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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

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Front. Med.    2023, Vol. 17 Issue (5) : 823-854    https://doi.org/10.1007/s11684-023-1027-5
REVIEW
Discovery of small molecule degraders for modulating cell cycle
Liguo Wang1, Zhouli Yang1, Guangchen Li1, Yongbo Liu1, Chao Ai2(), Yu Rao1()
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
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Abstract

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.
Keywords PROTAC      molecular glue      degrader      cell cycle      CDK      cyclin     
Corresponding Author(s): Chao Ai,Yu Rao   
Just Accepted Date: 28 September 2023   Online First Date: 07 November 2023    Issue Date: 07 December 2023
 Cite this article:   
Liguo Wang,Zhouli Yang,Guangchen Li, et al. Discovery of small molecule degraders for modulating cell cycle[J]. Front. Med., 2023, 17(5): 823-854.
 URL:  
https://academic.hep.com.cn/fmd/EN/10.1007/s11684-023-1027-5
https://academic.hep.com.cn/fmd/EN/Y2023/V17/I5/823
Fig.1  Typical functions of CDKs. CDKs involved in cell cycle and transcription.
FunctionsCDKsCyclinsMain functionsAchieved degradation
Cell cycleCDK1A1, A2, B1, B2, D1, D3, E1, F, KTrigger S–G2 and G2–M transitions and G2 progressionY
CDK2A1, A2, B1, B2, B3, D1, D2, D3, E1, E2, G1, H, J, KTrigger G1–S transition; control G1–S and G2–M transitionsY
CDK4/6A2, D1, D2, D3, E1, T1, T2Mediate the monophosphorylation of Rb in G1; promotes G1–S transitionY
TranscriptionCDK7A2, B1, B2, E1, HMediate the activation of CDK1/2/4/6/11 by catalyzing the phosphorylation of a threonine residue within the T-loop or activation segmentY
CDK8/19C, HRegulation of RNA polymerase II transcription; phosphorylation of NOTCH leads to its degradationY
CDK9H, K, T1, T2A, T2BRegulation of RNA polymerase II transcription; genome integrity maintenanceY
CDK12/13KRegulation of RNA polymerase II and transcription elongationY
Special rolesCDK3A2, C, E1, E2Function is poorly defined: may trigger reentry from G0–G1 and through phosphorylation of Rb; may trigger G1–S transitions by catalyzing the phosphorylation of E2F1/2/3N
CDK5A2, B1, D2, G1, E1, I1, I2Function is poorly defined: may produce neuronal cell cycle arrest and differentiation and participates in many aspects of neuronal functionY
CDK10L2, MTraversing start point and phosphorylation of transcription factor ETS2 leading to its degradationY
CDK11L1, L2Regulation of apoptosis cytokinesisY
CDK14D3, YRegulate cell cycle and neuronal differentiationY
CDK15YAntiapoptoticN
CDK16YRegulation of neuron differentiation and exocytosisY
CDK17/18K, YPlay a role in terminally differentiated neuronsY
CDK20HRegulation of neural developmentN
Tab.1  Typical functions and corresponding cyclins of CDKs
Fig.2  The structure of PROTACs and molecule glue. The mechanism of PROTACs (A) and molecular glue (C). (B) Chemical structures of representative E3 ligands.
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 – Cyclin K [ 63]
Tab.2  Information of representative degraders
Fig.3  Structure of CDK2 degraders.
Fig.4  Structure of CDK4/6 degraders.
Fig.5  Structure of CDK8 degraders.
Fig.6  Structure of CDK9 degraders.
Fig.7  Structure of CDK12/13 degraders.
Fig.8  Structure of special degraders.
Fig.9  Structure of cyclin K degraders.
Fig.10  Structure of DDB1-CR8-CDK12-cyclin K complex. Cyclin K (green, left), CDK12 (orange, middle) and DDB1 (red, right). PDB code: 6TD3.
Target(s)Proteomics?TypeCompound No. and references
CDK2YesPROTACs8 [34]
NoPROTACs1 [31], 9 [35]
CDK4YesPROTACs17 [37]
NoPROTACs13 [37]
CDK6YesPROTACs16 [37], 18 [38], 25 [42]
NoPROTACs14 [37], 19 [39], 30 [44]
CDK8NoPROTACs32 [46]
CDK9YesPROTACs34 [48], 35 [49], 37 [51], 39 [53], 41 [55]
NoPROTACs2 [31], 33 [47], 36 [50], 38 [52]
CDK12YesPROTACs43 [57]
Cyclin KYesMolecular glue47 [61], 50 [63], 51 [63], 52 [63]
CDK2/9NoPROTACs3 [31]
CDK2/4/5/6NoPROTACs4 [32]
CDK2/5YesPROTACs5 [32]
CDK2/4/6NoPROTACs6 [32]
CDK4/6YesPROTACs12 [37], 15 [37]
NoPROTACs10 [36], 11 [36], 20 [40], 21 [40], 22 [40], 23 [41], 24 [41], 26 [43], 27 [43], 28 [43]
CDK4/6, HeliosYesPROTACs (Helios for MGs)31 [45]
CDK6, cyclin D1YesPROTACs29 [44]
CDK9, cyclin T1YesPROTACs40 [54]
CDK12/13YesPROTACs45 [59]
CDK12, cyclin KYesPROTACs44 [58]
Molecular glue48 [62]
CDK1/7/10/11/14/15/16/17/18/19YesPROTACs46 [60]
CDK9/10YesPROTACs42 [56]
Tab.3  Features of the PROTACs or molecular glue targeting CDKs/cyclins
CharactersCDKs
Exist degraderaCDK2/4/5/6/8/9/10/12/13
Suggested to be degradablebCDK1/7/11/14/15/16/17/18/19
No dataCDK3/20
Tab.4  The development of corresponding CDK degraders
Fig.11  The workflow of the method of AI-aided molecular glue design by Kishan Gurram and colleagues.
Fig.12  The workflow of the method of AI-aided molecular glue design by Yang group.
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