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Tumor Discovery RNA-protein complexes deregulated in cancer

established and validated epigenetic drugs. Concurrently, In pancreatic cancer, the inhibitor ZW-115 targets the
small molecules targeting RNAs and their interacting stress-inducible nuclear protein 1 (NUPR1), an intrinsically
partners are being explored for applications in RNA disordered protein, triggering apoptosis in PDAC cells that
therapeutics. depend on K-RAS expression. 259,260
Drugs that inhibit enzymes involved in PTMs can The androgen receptor (AR), involved in nuclear
influence condensate behavior and modify oncogenic condensates, has transiently stable secondary structures
activities localized in these condensates. Alterations in that are targeted by small molecules. Antiandrogens and
the charges of residues within protein–protein interaction abiraterone used in androgen-deprivation therapy induce
domains can impact proteins with IDR or prion-like the expression of constitutively active AR splice variants
domains ability to form BCs and undergo LLPS. (AR-Vs), which promote resistance to radiotherapy
While chemotherapies aim to induce cancer cell death, by aiding DDR. Small molecules such as EPI-001
certain drugs (e.g., bortezomib, sorafenib, 5-fluorouracil (ralaniten) selectively bind to the transactivation domain
(5-FU), lapatinib, morusin, 5-azacytidine, 6-thioguanine, of AR, forming a binding pocket that blocks AR-DNA
cisplatin, oxaliplatin, doxorubicin, and sodium selenite) interaction. Other molecules like ETI-516 and EPI-7170
paradoxically enhance cancer cell survival by promoting (a derivative of EPI-001) also block AR transcriptional
SG formation. For instance, K-RAS-dependent tumors activity and condensate formation in prostate cancer. EPI-
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upregulate SG formation. Targeting or reducing SGs and 7170 is currently in clinical trials (NCT04421222). The
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their functions may yield therapeutic benefits. A notable ReACp53 peptide (patent WO2014182961A1) inhibits p53
PTM affecting condensate formation is myristoylation. amyloid-like aggregation, effectively targeting high-grade
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In lung cancer cells, EZH2 myristoylation induces phase- serous ovarian carcinomas (HGSOC). BAY 249716
separated liquid droplets containing EZH2, leading to stabilizes both wild-type p53 and its mutants (R175H and
compartmentalization, activation of STAT3, and enhanced Y220C), 11,268 while ADH-6 rescues mutant p53 activity.
cell proliferation. 262,263 Inhibiting myristoylation may The aminothiazole compound BAY 1892005 covalently
potentially suppress cell growth. The subsequent section binds to mutant p53 variants (e.g., R175H, R282W, and
will discuss approaches for SG inhibition and specific cases Y220C) and dissolves nuclear condensates. In addition,
of oncogenic protein chimeras impacting BCs in cancer. PRIMA-1 reactivates mutated p53, inducing apoptosis
under normoxic and hypoxic conditions, whereas nutlin-3
4.5. Targeting the interaction between intrinsically inhibits the MDM2-p53 interaction, increasing p53
disordered proteins and their partners stability and longevity.
Proteins essential for BC formation, such as G3BP1, which Small molecule ligands have been screened from
assembles SGs, are promising targets for interfering with libraries of backbone-modified compounds for their RNA-
stress responses in cancer. 168,176 Key residues like V11 binding capabilities. For example, diphenylfuran (DPF)
in G3BP are necessary for the formation of the G3BP– compounds targeting MALAT1 bind to its triple helix,
Caprin-1 complex; mutations at these sites block SG inducing RNA degradation. 269
assembly. This opens the possibility for small compounds
targeting protein interactions and specific G3BP domains Small molecules targeting RNAs are under development
to disrupt SG and BC formation or stability. 176,264 Small with promising therapeutic applications. In alignment
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molecule interactors of SG proteins have shown potential with the experimental work by Kovachka, Meyer et al.
in addressing cancer resistance to environmental described receptor tyrosine kinase inhibitors (RTKis).
stresses. 264,265 RTKis can serve as RNA binders and can be reprogrammed
and repurposed, given that they are FDA-approved drugs.
SG inhibitory peptides (SIPs), derived from Caprin1 For instance, the RTKi dovitinib inhibited the biogenesis
and USP10, have been fused with cell-penetrating peptides of oncogenic miR-21 through direct interaction, paving
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to create cancer inhibitors such as TAT-SIP-C1/2 and the way for designing small molecule RNA inhibitors to
SIP-U1-Antp. These SIPs disrupt SGs and enhance the minimize off-target effects. Recently, the FDA approved a
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sensitivity of cancer cells to sorafenib. small molecule capable of interacting with the U1 snRNP
Inhibitors based on small compounds targeting the complex of the splicing machinery. Risdiplam, tested
disordered regions of proteins have shown promise, with in clinical trials for both infantile and later-onset spinal
some progressing to clinical trials or therapeutic approval. muscular atrophy (SMA), is now an orally administered
For example, AC1Q3QWB selectively disrupts HOTAIR- drug for SMA treatment. Furthermore, small molecules
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mediated PRC2 recruitment, preventing silencing of gene targeting RNA G-quadruplexes have been explored for
promoters. 206 the downregulation of K-RAS and N-RAS mRNAs and

Volume 3 Issue 4 (2024) 19 doi: 10.36922/td.4657