Recent progress in the development of hypoxia-inducible factor 2α (HIF-2α) modulators: Inhibitors, agonists, and degraders (2009-2024).

Hypoxia-inducible factor 2α (HIF-2α) is a critical transcription factor that regulates cellular responses under hypoxic conditions. In situations of insufficient oxygen supply or patients with Von Hippel-Lindau (VHL) mutations, HIF-2α accumulates and forms a heterodimeric complex with aryl hydrocarbon receptor nuclear translocator (ARNT, or HIF-ß). This complex further binds to coactivator p300 and interacts with hypoxia response elements (HREs) on the DNA of downstream target genes, regulating the transcription of a variety of genes (e.g. VEGFA, CCND1, CXCR4, SLC2A1, etc) involved in various processes like angiogenesis, mitochondrial metabolism, cell proliferation, and metastasis. Targeting HIF-2α holds great promise for effectively addressing solid tumors associated with aberrant oxygen-sensing pathways and hypoxia mechanisms, offering broad application prospects. In this review, we provide an overview of recent advancements (2009-2024) in HIF-2α modulators such as inhibitors, agonists, and degraders for cancer therapy. Additionally, we discuss in detail the challenges and future directions regarding HIF-2α modulators.

Recent Progress in DNA Damage Response-Targeting PROTAC Degraders.

DNA damage response (DDR) defects in cells play a crucial role in tumor development by promoting DNA mutations. These mutations create vulnerabilities specific to cancer cells, which can be effectively targeted through synthetic lethality-based therapies. To date, numerous small molecule DDR inhibitors have been identified, and some of them have already been approved for clinical use. However, due to the complexity of the tumor microenvironment, mutations may occur in the amino acid residues of DDR targets. These mutations can affect the efficacy of small molecule inhibitors targeting DDR pathways. Therefore, researchers have turned their attention to next-generation DNA damage repair modulators, particularly those based on PROTAC technology. From this perspective, we overviewed the recent progress on DDR-targeting PROTAC degraders for cancer therapy. In addition, we also summarized the biological functions of different DDR targets. Finally, the challenges and future directions for DDR-target PROTAC degraders are also discussed in detail.

Discovery of Novel Potent and Fast BTK PROTACs for the Treatment of Osteoclasts-Related Inflammatory Diseases.

Bruton's tyrosine kinase (BTK) is an attractive target in inflammatory and autoimmune diseases. However, the effectiveness of BTK inhibitors is limited by side effects and drug resistance. In this study, we report the development of novel BTK proteolysis targeting chimeras (PROTACs) with different classes of BTK-targeting ligands (e.g., spebrutinib) other than ibrutinib. Compound 23 was identified as a potent and fast BTK PROTAC degrader, exhibiting outstanding degradation potency and efficiency in Mino cells (DC50, 4 h = 1.29 ± 0.3 nM, t1/2, 20 nM = 0.59 ± 0.20 h). Furthermore, compound 23 forms a stable ternary complex, as confirmed by the HTRF assay. Notably, 23 down-regulated the BTK-PLCγ2-Ca2+-NFATc1 signaling pathway activated by RANKL, thus inhibiting osteoclastogenesis and attenuating alveolar bone resorption in a mouse periodontitis model. These findings suggest that compound 23 is a potent and promising candidate for osteoclast-related inflammatory diseases, expanding the potential of BTK PROTACs.

Overview of epigenetic degraders based on PROTAC, molecular glue, and hydrophobic tagging technologies.

Epigenetic pathways play a critical role in the initiation, progression, and metastasis of cancer. Over the past few decades, significant progress has been made in the development of targeted epigenetic modulators (e.g., inhibitors). However, epigenetic inhibitors have faced multiple challenges, including limited clinical efficacy, toxicities, lack of subtype selectivity, and drug resistance. As a result, the design of new epigenetic modulators (e.g., degraders) such as PROTACs, molecular glue, and hydrophobic tagging (HyT) degraders has garnered significant attention from both academia and pharmaceutical industry, and numerous epigenetic degraders have been discovered in the past decade. In this review, we aim to provide an in-depth illustration of new degrading strategies (2017-2023) targeting epigenetic proteins for cancer therapy, focusing on the rational design, pharmacodynamics, pharmacokinetics, clinical status, and crystal structure information of these degraders. Importantly, we also provide deep insights into the potential challenges and corresponding remedies of this approach to drug design and development. Overall, we hope this review will offer a better mechanistic understanding and serve as a useful guide for the development of emerging epigenetic-targeting degraders.

HDAC-targeting epigenetic modulators for cancer immunotherapy.

HDAC inhibitors, which can inhibit the activity of HDAC enzymes, have been extensively studied in tumor immunotherapy and have shown potential therapeutic effects in cancer immunotherapy. To date, numerous small molecule HDAC inhibitors have been identified, but many of them suffer from limited clinical efficacy and serious toxicity. Hence, HDAC inhibitor-based combination therapies, and other HDAC modulators (e.g. PROTAC degraders, dual-acting agents) have attracted great attention with significant advancements achieved in the past few years due to their superior efficacy compared to single-target HDAC inhibitors. In this review, we overviewed the recent progress on HDAC-based drug discovery with a focus on HDAC inhibitor-based drug combination therapy and other HDAC-targeting strategies (e.g. selective HDAC inhibitors, HDAC-based dual-target inhibitors, and PROTAC HDAC degraders) for cancer immunotherapy. In addition, we also summarized the reported co-crystal structures of HDAC inhibitors in complex with their target proteins and the binding interactions. Finally, the challenges and future directions for HDAC-based drug discovery in cancer immunotherapy are also discussed in detail.

Recent advancements in the discovery of small-molecule non-nucleoside inhibitors targeting SARS-CoV-2 RdRp.

The RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 plays a pivotal role in the life cycle of the novel coronavirus and stands as a significant and promising target for anti-SARS-CoV-2 drugs. Non-nucleoside inhibitors (NNIs), as a category of compounds directed against SARS-CoV-2 RdRp, exhibit a unique and highly effective mechanism, effectively overcoming various factors contributing to drug resistance against nucleoside inhibitors (NIs). This review investigates various NNIs, including both natural and synthetic inhibitors, that closely interacting with the SARS-CoV-2 RdRp with valid evidences from in vitro and in silico studies.

Exploring the potential of histone demethylase inhibition in multi-therapeutic approaches for cancer treatment.

Histone demethylases play a critical role in gene transcription regulation and have been implicated in cancer. Numerous reports have highlighted the overexpression of histone demethylases, such as LSD1 and JmjC, in various malignant tumor tissues, identifying them as effective therapeutic targets for cancer treatment. Despite many histone demethylase inhibitors entering clinical trials, their clinical efficacy has been limited. Therefore, combination therapies based on histone demethylase inhibitors, along with other modulators like dual-acting inhibitors, have gained significant attention and made notable progress in recent years. In this review, we provide an overview of recent advances in drug discovery targeting histone demethylases, focusing specifically on drug combination therapy and histone demethylases-targeting dual inhibitors. We discuss the rational design, pharmacodynamics, pharmacokinetics, and clinical status of these approaches. Additionally, we summarize the co-crystal structures of LSD1 inhibitors and their target proteins as well as describe the corresponding binding interactions. Finally, we also provided the challenges and future directions for utilizing histone demethylases in cancer therapy, such as PROTACs and molecular glue etc.

Small molecules targeting selected histone methyltransferases (HMTs) for cancer treatment: Current progress and novel strategies.

Histone methyltransferases (HMTs) play a critical role in gene post-translational regulation and diverse physiological processes, and are implicated in a plethora of human diseases, especially cancer. Increasing evidences demonstrate that HMTs may serve as a potential therapeutic target for cancer treatment. Thus, the development of HMTs inhibitor have been pursued with steadily increasing interest over the past decade. However, the disadvantages such as insufficient clinical efficacy, moderate selectivity, and propensity for acquired resistance have hindered the development of conventional HMT inhibitors. New technologies and methods are imperative to enhance the anticancer activity of HMT inhibitors. In this review, we first review the structure and biological functions of the several essential HMTs, such as EZH2, G9a, PRMT5, and DOT1L. The internal relationship between these HMTs and cancer is also expounded. Next, we mainly focus on the latest progress in the development of HMT modulators encompassing dual-target inhibitors, targeted protein degraders and covalent inhibitors from perspectives such as rational design, pharmacodynamics, pharmacokinetics, and clinical status. Lastly, we also discuss the challenges and future directions for HMT-based drug discovery for cancer therapy.

Investigation on the effect of ulinastatin on the apoptosis of vascular smooth muscle cells in rats with aortic dissection based on the Sirt1/FoxO3a pathway.

This study aimed to investigate the effects of ulinastatin on the apoptosis and (Sirt1/FoxO3a) pathway of vascular smooth muscle cells (VSMC) in aortic dissection (AD) rats. For this purpose a rat model of aortic dissection (AD) was constructed by giving drinking water containing 0.08% ß-aminopropionitrile (BAPN) to rats, HE staining was used to observe the pathological changes of the aorta in AD rats; the diseased blood vessels of AD rats were taken for primary culture and passage of VSMCs, the morphology of VSMCs was observed, and VSMCs were identify with immunofluorescence staining; VSMCs were treated with culture media containing 0, 1000, 2000, 3000, 4000, 5000, 6000, 7000 U/mL ulinastatin, and MTT kit was used to determine the effect of ulinastatin on VSMC proliferation in AD rats; the VSMC of AD rats were divided into blank group (normal culture), ulinastatin group (medium containing 5000 U/mL ulinastatin), Sirt1 inhibitor group (medium containing 1 µmol/L EX527), ulinastatin + Sirt1 inhibitor group (medium containing 5000 U/mL ulinastatin, 1 µmol/L EX527), flow cytometry was used to detect the VSMC apoptosis in each group, WB was used to detect the expression of VSMC apoptosis-related proteins and Sirt1/FoxO3a pathway-related proteins in each group. Findings suggested that the aortic wall of AD rats was thickened, and the dissection false cavity appeared; VSMC mostly presented different shapes such as triangles and stars, the immunofluorescence staining results showed that α-SMA was arranged in the cytoplasm in the form of myofilaments, showing green fluorescence, and the nucleus showed blue fluorescence, and the rate of positive cells was more than 95%; various doses of ulinastatin had a certain inhibitory effect on the proliferation of VSMC, and 5000 U/mL ulinastatin had a higher proliferation inhibition rate; compared with the blank group, the VSMC apoptosis rate, Caspase-3, Bax protein, Sirt1/FoxO3a pathway related protein expression in the ulinastatin group were significantly increased, and the Bcl-2 protein expression was significantly decreased (P<0.05), the VSMC apoptosis rate, Caspase-3, Bax protein, Sirt1/FoxO3a pathway related protein expression in the Sirt1 inhibitor group were significantly decreased, and the Bcl-2 protein expression was significantly increased (P<0.05); compared with the ulinastatin group, the VSMC apoptosis rate, Caspase-3, Bax protein, Sirt1/FoxO3a pathway related protein expression in the ulinastatin + Sirt1 inhibitor group were significantly decreased, and the Bcl-2 protein expression was significantly increased (P<0.05). It was concluded that ulinastatin can inhibit the proliferation of VSMCs in AD rats and promote their apoptosis, which may be achieved by activating the Sirt1/FoxO3a pathway.

Mn(OAc)2-promoted [3+2] cyclization of enaminone with isocyanoacetate: Rapid access to pyrrole-2-carboxylic ester derivatives with potent anticancer activity.

The practical and facile Mn(OAc)2-promoted [3+2] cycloaddition reaction of enaminones with isocyanoacetate was developed, that delivered a diversity of 3-aroyl pyrrole-2-carboxylic esters with broad substrates scope. The most of the newly synthesized compounds exhibit moderate antiproliferative activity against four cancer cells. Notably, compound 2n demonstrate the most potent activity with average IC50 values of 5.61 µM against four distinct cancer cell lines. Moreover, 2n exhibit favorable anti-migration activity and drug-like properties. The further investigation suggests that compound 2n possesses the ability to inhibit ERK5 activity and exhibits effective binding with the ERK5 protein, making it a promising candidate as a lead compound for a new class of ERK5 inhibitors discovery.

Discovery of Ibrutinib-based BTK PROTACs with in vivo anti-inflammatory efficacy by inhibiting NF-κB activation.

As a critical upstream regulator of nuclear factor-κB (NF-κB) activation, Bruton's tyrosine kinase (BTK) has been identified to be an effective therapeutic target for the treatment of acute or chronic inflammatory diseases. Herein, we describe the design, synthesis and structure-activity-relationship analysis of a novel series of Ibrutinib-based BTK PROTACs by recruiting Cereblon (CRBN) ligase. Among them, compound 15 was identified as the most potent degrader with a DC50 of 3.18 nM, significantly better than the positive control MT802 (DC50 of 63.31 nM). Compound 15 could also degrade BTK protein in Lipopolysaccharide (LPS)-stimulated RAW264.7 cells, and suppress the mRNA expression and secretion of proinflammatory cytokines such as IL-1ß and IL-6 by inhibiting NF-κB activation. Furthermore, compound 15 reduced inflammatory responses in a mouse zymosan-induced peritonitis (ZIP) model. Our findings demonstrated for the first time that targeting BTK degradation by PROTACs might be an alternative option for the treatment of inflammatory disorders, and compound 15 represents one of the most efficient BTK PROTACs (DC50 = 3.18 nM; Dmax = 99.90%; near 100% degradation at 8 h) reported so far and could serve as a lead compound for further investigation as an anti-inflammatory agent.

Overexpression of a gibberellin 20-oxidase gene in poplar xylem led to an increase in the size of nanocellulose fibrils and improved paper properties.

Cellulose, the major component of secondary cell walls, is the most abundant renewable long-chain polymer on earth. Nanocellulose has become a prominent nano-reinforcement agent for polymer matrices in various industries. We report the generation of transgenic hybrid poplar overexpressing the Arabidopsis gibberellin 20-oxidase1 gene driven by a xylem-specific promoter to increase gibberellin (GA) biosynthesis in wood. X-ray diffraction (XRD) and sum frequency generation spectroscopic (SFG) analyses showed that cellulose in transgenic trees was less crystalline, but the crystal size was larger. The nanocellulose fibrils prepared from transgenic wood had an increased size compared to those from wild type. When such fibrils were used as a reinforcing agent in sheet paper preparation, the mechanical strength of the paper was significantly enhanced. Engineering the GA pathway can therefore affect nanocellulose properties, providing a new strategy for expanding nanocellulose applications.

Discovery of novel benzohydroxamate-based histone deacetylase 6 (HDAC6) inhibitors with the ability to potentiate anti-PD-L1 immunotherapy in melanoma.

In this study, a novel series of histone deacetylases 6 (HDAC6) inhibitors containing polycyclic aromatic rings were discovered and evaluated for their pharmacological activities. The most potent compound 10c exhibited high HDAC6 inhibitory activity (IC50 = 261 nM) and excellent HDAC6 selectivity (SI = 109 for HDAC6 over HDAC3). 10c also showed decent antiproliferative activity in vitro with IC50 of 7.37-21.84 µM against four cancer cell lines, comparable to that of tubastatin A (average IC50 = 6.10 µM). Further mechanism studies revealed that 10c efficiently induced apoptosis and S-phase arrest in B16-F10 cells. In addition, 10c markedly increased the expression of acetylated-α-tubulin both in vitro and in vivo, without affecting the levels of acetylated-H3 (marker of HDAC1 inhibition). Furthermore, 10c (80 mg/kg) exhibited moderate antitumor efficacy in a melanoma tumour model with a tumour growth inhibition (TGI) of 32.9%, comparable to that (TGI = 31.3%) of tubastatin A. Importantly, the combination of 10c with NP19 (a small molecule PD-L1 inhibitor discovered by us before) decreased tumour burden substantially (TGI% = 60.1%) as compared to monotherapy groups. Moreover, the combination of 10c with NP19 enhanced the anti-tumour immune response, mediated by a decrease of PD-L1 expression levels and increased infiltration of anti-tumour CD8+ T cells in tumour tissues. Collectively, 10c represents a novel HDAC6 inhibitor deserving further investigation as a potential anti-cancer agent.

Synthesis, biological activity and mechanism of action of novel allosecurinine derivatives as potential antitumor agents.

Cancer with low survival rates is the second main cause of death among all diseases in the world and consequently, effective antineoplastic agents are urgently needed. Allosecurinine is a plant-derived indolicidine securinega alkaloid shown bioactivity. The object of this study is to investigate synthetic allosecurinine derivatives with considerable anticancer capacity against nine human cancer cell lines as well as mechanism of action. We synthesized twenty-three novel allosecurinine derivatives and evaluated their antitumor activity against nine cancer cell lines for 72 h by MTT and CCK8 assays. FCM was applied to analyze the apoptosis, mitochondrial membrane potential, DNA content, ROS production, CD11b expression. Western blot was selected to analyze the protein expression. Structure-activity relationships were established and potential anticancer lead BA-3 which induced differentiation of leukemia cells towards granulocytosis at low concentration and apoptosis at high concentration was identified. Mechanism studies showed that mitochondrial pathway mediated apoptosis within cancer cells with cell cycle blocking was induced by BA-3. In addition, western blot assays revealed that BA-3 induced expression of the proapoptotic factor Bax, p21 and reduced the levels of antiapoptotic protein such as Bcl-2, XIAP, YAP1, PARP, STAT3, p-STAT3, and c-Myc. Collectively, BA-3 was a lead compound for oncotherapy at least in part, through the STAT3 pathway. These results were an important step in further studies on allosecurinine-based antitumor agent development.

Bamboo Nanocellulose/Montmorillonite Nanosheets/Polyethyleneimine Gel Adsorbent for Methylene Blue and Cu(II) Removal from Aqueous Solutions.

In recent years, the scarcity of pure water resources has received a lot of attention from society because of the increasing amount of pollution from industrial waste. It is very important to use low-cost adsorbents with high-adsorption performance to reduce water pollution. In this work, a gel adsorbent with a high-adsorption performance on methylene blue (MB) and Cu(II) was prepared from bamboo nanocellulose (BCNF) (derived from waste bamboo paper) and montmorillonite nanosheet (MMTNS) cross-linked by polyethyleneimine (PEI). The resulting gel adsorbent was characterized by Fourier transform infrared spectroscopy (FTIR), field emission scanning electron microscopy (SEM), X-ray photoelectron spectroscopic (XPS), etc. The results indicated that the MB and Cu(II) adsorption capacities of the resulting gel adsorbent increased with the solution pH, contact time, initial concentration, and temperature before equilibrium. The adsorption processes of MB and Cu(II) fitted well with the fractal-like pseudo-second-order model. The maximal adsorption capacities on MB and Cu(II) calculated by the Sips model were 361.9 and 254.6 mg/g, respectively. The removal of MB and Cu(II) from aqueous solutions mainly included electrostatic attraction, ion exchange, hydrogen bonding interaction, etc. These results suggest that the resulting gel adsorbent is an ideal material for the removal of MB and Cu(II) from aqueous solutions.

Recent Progress in Cyclic Aryliodonium Chemistry: Syntheses and Applications.

Hypervalent aryliodoumiums are intensively investigated as arylating agents. They are excellent surrogates to aryl halides, and moreover they exhibit better reactivity, which allows the corresponding arylation reactions to be performed under mild conditions. In the past decades, acyclic aryliodoniums are widely explored as arylation agents. However, the unmet need for acyclic aryliodoniums is the improvement of their notoriously low reaction economy because the coproduced aryl iodides during the arylation are often wasted. Cyclic aryliodoniums have their intrinsic advantage in terms of reaction economy, and they have started to receive considerable attention due to their valuable synthetic applications to initiate cascade reactions, which can enable the construction of complex structures, including polycycles with potential pharmaceutical and functional properties. Here, we are summarizing the recent advances made in the research field of cyclic aryliodoniums, including the nascent design of aryliodonium species and their synthetic applications. First, the general preparation of typical diphenyl iodoniums is described, followed by the construction of heterocyclic iodoniums and monoaryl iodoniums. Then, the initiated arylations coupled with subsequent domino reactions are summarized to construct polycycles. Meanwhile, the advances in cyclic aryliodoniums for building biaryls including axial atropisomers are discussed in a systematic manner. Finally, a very recent advance of cyclic aryliodoniums employed as halogen-bonding organocatalysts is described.

Discovery of Novel Acridane-Based Tubulin Polymerization Inhibitors with Anticancer and Potential Immunomodulatory Effects.

A series of novel acridane-based tubulin polymerization inhibitors were designed, synthesized, and bioevaluated as anticancer agents. The most potent compound NT-6 exhibited high tubulin polymerization inhibitory activity (IC50 = 1.5 µM) and remarkable antiproliferative potency against four cancer cell lines with an average IC50 of 30 nM, better than colchicine and the hit compound 1f (IC50 of 65 and 126 nM, respectively). In addition, NT-6 (10 mg/kg) exerted excellent antitumor efficacy in a melanoma tumor model with a tumor growth inhibition (TGI) of 65.1% without apparent toxicity. Importantly, the combination of NT-6 with a small-molecule PD-L1 inhibitor NP-19 decreased tumor burden significantly (TGI% = 77.6%). Moreover, the combination of NT-6 with NP-19 enhanced the antitumor immune response, mediated by a decrease of PD-L1 expression levels and increased infiltration of antitumor CD8+ effector T cells in tumor tissues. Collectively, NT-6 represents a novel tubulin polymerization inhibitor with immunopotentiating effects.

Two-stage one-pot synthetic strategy for the key triazone-triazole intermediate of ensitrelvir (S-217622), an oral clinical candidate for treating COVID-19.

Herein, the preparation of the key triazone-triazole intermediate of ensitrelvir (S-217622) via sequential cyclization and alkylation reaction is described. Firstly, chloromethyl triazole was synthesized through a one-pot tandem process (condensation and cyclization reaction) from commercially available chloroacetamide in a 72% yield. Then, the key triazone-triazole intermediate was obtained in a second one-pot process by N-alkylation with triazone followed by highly selective N 1-methylation with iodomethane in a 54% yield. In addition, two of the main process impurities were synthesized and identified. This novel alternative two-stage one-pot strategy for synthesizing the key triazone-triazole intermediate opens a new avenue for further research and development of ensitrelvir analogs.

Selective PARP1 inhibitors, PARP1-based dual-target inhibitors, PROTAC PARP1 degraders, and prodrugs of PARP1 inhibitors for cancer therapy.

Poly ADP-ribose polymerase (PARP) plays a critical role in many cellular processes such as DNA damage repair, gene transcription and cell apoptosis. Therefore, targeting PARP represents a promising strategy for cancer therapy. To date, numerous small molecule PARP1 inhibitors have been identified, but many of them suffer from limited clinical efficacy and serious toxicity. Hence, PARP1 inhibitor-based combination therapies, and other PARP1 modulators (e.g. PROTAC degraders, dual acting agents) have attracted great attention with significant advancements achieved in the past few years. In this review, we overviewed the recent progress on PARP1-based drug discovery with a focus on PARP1 inhibitor-based drug combination therapy and other PARP1-targeting strategies (e.g. selective PARP1 inhibitors, PARP1-based dual-target inhibitors, PROTAC PARP1 degraders, and prodrugs of PARP1 inhibitors). In addition, we also summarized the reported co-crystal structures of PARP1 inhibitors in complex with their target proteins as well as the binding interactions. Finally, the challenges and future directions for PARP-based drug discovery in cancer therapy are also discussed in detail.

CDK12 orchestrates super-enhancer-associated CCDC137 transcription to direct hepatic metastasis in colorectal cancer.

BACKGROUND: Hepatic metastasis is the primary and direct cause of death in individuals with colorectal cancer (CRC) attribute to lack of effective therapeutic targets. The present study aimed to identify potential druggable candidate targets for patients with liver metastatic CRC. METHODS: The transcriptional profiles of super-enhancers (SEs) in primary and liver metastatic CRC were evaluated in publicly accessible CRC datasets. Immunohistochemistry of human CRC tissues was conducted to determine the expression level of CDK12. Cellular proliferation, survival and stemness were examined upon CDK12 inhibition by shCDK12 or a selective CDK12 inhibitor named SR-4835 with multiple in vitro and in vivo assays. RNA sequencing and bioinformatics analyses were carried out to investigate the mechanisms of CDK12 inhibition in CRC cells. RESULTS: We identified CDK12 as a driver gene for direct hepatic metastasis in CRC. Suppression of CDK12 led to robust inhibition of proliferation, survival and stemness. Mechanistically, CDK12 intervention preferentially repressed the transcription of SE-associated genes. Integration of the SE landscape and RNA sequencing, BCL2L1 and CCDC137 were identified as SE-associated oncogenic genes to strengthen the abilities of cellular survival, proliferation and stemness, eventually increasing liver metastasis of CRC. CONCLUSIONS: Our data highlight the potential of CDK12 and SE-associated oncogenic transcripts as therapeutic targets for patients with liver metastatic CRC.