Table 4 Summary of strategies and drugs that use phase separation to intervene in tumorigenesis and progression
Targeting strategy | Drug/molecules | Tumor types | Associated protein/condensate | Mechanism of action | References |
|---|---|---|---|---|---|
Disruptions of the BMCs’ formations | IIA4B20, IIA6B17, mycmycin-1/2 | Pan-cancer | Myc | Preventing the Myc/Max dimerization inhibit Myc-induced malignant transformation | [196] |
YK-4–279 | EWS | EWS-FLI1 fusion | Binding to the IDR of the oncogenic transcription factor EWS-FLI1 and prevents the interaction between EWS-FLI1 and RNA helicase A, thereby slowing down EWS cell growth | [197] | |
elvitegravir | Lung cancer | SRC1 | Directly binding to the highly disordered SRC1 and effectively inhibit YAP oncogene transfer by disrupting liquid–liquid separation in SRC1/YAP/TEAD condensates | [117] | |
C108 | Breast cancer | G3BP2 (SG core component) | Diminishing the role of SG core component G3BP2 in breast cancer initiation and improve the efficacy of chemotherapy drugs | [198] | |
2142–R8 peptide | Pan-cancer | KAT8–IRF1 condensates | disrupt the formation of KAT8–IRF1 condensates, subsequently suppressing PD-L1 expression and enhancing antitumor immunity in vitro and in vivo | [198] | |
BAY 249716 | Pan-cancer | p53 | Inducing condensate formation of DNA-binding defective mutants; dissolve nuclear condensates of structural mutants; covalent binders | [199] | |
BAY 1892005 | |||||
Avrainvillamide | Aml | NPM1 | Restoring nucleolar localization of cytoplasmic NPM1 mutant; covalent binder | [200] | |
SHP099 | RTK-driven human cancer | SHP2 | Stabilizing SHP2 in an auto-inhibited conformation and suppressing RAS–ERK signalling to inhibit the proliferation of receptor-tyrosine-kinase-driven human cancer cells | [201] | |
ET070 | RTK-driven human cancer | SHP2 | Inhibiting the phase separation ability of SHP2 mutants by locking SHP2 in the “off” conformation | [126] | |
JQ1 | Breast cancer and colon cancer | BET family of bromodomain proteins | Partitions into transcriptional condensates; dissolving MED1 nuclear condensates | [202] | |
EPI-001 | Prostate cancer | Androgen receptor | Dissolving androgen receptor-rich transcriptional condensates | [203] | |
Leptomycin B | Leukemia | CRM1 | Inhibiting formation of aberrant NUP98–HOXA9 transcriptional condensates | [204] | |
Ribavirin | Prostate cancer | OCT4/AR/FOXA1, OCT4/NRF1 | Inhibiting the formation of OCT4-AR axis by modulating OCT4 condensates in the nucleus | [205] | |
Tin (IV) oxochloride-derived cluster | Pan-cancer | IDR of TAF2 in TFIID | Disrupting transcription initiation by selectively impairing the function of TFIID | [206] | |
PRIMA-1; ReACp53 | Ovarian carcinoma | p53 mutants | Induction of cell cycle arrest in cancer cells with mutant p53 by restoring the native conformation of aggregated mutant p53 proteins | [207] | |
PCG | Breast cancer | IDR of BRD4 | Suppression of BRD4-dependent gene transcription | [208] | |
bis-ANS | Colon cancer | LCD of TDP-43 | high concentrations of bis-ANS inhibit TDP-43 condensate assembly, whereas low concentrations facilitate the formation of liquid droplets | [209] | |
Modifications of PTMs and physicochemical conditions | SI-2 | Multiple myeloma | SRC3/NSD2 condensate | Phase separation of SRC3 mediated by histone methyltransferase NSD2 leads to resistance to bleitinib in multiple myeloma, whereas the inhibitor SI-2 Inhibits formation of drug-resistant SRC3/NSD2 condensates and improves the therapeutic efficacy of bleitinib | [210] |
Olaparib | Pan-cancer | PARP1/2 DNA repair condensate | Inhibiting PARP1/2 and thus interferes with the formation of PARylation related DNA repair condensates | [211] | |
GSK-J4 | Osteosarcoma | HOXB8/FOSL1 CRC | The H3K27 demethylase inhibitor GSK-J4, inhibits the CRC phase separation and results in metastasis suppression and re-sensitivity to chemotherapy drugs | [212] | |
icFSP1 | Melanoma and lung cancer | hFSP1 | Inducing phase separation of myristoylated hFSP1, thus promoting ferroptosis and inhibit tumor proliferations | [195] | |
GSK-626616 | Pan-cancer | DYRK3 | Inhibit PRAS40 phosphorylation and restrain mTORC1 signaling in SGs | [213] | |
JQ1 | AML | BRD4 | Release the Mediator complex from SEs | [214] | |
SGC0946 | MLL leukemia | DOT1L | Inhibit histone H3K79 methylation and histone H4 acetylation | [215] | |
THZ1 | Pan-cancer | CDK7 | Inhibit RNAPII phosphorylation | [216] | |
THZ531 | Pan-cancer | CDK12 and CDK13 | Inhibit RNAPII phosphorylation | [217] | |
Drug interventions and distributions of the dynamics of condensates | Cisplatin | Breast cancer and colon cancer | MED1 transcriptional condensates | Partitions into transcriptional condensates; dissolves MED1 and BRD4 nuclear condensates | [202] |
Tamoxifen | breast cancer and colon cancer | Estrogen receptor | Seletively partitions into transcriptional condensates | [202] | |
mitoxantrone | breast cancer and colon cancer | Estrogen receptor | Seletively partitions into transcriptional condensates | [202] | |
PML-retinoic acid receptor α | APL | PML bodies | Hindering the assembly of PML bodies and result in the suppression of differentiation genes. Successful APL treatment involves the restoration of PML nuclear bodies using empirically discovered drugs | [109] |