1. MOE Key Laboratory of Protein Sciences, School of Pharmaceutical Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Tsinghua University, Beijing 100084, China 2. Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102218, China
The cell cycle is a complex process that involves DNA replication, protein expression, and cell division. Dysregulation of the cell cycle is associated with various diseases. Cyclin-dependent kinases (CDKs) and their corresponding cyclins are major proteins that regulate the cell cycle. In contrast to inhibition, a new approach called proteolysis-targeting chimeras (PROTACs) and molecular glues can eliminate both enzymatic and scaffold functions of CDKs and cyclins, achieving targeted degradation. The field of PROTACs and molecular glues has developed rapidly in recent years. In this article, we aim to summarize the latest developments of CDKs and cyclin protein degraders. The selectivity, application, validation and the current state of each CDK degrader will be overviewed. Additionally, possible methods are discussed for the development of degraders for CDK members that still lack them. Overall, this article provides a comprehensive summary of the latest advancements in CDK and cyclin protein degraders, which will be helpful for researchers working on this topic.
Trigger G1–S transition; control G1–S and G2–M transitions
Y
CDK4/6
A2, D1, D2, D3, E1, T1, T2
Mediate the monophosphorylation of Rb in G1; promotes G1–S transition
Y
Transcription
CDK7
A2, B1, B2, E1, H
Mediate the activation of CDK1/2/4/6/11 by catalyzing the phosphorylation of a threonine residue within the T-loop or activation segment
Y
CDK8/19
C, H
Regulation of RNA polymerase II transcription; phosphorylation of NOTCH leads to its degradation
Y
CDK9
H, K, T1, T2A, T2B
Regulation of RNA polymerase II transcription; genome integrity maintenance
Y
CDK12/13
K
Regulation of RNA polymerase II and transcription elongation
Y
Special roles
CDK3
A2, C, E1, E2
Function is poorly defined: may trigger reentry from G0–G1 and through phosphorylation of Rb; may trigger G1–S transitions by catalyzing the phosphorylation of E2F1/2/3
N
CDK5
A2, B1, D2, G1, E1, I1, I2
Function is poorly defined: may produce neuronal cell cycle arrest and differentiation and participates in many aspects of neuronal function
Y
CDK10
L2, M
Traversing start point and phosphorylation of transcription factor ETS2 leading to its degradation
Y
CDK11
L1, L2
Regulation of apoptosis cytokinesis
Y
CDK14
D3, Y
Regulate cell cycle and neuronal differentiation
Y
CDK15
Y
Antiapoptotic
N
CDK16
Y
Regulation of neuron differentiation and exocytosis
Y
CDK17/18
K, Y
Play a role in terminally differentiated neurons
Y
CDK20
H
Regulation of neural development
N
Tab.1
Fig.2
Compound No.
Original name
Validation
Claimed application
Claimed major target(s)
Structure
Reference
1
A9
In vitro RescueConcentration-dependentCell inhibition
Tumor inhibition
CDK2
[ 31]
2
F9
In vitro Concentration-dependentCell inhibition
Tumor inhibition
CDK9
[ 31]
3
F3
In vitro RescueConcentration-dependentCell inhibitionCell-cycle
Tumor inhibition
CDK2CDK9
[ 31]
4
TMX-1160
In vitro Concentration-dependent
–
CDK2CDK4CDK5CDK6
[ 32]
5
TMX-2172
In vitro RescueConcentration-dependentCell inhibitionProteomics
Tumor inhibition
CDK2CDK5
[ 32]
6
Compound 3
In vitro and in vivo Concentration-dependentRescueCell inhibitionCell-cyclePKXenograftIHC
Orally availableTumor inhibition
CDK2CDK4CDK6
[ 33]
7
Compound 11
Prodrug of 6
–
–
[ 33]
8
CPS2
In vitro Time-courseConcentration-dependentRescueCell inhibitionProteomics
AML differentiation
CDK2
[ 34]
9
PROTAC-8
In vitro and in vivo Concentration-dependent
Hearing loss
CDK2
[ 35]
10
pal-pom
In vitro Concentration-dependentRescueTime-course
Tumor inhibition
CDK4CDK6
[ 36]
11
rib-pom
In vitro Concentration-dependent
Tumor inhibition
CDK4CDK6
[ 36]
12
BSJ-02-162
In vitro RescueConcentration-dependentCell-cycleCell inhibitionProteomics
Tumor inhibition
CDK4CDK6IKZF1IKZF3
[ 37]
13
BSJ-01-187
In vitro RescueConcentration-dependent
–
CDK4IKZF1IKZF3
[ 37]
14
YKL-06-102
In vitro RescueConcentration-dependent
–
CDK6IKZF1IKZF3
[ 37]
15
BSJ-03-204
In vitro RescueConcentration-dependentCell-cycleCell inhibitionProteomics
Tumor inhibition
CDK4CDK6
[ 37]
16
BSJ-03-123
In vitro RescueConcentration-dependentProteomics
–
CDK6
[ 37]
17
BSJ-04-132
In vitro RescueConcentration-dependentProteomics
–
CDK4
[ 37]
18
CP-10
In vitro RescueConcentration-dependentProteomics
Tumor inhibition
CDK6
[ 38]
19
Degrader 6
In vitro Concentration-dependentRescueTime-course
–
CDK6
[ 39]
20
PROTAC-10-CRBN
In vitro Concentration-dependentRescue
–
CDK4CDK6
[ 40]
21
PROTAC-4-VHL
In vitro Concentration-dependentRescue
–
CDK4CDK6
[ 40]
22
PROTAC-7-IAP
In vitro Concentration-dependentRescue
–
CDK4CDK6
[ 40]
23
CST651
In vitro Concentration-dependentTime-courseCell inhibitionRescueWashoutPK
Tumor inhibition
CDK4CDK6
[ 41]
24
35
In vitro Concentration-dependentCell inhibition
Tumor inhibition
CDK4CDK6
[ 41]
25
YX-2-107
In vitro and in vivo Concentration-dependentXenograftProteomicsCell cyclePK
Tumor inhibition
CDK6
[ 42]
26
A4
In vitro RescueTime-courseConcentration-dependentCell inhibitionCell cycle
Tumor inhibition
CDK4CDK6
[ 43]
27
C6
In vitro Cell inhibition
Tumor inhibition
CDK4CDK6
[ 43]
28
C7
In vitro Cell inhibition
Tumor inhibition
CDK4CDK6
[ 43]
29
MS28
In vitro Concentration-dependentTime-courseRescueKinomeClonogenicity inhibitionProteomics
Tumor inhibition
Cyclin D1CDK6
[ 44]
30
MS140
In vitro Concentration-dependent
–
CDK6
[ 44]
31
ALV-07-082-03
In vitro RescueConcentration-dependentProteomicsCell cycle
IL-2 derepression
CDK4/6, Helios
[ 45]
32
JH-XI-10-02
In vitro Time-courseConcentration-dependent
–
CDK8
[ 46]
33
PROTAC-3-CDK9
In vitro Concentration-dependent
–
CDK9
[ 47]
34
PROTAC-2-CDK9
In vitro Concentration-dependentProteomicsCell inhibitionRescue
Tumor inhibition
CDK9
[ 48]
35
THAL-SNS-032
In vitro Time-courseConcentration-dependentRescueCell inhibitionProteomicsRNA-seqChIP-seqKinome
Tumor inhibition
CDK9
[ 49]
36
11c
In vitro Concentration-dependentRescueCell inhibition
Tumor inhibition
CDK9
[ 50]
37
B03
In vitro and in vivo Time-courseKinomeRescueConcentration-dependentProteomicsPK
Tumor inhibition
CDK9
[ 51]
38
Degrader 45
In vitro and in vivo Time-courseConcentration-dependentRescueCell inhibitionRNA-seqPKIHCXenograft
Tumor inhibition
CDK9
[ 52]
39
CD-5
In vitro ProteomicsConcentration-dependentTime-courseRescue
–
CDK9
[ 53]
40
LL-K9-3
In vitro Concentration-dependentProteomicsTime-courseRescueCell inhibitionRNA-seq
Tumor inhibition
CDK9Cyclin T1
[ 54]
41
15e
In vitro Concentration-dependentTime-courseCell inhibitionProteomics
–
CDK9
[ 55]
42
955
In vitro RescueProteomicsConcentration-dependentRNAseq
Tumor inhibition
CDK9CDK10And others
[ 56]
43
BSJ-4-116
In vitro Time-courseProteomicsRescue
Tumor inhibition
CDK12
[ 57]
44
PP-C8
In vitro RescueConcentration-dependentProteomicsCell inhibitionRNA-seq
Tumor inhibition
CDK12Cyclin K
[ 58]
45
7f
In vitro and in vivo Concentration-dependentProteomicsPK
Tumor inhibition
CDK12CDK13
[ 59]
46
TL12-186
In vitro Proteomics
–
Multi-target
[ 60]
47
(R)-CR8
In vitro RescueTime-courseConcentration-dependentProteomicsCrystal structureCell inhibition
–
Cyclin K
[ 61]
48
HQ461
In vitro ProteomicsTime-courseConcentration-dependentRescue
Tumor inhibition
CDK12Cyclin K
[ 62]
49
dCeMM1
In vitro ProteomicsRescueCell inhibitionTime-courseRNA-seq
–
RPM39
[ 63]
50
dCeMM2
In vitro ProteomicsTime-courseRescueCell inhibitionCell-cycleRNA-seq
–
Cyclin K
[ 63]
51
dCeMM3
In vitro ProteomicsTime-courseCell inhibitionCell-cycleRNA-seq
–
Cyclin K
[ 63]
52
dCeMM4
In vitro ProteomicsTime-courseCell inhibitionCell-cycleRNA-seq
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