Proteolysis-targeting chimaeras (PROTACs) as pharmacological tools and therapeutic agents: advances and future challenges

Figures & data

Figure 1. The number of publications on PROTACs in PubMed (accessed on 21 February 2022).

Figure 2. The schematic diagram of PROTACs.

Figure 3. The limitations of small-molecule inhibitors.

Table 1. Selected PROTACs in and approaching the clinic.^34,35

Agent	Company	Target	Indication	Stage
ARV-110	Arvinas	AR	Prostate cancer	Phase II
ARV-766	Arvinas	AR	Prostate cancer	Phase I
CC-94676	Bristol Myers Squibb	AR	Prostate cancer	Phase I
ARV-471	Arvinas	ER	Breast cancer	Phase II
DT2216	Dialectic	BCL-XL	Liquid and solid tumours	Phase I
FHD-609	Foghorn	BRD9	Synovial sarcoma	Phase I
CFT8364	C4 Therapeutics	BRD9	Synovial sarcoma, SMARCB1^- tumours	IND 2H2021
NX-2127	Nurix	BTK, Ikaros, Aiolos	B-cell malignancies	Phase I
NX-5948	Nurix	BTK	B-cell malignancies	IND 2H2021
KT-474	Kymera	IRAK4	Atopic dermatitis, HS	Phase I
KT-413	Kymera	IRAK4, Ikaros, Aiolos	MYD88-mutant DLBCL	IND 2H2021
CFT8919	C4 Therapeutics	EGFR^L858R	NSCLC	IND mid-2022
KT-333	Kymera	STAT3	Liquid and solid tumours	IND 4Q2021
CG001419	Cullgen	TRK	Cancer and other diseases	IND pending

Table 2. Representative CRBN-based PROTACs targeting AR.

Compounds	Target protein	Structure	Ref.
PROTAC 1	AR		^40
PROTAC 2	AR		^41
PROTAC 3	AR		^42
PROTAC 4	AR		^43
PROTAC 5	AR		^44
PROTAC 6	AR		^45
PROTAC 7	AR		^46

Table 3. Representative VHL-based PROTACs targeting AR.

Compounds	Target protein	Structure	Ref.
PROTAC 8	AR		^47
PROTAC 9	AR		^38
PROTAC 10	AR		^48
PROTAC 11	AR		^49
PROTAC 12	AR		^50
PROTAC 13	AR		^51
PROTAC 14	AR		^42
PROTAC 15	AR		^52

Table 4. Representative IAP-based PROTAC targeting AR.

Compound	Target protein	Structure	Ref.
PROTAC 16	AR		^53

Table 5. Representative CRBN-based PROTACs targeting BCL-X_L.

Compounds	Target protein	Structure	Ref.
PROTAC 17	BCL-XL		^56
PROTAC 18	BCL-XL		^57

Table 6. Representative VHL-based PROTACs targeting BCL-X_L.

Compounds	Target protein	Structure	Ref.
PROTAC 19	BCL-XL		^58
PROTAC 20	BCL-XL		^59
PROTAC 21	BCL-XL		^60

Table 7. Representative IAP-based PROTAC targeting BCL-X_L.

Compound	Target protein	Structure	Ref.
PROTAC 22	BCL-XL		^61

Table 8. Representative CRBN-based PROTACs targeting BRD9.

Compounds	Target protein	Structure	Ref.
PROTAC 23	BRD9		^63
PROTAC 24	BRD9		^64

Table 9. Representative CRBN-based PROTAC targeting BRD7/9.

Compound	Target protein	Structure	Ref.
PROTAC 25	BRD7/9		^65

Table 10. Representative CRBN-based PROTACs targeting BTK.

Compounds	Target protein	Structure	Ref.
PROTAC 26	BTK		^25^,^71
PROTAC 27	BTK		^72
PROTAC 28	BTK		^73
PROTAC 29	BTK		^74
PROTAC 30	BTK		^75
PROTAC 31	BTK		^75
PROTAC 32	BTK		^76
PROTAC 33	BTK		^77
PROTAC 34	BTK		^78

Table 11. Representative CRBN-based PROTACs targeting BTK.

Compounds	Target protein	Structure	Ref.
PROTAC 35	BTK		^74
PROTAC 36	BTK		^79
PROTAC 37	BTK		^79

Table 12. Representative CRBN-based PROTACs targeting EGFR.

Compounds	Target protein	Structure	Ref.
PROTAC 38	EGFR		^87
PROTAC 39	EGFR		^88
PROTAC 40	EGFR		^89
PROTAC 41	EGFR		^90
PROTAC 42	EGFR		^91
PROTAC 43	EGFR		^91
PROTAC 44	EGFR		^92
PROTAC 45	EGFR		^93

Table 13. Representative VHL-based PROTACs targeting EGFR.

Compounds	Target protein	Structure	Ref.
PROTAC 46	EGFR		^22
PROTAC 47	EGFR		^22
PROTAC 48	EGFR		^22
PROTAC 49	EGFR		^87
PROTAC 50	EGFR		^88
PROTAC 51	EGFR		^94
PROTAC 52	EGFR		^95
PROTAC 53	EGFR		^90
PROTAC 54	EGFR		^96

Table 14. Representative PROTAC targeting EGFR.

Compound	Target protein	Structure	Ref.
PROTAC 55	EGFR		^95

Table 15. Representative VHL-based PROTAC targeting EGFR/PARP.

Compound	Target protein	Structure	Ref.
PROTAC 56	EGFR/ PARP		^98

Table 16. Representative VHL-based PROTACs targeting ER.

Compounds	Target protein	Structure	Ref.
PROTAC 57	ER		^102
PROTAC 58	ER		^103
PROTAC 59	ER		^104
PROTAC 60	ER		^104
PROTAC 61	ER		^105
PROTAC 62	ER		^105

Table 17. Representative IAP-based PROTACs targeting ER.

Compounds	Target protein	Structure	Ref.
PROTAC 63	ER		^106
PROTAC 64	ER		^107
PROTAC 65	ER		^108
PROTAC 66	ER		^108
PROTAC 67	ER		^109
PROTAC 68	ER		^110
PROTAC 69	ER		^105
PROTAC 70	ER		^111
PROTAC 71	ER		^111

Table 18. Representative VHL-based PROTACs targeting ER/GPER.

Compounds	Target protein	Structure	Ref.
PROTAC 72	ER/ GPER		^114
PROTAC 73	ER/ GPER		^114

Table 19. Representative CRBN-based PROTAC targeting STAT3.

Compound	Target protein	Structure	Ref.
PROTAC 74	STAT3		^20

Table 20. Representative CRBN-based PROTACs targeting TRK.

Compounds	Target protein	Structure	Ref.
PROTAC 75	TRK		^118
PROTAC 76	TRK		^118

Table 21. Representative CRBN-based PROTACs targeting IRAK4.

Compounds	Target protein	Structure	Ref.
PROTAC 77	IRAK4		^121
PROTAC 78	IRAK4		^122

Table 22. Representative VHL-based PROTAC targeting IRAK4.

Compound	Target protein	Structure	Ref.
PROTAC 79	IRAK4		^123

Table 23. Representative IAP-based PROTACs targeting IRAK4.

Compounds	Target protein	Structure	Ref.
PROTAC 80	IRAK4		^123
PROTAC 81	IRAK4		^123

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