Table 1

Molecules that target disease-related proteins for proteasomal degradation

Target	Target classification	Target ligand	Linker	Disease	Molecule/drug name	E3 ligase	Sorting signal	Evidence	References
RIPK2	Kinase	Vandetanib	12 atoms	Multiple cancers	PROTAC_RIPK2	VHL	Small molecule	Preclinical/xenograft	⁵³
BCR-ABL	Kinase	Dasatinib	5–10 carbon atoms	Chronic myeloid leukemia	SIAIS178	VHL	Small molecule	Preclinical/xenograft	⁷³
		Imatinib, bosutinib, dasatinib	4 different linkers		GMB-101/180/475/651	CRBN, VHL		Cultured cancer cells	^72,74
EGFR	Kinase	TKIs	Various linkers	Multiple cancers	EGFR-PROTACs	CRBN, VHL	Small molecule	Cultured cancer cells	^75,76
HER2	Kinase	Lapatinib	Diethylene glycol	Multiple cancers	HER2-PROTAC	VHL	Small molecule	Cultured cancer cells	⁷¹
c-Met	Kinase	Foretinib	Optimized linker	Multiple cancers	c-Met-PROTAC	VHL	Small molecule	Cultured cancer cells	⁷¹
TBK1	Kinase	TBK1 ligands	Alkyl ether	Multiple cancers	TBK1-PROTAC	VHL	Small molecule	Cultured cancer cells	⁷⁷
CDK6	Kinase	Palbociclib	Optimized linker	Multiple cancers	Palbociclib-based CDK6 PROTAC	CRBN	Small molecule	Cultured cancer cells	⁷⁸
CDK9	Kinase	Aminopyrazole analogs	Optimized linker	Multiple cancers	CDK9-PROTAC	CRBN	Small molecule	Cultured cancer cells	^79,80
ALK	Kinase	Ceritinib	Long PEG linker/short carbon linker	NSCLC, DLBCL, ALCL	MS4077/4078	CRBN	Small molecule	Cultured cancer cells	⁸¹
			Amide linkage		TD-004	VHL		Preclinical/xenograft	⁸²
SGK3	Kinase	308-R SGK inhibitor	3 PEG units medium length-ligand	Breast cancer	SGK3-PROTAC1	VHL	Small molecule	Cultured cancer cells	⁸³
CK2	Kinase	CX-4945	Alkyl linkers	Multiple cancers	CK2-PROTAC	CRBN	Small molecule	Cultured cancer cells	⁸⁴
ERK1/2	Kinase	Refametinib analogs	Various linkers (optimal 3 atoms)	Multiple cancers	MEK-PROTACs	CRBN, VHL	Small molecule	Cultured cancer cells	⁸⁵
		TCO-tagged inhibitor of ERK1/2 kinases	Optimized linker		ERK-CLIPTAC	CRBN			⁸⁶
FLT3	Kinase	Quizartinib	Optimized linker	Acute myeloid leukemia	FLT3-PROTAC	VHL	Small molecule	Preclinical/xenograft	⁸⁷
PI3K	Kinase	ZSTK474	Linkers longer than hexanamide	Multiple cancers	PI3K-PROTACs	CRBN	Small molecule	Cultured cancer cells	⁸⁸
Akt	Kinase	GDC-0068	10 hydrocarbon	Multiple cancers	INY-03-041	CRBN	Small molecule	Cultured cancer cells	⁸⁹
BTK	Kinase	Ibrutinib	8 atoms	Chronic lymphocytic leukemia	MT-802	CRBN	Small molecule	Cultured cancer cells	⁹⁰
			Optimized linker	Non-Hodgkin lymphomas	L18I	CRBN	Small molecule	Cultured cancer cells	⁹¹
			Optimized linker	B-cell malignancies	P13I	CRBN	Small molecule	Cultured cancer cells	⁹²
Fak	Kinase	Defactinib	Various linkers	Multiple cancers	Fak-PROTACs	CRBN, VHL	Small molecule	Cultured cancer cells	⁹³
IRAK4	Kinase	PF-06650833	Two flexible 12 atom linkers	Autoimmune disorders	IRAK4-PROTACs	CRBN, VHL, IAP	Small molecule	Cultured PBMCs	⁹⁴
BRD2/3/4	BET protein	1,4-oxazepines	Linker with an ethynyl group	Multiple cancers	QCA570	CRBN	small molecule	Preclinical/xenograft	⁹⁵
BRD4	BET protein	JQ1	Two ends: a carboxylic acid and an azide group	Multiple cancers	MZ1	VHL	small molecule	Cultured cancer cells	⁹⁶
		OTX015	Flexible polyethylene glycol linker	Burkitt lymphoma	ARV-825	CRBN			⁹⁷
		JQ1	13-atom long PEG-based linker	Multiple cancers	A1874	MDM2			⁹⁸
BRD7/9	BET protein	BrdL1	5 atoms	Multiple cancers	VZ185	VHL	small molecule	Cultured cancer cells	⁹⁹
AR	Nuclear receptor	Aryloxy tetramethylcyclobutanes	Optimized linker	Prostate cancer	ARD69	VHL	Small molecule	Cultured cancer cells	¹⁰⁰
		Undisclosed	Undisclosed		ARV-110	Undisclosed		Clinical stage I	¹⁰¹
		Enzalutamide	Optimized linker		ARCC4	VHL		Cultured cancer cells	¹⁰²
ER	Nuclear receptor	Raloxifene	Linker with a PEG	Breast cancer	ERD-308	VHL	Small molecule	Cultured cancer cells	¹⁰³
		Undisclosed	Undisclosed		ARV-471	Undisclosed		Clinical stage I	¹⁰¹
		Bisphenolic-adamantyl system	Alkyl linker		Novel SERDs	Unrestricted	Adamantyl motif	Cultured cancer cells	¹⁰⁴
TRIM24	Transcription coactivator	IACS-7e	Optimized linker	Acute leukemia	dTRIM24	VHL	Small molecule	Cultured cancer cells	¹⁰⁵
MetAp-2	Enzyme	Ovalicin	NA	Multiple cancers	MetAP-2-PROTAC-1	SCF(βTRCP)	Polypeptide	Lab research	¹⁰⁶
Bcl-xL	Transcription factor	A-1155463	Optimized linker	Acute lymphoblastic leukemia	XZ424	CRBN	Small molecule	Cultured cancer cells	¹⁰⁷
Sirt2	Sirtuin	Triazole-based SirReals	N-butyl-2-oxyacetamide linker	Multiple disorders	SirReal-based PROTAC	CRBN	Small molecule	Cultured cancer cells	¹⁰⁸
HDAC6	Histone deacetylase	Nexturastat A	Optimized linker	Multiple cancers	NP8	CRBN	Small molecule	Cultured cancer cells	¹⁰⁹
SMAD3	Transcription factor	SMC showing the best binding	Optimized linker	Renal fibrosis	EN300-72284	VHL	Small molecule	Cell models	¹⁰⁹
PCAF/GCN5	Acetyltransferase	GSK4027	Optimized linker	Multiple inflammatory diseases	GSK983	CRBN	Small molecule	Cultured immune cells	⁶⁴
EED, EZH2, and SUZ12	Polycomb-group proteins	Capped EED ligands	Various linkers	Multiple cancers	EED-targeted PROTACs	VHL	Small molecule	Cultured cancer cells	¹¹⁰
Tau	Pathologic protein	YQQYQDATADEQG	GSGS	Alzheimer disease	Keap1-dependent PROTAC	Keap1-Cul3	Polypeptide	Cultured Tau over-expressed cells	¹¹¹
SMARCA2/4	Catalytic subunit	2-(6-aminopyridazin-3-yl)phenols	Polyethylene glycol-based linkers	Multiple cancers	SMARCA2/4-degrading PROTACs	VHL	Small molecule	Cultured cancer cells	¹¹²
PARP1	Enzyme	Niraparib	Flexible linkers	BRCA1/2 mutant cancers	PARP1-PROTACs	CRBN, VHL, MDM2	Small molecule	Cultured cancer cells	¹¹³
STAT3	Transcription factor	SI-109	Optimized linker	Multiple cancers	SD-36	CRBN	Small molecule	Cultured cancer cells	¹¹⁴
MCL1	Bcl-2 protein	A-1210477	Various linkers	Multiple cancers	MCL1-PROTACs	CRBN	Small molecule	Cultured cancer cells	¹¹⁵
Murine double minute 2 protein	Oncoprotein	MI-1061	Optimized linker	Multiple cancers	MD-224	CRBN	Small molecule	Preclinical/xenograft	¹¹⁶