TABLE 1.
List of PROTACs targeting oncogenic lipid and protein kinases
Revised in (Sun et al., 2019) and (Yu et al., 2021) and searched from Pubmed (pubmed.ncbi.nlm.nih.gov) as of December 2021.
| Target | PROTAC Name | Parental Compound | E3 Ligase | Cancer Type | Reference |
|---|---|---|---|---|---|
| ABL1 | DAS-6-2-2-6-VHL | Dasatinib | VHL (ABL1-specific degrader) | CML | (Lai et al., 2016) |
| ABL1 / BCR-ABL1 | DAS-IAP | Dasatinib | IAP | CML | (Shibata et al., 2018) |
| ABL1 / BCR-ABL1 | SNIPER(ABL)-062 | ABL001a | IAP | CML | (Shimokawa et al., 2017) |
| ABL1 / BCR-ABL1 | GMB-475 | GNF-5a | VHL | CML | (Burslem et al., 2019) |
| ABL1 / BCR-ABL1 | BOS-6-2-2-6-CRBN | Bosutinib | CRBN | CML | (Lai et al., 2016) |
| ABL1 / BCR-ABL1 | DAS-6-2-2-6-CRBN | Dasatinib | CRBN | CML | (Lai et al., 2016) |
| AKT | INY-03-041 | GDC-0068 | CRBN | Multiple malignancies | (You et al., 2020) |
| AKT | MS21 | AZD5363 | VHL | Multiple malignancies | (Xu et al., 2021) |
| ALK | MS4077 | LDK378 (Ceritinib) | CRBN | ALCL, NSCLC | (Zhang et al., 2018) |
| ALK | MS4078 | LDK378 (Ceritinib) | CRBN | ALCL, NSCLC | (Zhang et al., 2018) |
| ALK | TL-13-112 | LDK378 (Ceritinib) | CRBN | ALCL, Neuroblastoma, NSCLC | (Powell et al., 2018) |
| ALK | TD-004 | LDK378 (Ceritinib) | VHL | ALCL, NSCLC | (Kang et al., 2018) |
| ALK | TL-13-12 | TAE684 | CRBN | ALCL, Neuroblastoma, NSCLC | (Powell et al., 2018) |
| BRAF (V600E) | BRAF PROTAC P4B | BI-882370 | CRBN | Melanoma | (Posternak et al., 2020) |
| BRAF (V600E)b | SJF-0628 | Vemurafenib | VHL | Melanoma | (Alabi et al., 2021) |
| BTK | DD-04-015 | RN486 | CRBN | CLL, B-cell malignancies | (Huang et al., 2018) |
| BTK | MT-802 | Ibrutinib | CRBN | CLL, B-cell malignancies | (Buhimschi et al., 2018) |
| BTK | P13I | Ibrutinib | CRBN | NHL | (Sun et al., 2018) |
| BTK | RC-1$c | Ibrutinib | CRBN | AML | (Guo et al., 2020) |
| CDK12 | BSJ-4-116 | THZ531 | CRBN | T-ALL, | (Jiang et al., 2021) |
| CDK12 | PP-C8d | SR-4835 derivative | CRBN | TNBC | (Niu et al., 2022) |
| CDK2 | CPS2 | J2 | CRBN | AML | (Wang et al., 2021) |
| CDK2/CDK9 | “Compound F3” | FN-1501 | CRBN | Multiple malignancies | (Zhou et al., 2020) |
| CDK4 | BSJ-04–132 | Ribociclib | CRBN | Multiple malignancies | (Jiang et al., 2019) |
| CDK4/6 | BSJ-03–204 | Palbociclib | CRBN | Multiple malignancies | (Jiang et al., 2019) |
| CDK6 | “PROTAC-6” | Palbociclib | CRBN | Multiple malignancies | (Rana et al., 2019) |
| CDK6 | BSJ-03-123 | Palbociclib | CRBN | AML, multiple malignancies | (Brand et al., 2019; Jiang et al., 2019) |
| CDK6 | CP-10 | Palbociclib | CRBN | Multiple malignancies | (Su et al., 2019) |
| CDK8 | JH-XI-10-02 | JH-VIII-49 | CRBN | Multiple malignancies | (Hatcher et al., 2018) |
| CDK9 | THAL-SNS-032 | SNS-032 | CRBN | Multiple malignancies | (Olson et al., 2018) |
| CK2 | “Compound 2” | CX-4945 | CRBN | Multiple malignancies | (Chen et al., 2018) |
| EGFR (L858R and Exon 19 del) | Gefitinib-PROTAC 3 | Gefitinib | VHL | NSCLC | (Burslem et al., 2018a) |
| EGFR (T790M/L858R) | Afatinib-PROTAC 4 | Afatinib | VHL | NSCLC | (Burslem et al., 2018a) |
| EGFR (WT and Exon 20 Ins) | Lapatinib-PROTAC 5 | Lapatinib | VHL | Multiple malignancies | (Burslem et al., 2018a) |
| EGFR (WT and Exon 20 Ins) / HER-2 (ERBB2) | Lapatinib-PROTAC 1 | Lapatinib | VHL | Multiple malignancies; HER-2+-breast cancer | (Burslem et al., 2018a) |
| ERK1/2 | ERK-CLIPTAC | “Probe 1” | CRBN | Melanoma | (Lebraud et al., 2016) |
| FAK (PTK2) | BI-3663 | BI-4464 | CRBN | Multiple malignancies | (Popow et al., 2019) |
| FAK (PTK2) | FC-11 | PF562271 | CRBN | Multiple malignancies | (Gao et al., 2019) |
| FAK (PTK2) | “PROTAC-3” | Defactinib | VHL | Multiple malignancies | (Cromm et al., 2018) |
| FAK (PTK2) | BI-0319 | BI-4464 | VHL | Multiple malignancies | (Popow et al., 2019) |
| FLT3-ITD | PF-15 | “Compound 9b” | CRBN | AML | (Chen et al., 2022) |
| FLT3-ITD | TL-13-117 | Quizartinib (AC220) | CRBN | AML | (Huang et al., 2018) |
| FLT3-ITD | TL-13-149 | Quizartinib (AC220) | CRBN | AML | (Huang et al., 2018) |
| FLT3-ITD | FLT3-PROTAC | Quizartinib (AC220) | VHL | AML | (Burslem et al., 2018b) |
| JAK2 | SJ988497e | Ruxolitinib | CRBN | CRLF2-rearranged ALL | (Chang et al., 2021) |
| MEK1/2 | MS432 | Mirdametinib (PD0325901) | VHL | Colorectal cancer, melanoma | (Wei et al., 2019) |
| MEK1/2 | “Compounds 3, 4, 5” | Refametinib | VHL | Melanoma | (Vollmer et al., 2020) |
| MET | Foretinib-CRBN-PROTAC 2f | Foretinib | CRBN | Multiple malignancies | (Bondeson et al., 2018) |
| MET | Foretinib-PROTAC 7f | Foretinib | VHL | Multiple malignancies | (Bondeson et al., 2018; Burslem et al., 2018a) |
| p38 MAP kinase alpha (MAPK14) | SJFα | Foretinib | VHL | Multiple malignancies | (Smith et al., 2019) |
| p38 MAP kinase delta (MAPK13) | SJFδ | Foretinib | VHL | Multiple malignancies | (Smith et al., 2019) |
| PI3K | “Compound B, D” | ZSTK474 | CRBN | Multiple malignancies | (Li et al., 2018) |
| RIPK2 | PROTAC_RIPK2 #3 | RIPK2 ligand (Vandetanib derivative) | CRBN | Multiple malignancies | (Mares et al., 2020) |
| RIPK2 | PROTAC_RIPK2 #2 | RIPK2 ligand (Vandetanib derivative) | IAP | Multiple malignancies | (Mares et al., 2020) |
| RIPK2 | PROTAC_RIPK2 | RIPK2 ligand (Vandetanib derivative) | VHL | Multiple malignancies | (Bondeson et al., 2015; Mares et al., 2020) |
| SGK3 | SGK3-PROTAC1 (DAT8) | 308-R | VHL | Breast cancer | (Tovell et al., 2019b) |
| TBK1 | “PROTAC-3i” | TBK1-ligand 1b (MRT67307 derivative) | VHL | NSCLC | (Crew et al., 2018) |
AML, acute myeloid leukemia; CLL, chronic lymphocytic leukemia; CML, chronic myeloid leukemia; CRBN, Cereblon; IAP, inhibitor of apoptosis; LCL, anaplastic large cell lymphoma; NHL, non-Hodgkin’s lymphoma; NSCLC, nonsmall cell lung cancer; T-ALL, T-cell acute lymphoblastic leukemia; TNBC, triple-negative breast cancer; VHL, von-Hippel Lindau; WT, wild-type.
aallosteric inhibitors.
bpartially degrades wild-type BRAF in cells with amplified receptor tyrosine kinase or mutant RAS.
ccovalent reversible.
dtriggers cyclin-K degradation.
ealso degrades GSPT1.
fnonselective PROTAC.