ritlectinib (Litfulo)
285 Pzer
(continued)
1.1 Introduction
https://t.me/med1917
22
Table 1.2 (continued)
Year Drug structure and generic name (trade name) MW Company
2023
N
N
N
N
Me
O
F
3
C
HN
N
O
Leniolisib
(Joenja)
450 Novartis
2023
N
NHN
N
H
CN
O
N
O
Momelotinib (Ojjaara)
414 GSK
2023
N
S
N
NH
O
HN
O
N
O
N
O
Quizartinib (Vanyta)
560 Daiichi Sankyo
2023
N
N
N
H
N
H
H
2
N
O
Cl
OH
Capivasertib (Truqap)
428 AstraZeneca
2023
N
N
Me
O
MeO
O
O
NHMe
O
Fruquintinib (Fruzaqla)
393 Takeda
1 An Overview ofProtein Kinase Inhibitors
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23
1.1.1 Classication ofKinases
According to the phosphorylation of amino acids, protein kinases are classied into
the following groups:
1. Ser/Thr protein kinases.
(a) Cyclic nucleotide-dependent.
(b) Calcium-calmodulin-dependent.
(c) Protein kinase C (PKC).
(d) Mitogen-activated protein kinases (MAPK).
(e) G-protein-coupled/Rhodospin/BARK.
2. Ser/Thr/Tyr protein kinases.
(a) MAP kinase kinase (MAPKK).
3. Tyrosine protein kinases.
(a) Cytosolic tyrosine kinases or non-receptor tyrosine kinases (32 members).
(b) Receptor tyrosine kinases (58 members).
1.1.2 Protein Kinase Domains
478 typical kinases share a eukaryotic protein kinase domain. 40 atypical kinases do
not have this protein kinase domain, but still show kinase activity.
Based on the sequence similarity of kinase domains, 478 typical kinases are
divided into eight major groups:
(i) TK (tyrosine kinase, 90 members).
(ii) TKL (tyrosine kinase-like kinase, 43 members).
(iii) STE (STE7-, STE11-, and STE20-related kinase, 47 members).
(iv) CK1 (casein kinase 1, 12 members).
(v) AGC (protein kinase A/G/C-related kinase, 63 members).
(vi) CAMK (calcium/calmodulin-dependent kinase, 74 members).
(vii) CMGC (CDK/MAPK/GSK/CDK like-related, 61 members).
(viii) RGC (receptor guanylyl cyclase, 5 members).
40 atypical protein kinases are pyruvate dehydrogenase kinases, bromodomain
kinases, B cell receptors (BCRs), and PI3 kinase-related kinases.
Knighton etal. published the rst crystal structure of protein kinase A (PKA) in
1991 (Fig.1.2a, b). The catalytic domain of a kinase comprises two lobes, a smaller
N-terminal lobe (N-lobe: almost 80 amino acids) and a larger C-terminal lobe
(C-lobe: almost 180 amino acids). As shown in Fig. 1.2, N-lobe has 5-stranded
β-sheets (β1–β5). The cleft between the two lobes lies the ATP-binding site. The
phosphates of ATP hold under the Gly-rich loop. A conserved Lys residue on β3 is
connected to the C-lobe via a divalent cation, generally with Mg
2+
(as shown in
1.1 Introduction
https://t.me/med1917
24
Fig. 1.2 (a) and (b): Key structural features of a kinase domain N-lobe (orange), C-lobe (green),
ATP (red): Images are based on the structure of Aurora-A kinase domain (Protein Data Bank entry:
1OL5). (Adapted from Arter etal. [14])
Fig.1.2b). The lobes are connected by a short linker sequence generally called the
hinge region. The hinge region forms two important hydrogen bonding interactions
with the adenine base of the ATP molecule. The central residue that mostly con-
served the 3-residue sequence is the DFG motif, located at the N-terminus of the
A-loop, recognizing the protein substrate and controlling kinase activity.
1.1.3 Types ofKinase Inhibitors
Based on binding mode, kinase inhibitors are divided into the following groups (see
Table1.1):
1 An Overview ofProtein Kinase Inhibitors
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25
(a) Type I kinase inhibitor: An inhibitor that binds to the active site of ATP pocket
of a kinase, DFG-in and αC-in.
(b) Type II: An inhibitor that binds to the inactive conformation of a kinase DFG-
out and αC-out.
(c) Type I ½ inhibitor: It belongs to between type I and type II, DFG-in and αC-out
inactive conformation.
(d) Type III: An inhibitor binds to an allosteric pocket next to the ATP-binding site,
with no formation of hydrogen bonding interaction with the hinge residues of
a kinase.
(e) Type IV: An inhibitor that binds to any allosteric sites distant from the ATP
pocket in the inactive conformation of a kinase.
(f) Type V or covalent inhibitor: An inhibitor that targets an active site cysteine
residue in or around the ATP binding site of a kinase.
1.1.4 FDA-Approved Kinase Inhibitors
Table 1.1 summarizes approved kinase inhibitors, their name, target kinase, phos-
phorylation site, binding mode, medical uses, and protein data bank code with
reference.
1.1.5 Chemical Structure ofFDA-Approved Kinase Inhibitors
Table 1.2 describes chemical structure, year of approval, molecular weight, and
drug developer name.
1.1.6 MAP Kinases
Mitogen-activated protein kinases (MAP kinases or MAPKs) are a family of protein
kinases that play crucial roles in various cellular processes, including cell growth,
differentiation, proliferation, gene expression, mitosis, apoptosis, and response to
extracellular signals. MAP kinases are part of a larger signaling cascade that trans-
mits signals from the cell surface to the nucleus, where they regulate gene expres-
sion and other cellular responses [75–82]. Dysregulation of MAP kinase signaling
has been implicated in various diseases, including cancer, inammatory disorders,
neurodegenerative diseases, and cardiovascular diseases. Therefore, understanding
the mechanisms of MAP kinase signaling and developing targeted therapies to mod-
ulate these pathways represent important areas of research in biomedicine and drug
discovery [75–82].
1.1 Introduction
https://t.me/med1917
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