count	source_label	source_id	relationship	target_label	target_id	entity_type	solr_id	publication_id	sentences
14	THZ531	CHEBI:143122	activates		GO:0006914	Phenotype	b8ff305a-1bdc-11f0-b759-0050569a791b	10.1016/j.phrs.2024.107097	ATG7 involves in THZ531-induced autophagy in CRC To further verify how THZ531 promoted autophagy in CRC, we examined the autophagy related genes.|||Taken together, our data demonstrated that ATG7 involves in THZ531-induced autophagy in CRC.|||2D, GFP-mRFP+ dots per cell were significantly increased in the THZ531-treated groups compared with those in the control groups, and THZ531-induced GFP+mRFP+ dots were further increased when exposed to chloroquine (CQ) treatment, indicating that THZ531 induced autophagy flux.|||To further verify how THZ531 promoted autophagy in CRC, we examined the autophagy related genes.
8	THZ531	CHEBI:143122	inhibits		UNIPROT:Q16531	Protein	49545664-1bf9-11f0-b759-0050569a791b	10.1016/j.slasd.2023.12.008	The AlphaScreen assay was also used to show the competitive effect of THZ531 that inhibits the HQ461-dependent formation of the CDK12KD/CCNKΔC/DDB1 complex[67],Fig. 3D.
4	THZ531	CHEBI:143122	increases		UNIPROT:O95352	Protein	b8ff305a-1bdc-11f0-b759-0050569a791b	10.1016/j.phrs.2024.107097	The results showed that the protein expression of ATG7 was significantly increased by THZ531, whereas Beclin1 and ATG5 increased slightly in the same cellular context (Fig, 3B, SupplFig.
4	THZ531	CHEBI:143122	decreases		UNIPROT:Q9NYV4	Protein	b8ff305a-1bdc-11f0-b759-0050569a791b	10.1016/j.phrs.2024.107097	Consistently, THZ531 treatment resulted in the increased expression of apoptosis-related protein, cleaved caspase 3 and cleaved PARP and decreased expression of CDK12 (Fig. 1G).
4	THZ531	CHEBI:143122	activates		MESH:D004249	Phenotype	f92a171c-0043-11f0-9c09-0050569a791b	10.1016/j.pharmthera.2024.108765	The CDK12 inhibitor THZ531 was found to impair DNA damage repair in an EWS-FLI1-dependent manner, resulting in a “synthetic lethal” effect (Iniguez et al., 2018).
4	THZ531	CHEBI:143122	inhibits		MESH:D002470	Phenotype	b8ff305a-1bdc-11f0-b759-0050569a791b	10.1016/j.phrs.2024.107097	CCK8 assays demonstrated that the reduced cell survival rate induced by THZ531 was stronger when ATG7 was knocked down (Fig. 4D).
4	THZ531	CHEBI:143122	activates		UNIPROT:Q8L925	Protein	b8ff305a-1bdc-11f0-b759-0050569a791b	10.1016/j.phrs.2024.107097	ATG7 involves in THZ531-induced autophagy in CRC To further verify how THZ531 promoted autophagy in CRC, we examined the autophagy related genes.|||To further verify how THZ531 promoted autophagy in CRC, we examined the autophagy related genes.
4	THZ531	CHEBI:143122	inhibits		GO:0008283	Phenotype	cffa0770-c701-11ee-b346-0050569a791b	10.1016/j.ejmech.2023.115648	We observed that THZ531 combined with Olaparib at the dose ratio of 1:3 (THZ531/Olaparib) synergistically inhibited the proliferation of MDA-MB-231, MDA-MB-468 and MDA-MB-436 cells (combination index (CI) < 1.0) (Fig. 2C–H).|||The proliferation of three TNBC cell lines were significantly inhibited by THZ531 and Olaparib in a dose-dependent manner (Fig. 2A and B).|||Results THZ531 and Olaparib synergistically inhibit the proliferation of TNBC cells To explore the synthetic lethality induced by the combination of CDK12 inhibitor and PARP1 inhibitor, we first analyzed whether genetic inactivation of CDK12 or PARP1 would affect the proliferation of TNBC cells.|||Taken together, these findings suggest that THZ531 and Olaparib synergistically inhibit the proliferation of TNBC cells.
2	THZ531	CHEBI:143122	phosphorylatesProtein		FPLX:RNApo:II	ProteinFamily	7f367e80-3405-11e8-a51f-001a4a160176	28609675	THZ531 causes loss of gene expression with concurrent loss of elongating and hyperphosphorylated RNA polymerase II, and substantially decreases the expression of DNA damage response genes and key super-enhancer-associated transcription factor genes [18].
2	THZ531	CHEBI:143122	inhibits		GO:0006281	Phenotype	d3b3a8bc-ae94-11ec-ae7b-0050569a1f61	PMCPMC8835885	We provide evidence that THZ531 could disrupt DNA repair pathway in MM cells, leading to contextual synthetic lethality if combined with DNA repair inhibitors such as PARP inhibitors.|||THZ531 Treatment Represses Genes Involved in DNA Repair and Induces a State of BRCAness Treatment of cells with CDK inhibitors causes a massive change in gene expression profiles [28].
2	THZ531	CHEBI:143122	inhibits		GO:0000725	Phenotype	d3b3a8bc-ae94-11ec-ae7b-0050569a1f61	PMCPMC8835885	Specific Targeting of NHEJ and BER Pathway Is Effective in MM Cells As THZ531 treatment downregulated HR pathway genes and given the sensitivity of MM cells to DNA, alkylating agents’ combination treatment of THZ531 with DNA repair pathway inhibitors was tested.|||THZ531 altered the phosphorylation of γ-H2AX and decreased both mRNA and protein levels of RAD51, a core member essential for HR repair [41].
1	THZ531	CHEBI:143122	inhibits		UNIPROT:Q07820	Protein	80694098-c89d-11ee-b346-0050569a791b	PMC10140597	Finally, because THZ1 inhibits CDK7, CDK12, and CDK13, we also investigated the therapeutic effects of trametinib and THZ531, which is more selective for CDK12 and CDK13.36Interestingly, THZ531 similarly prevented Mcl-1 upregulation in response to MEK inhibition (Figure S4C), and together these agents triggered apoptosis (Figure 4D) and a cooperative loss of cells over time (Figure S4E).
1	THZ531	CHEBI:143122	activates		UNIPROT:P03973	Protein	abb981c4-c85a-11ee-ae05-0050569a1f61	10.1016/j.phymed.2023.154745	2r, 48 h treatment of THZ531 increased ALP activity in primary osteoblasts and dramatically increased Runx2 and ColIα1 expression (Fig. 2s,Fig. 2t).
1	THZ531	CHEBI:143122	inhibits		UNIPROT:O43502	Protein	d3b3a8bc-ae94-11ec-ae7b-0050569a1f61	PMCPMC8835885	Moreover, gene expression data identified that THZ531 preferentially downregulated DDR genes, especially those involved in HR pathway (BRCA1, BRCA2, FANCF, RAD51, and its paralogs RAD51C, RAD51D, and XRCC2).
1	THZ531	CHEBI:143122	inhibits		UNIPROT:O75771	Protein	d3b3a8bc-ae94-11ec-ae7b-0050569a1f61	PMCPMC8835885	Moreover, gene expression data identified that THZ531 preferentially downregulated DDR genes, especially those involved in HR pathway (BRCA1, BRCA2, FANCF, RAD51, and its paralogs RAD51C, RAD51D, and XRCC2).
1	THZ531	CHEBI:143122	inhibits		UNIPROT:Q06609	Protein	d3b3a8bc-ae94-11ec-ae7b-0050569a1f61	PMCPMC8835885	Moreover, gene expression data identified that THZ531 preferentially downregulated DDR genes, especially those involved in HR pathway (BRCA1, BRCA2, FANCF, RAD51, and its paralogs RAD51C, RAD51D, and XRCC2).
1	THZ531	CHEBI:143122	activates		UNIPROT:P16104	Protein	3a448798-3546-11e9-8741-001a4a160176	PMC5846483	THZ531 and olaparib alone induced γH2AX foci staining in Ewing sarcoma cells (Figures 5A and 5B), and the combination synergistically induced γH2AX foci formation, suggesting that this combination impairs the ability of Ewing sarcoma cells to repair DNA damage.
1	THZ531	CHEBI:143122	inhibits		UNIPROT:P38398	Protein	d3b3a8bc-ae94-11ec-ae7b-0050569a1f61	PMCPMC8835885	Moreover, gene expression data identified that THZ531 preferentially downregulated DDR genes, especially those involved in HR pathway (BRCA1, BRCA2, FANCF, RAD51, and its paralogs RAD51C, RAD51D, and XRCC2).
1	THZ531	CHEBI:143122	inhibits		UNIPROT:P51587	Protein	d3b3a8bc-ae94-11ec-ae7b-0050569a1f61	PMCPMC8835885	Moreover, gene expression data identified that THZ531 preferentially downregulated DDR genes, especially those involved in HR pathway (BRCA1, BRCA2, FANCF, RAD51, and its paralogs RAD51C, RAD51D, and XRCC2).
1	THZ531	CHEBI:143122	inhibits		UNIPROT:O43543	Protein	d3b3a8bc-ae94-11ec-ae7b-0050569a1f61	PMCPMC8835885	Moreover, gene expression data identified that THZ531 preferentially downregulated DDR genes, especially those involved in HR pathway (BRCA1, BRCA2, FANCF, RAD51, and its paralogs RAD51C, RAD51D, and XRCC2).
1	THZ531	CHEBI:143122	inhibits		UNIPROT:P50750	Protein	3a448798-3546-11e9-8741-001a4a160176	PMC5846483	The authors reported that THZ531 inhibits CDK12 and CDK13 with half maximal inhibitory concentrations (IC50) of 158 and 69 nM, respectively, whereas THZ531 inhibits CDK7 and CDK9 at 8.5 and 10.5 μM, respectively (Zhang et al., 2016).
1	THZ531	CHEBI:143122	inhibits		UNIPROT:P50613	Protein	3a448798-3546-11e9-8741-001a4a160176	PMC5846483	The authors reported that THZ531 inhibits CDK12 and CDK13 with half maximal inhibitory concentrations (IC50) of 158 and 69 nM, respectively, whereas THZ531 inhibits CDK7 and CDK9 at 8.5 and 10.5 μM, respectively (Zhang et al., 2016).
1	THZ531	CHEBI:143122	inhibits		UNIPROT:Q13315	Protein	8b340dc6-ae93-11ec-b4ed-0050569a1f61	PMCPMC8267727	In the treatment of anaplastic thyroid carcinoma (ATC), THZ531 inhibits CDK12 and help overcome the resistance of ATC to adriamycin and other conventional chemotherapeutic drugs [143].
1	THZ531	CHEBI:143122	inhibits		UNIPROT:Q9BYI3	Protein	4901a042-6faf-11ee-add2-0050569a791b	10.1007/s10565-021-09686-x	THZ531, a CDK12 inhibitor, can inhibit DNA repair–related genes at the protein level and cause strong DNA damage in HCC cells (Wang et al.2020).
1	THZ531	CHEBI:143122	activates		UNIPROT:P09874	Protein	3a448798-3546-11e9-8741-001a4a160176	PMC5846483	In addition, THZ531 increased PARP cleavage and Annexin V+cell populations and decreased anchorage-independent growth in soft agar in Ewing sarcoma cells (Figures S2E–S2G).
1	THZ531	CHEBI:143122	inhibits		UNIPROT:Q9NPI8	Protein	d3b3a8bc-ae94-11ec-ae7b-0050569a1f61	PMCPMC8835885	Moreover, gene expression data identified that THZ531 preferentially downregulated DDR genes, especially those involved in HR pathway (BRCA1, BRCA2, FANCF, RAD51, and its paralogs RAD51C, RAD51D, and XRCC2).
1	THZ531	CHEBI:143122	inhibits		UNIPROT:Q9NYV4	Protein	22a21608-ae94-11ec-89b1-0050569a791b	PMCPMC8883996	For instance, suppression of cyclin-dependent kinase 12 (CDK12)—which is essential for PCa cell survival—by the covalent inhibitor THZ531 had an anti-PCa effect by downregulating androgen receptor signaling [70].
1	THZ531	CHEBI:143122	inhibits		UNIPROT:Q9NYV4	Protein	da744692-ae95-11ec-8f68-0050569a1f61	PMCPMC8316367	CDK12 inhibition shows powerful antineoplastic properties against PCa cells We further treated the panel of PCa cells with THZ531 (a covalent inhibitor of CDK12) [22].
1	THZ531	CHEBI:143122	inhibits		UNIPROT:Q9NYV4	Protein	83817f7e-dc3e-11ea-a289-001a4a160175	PMC6456927	To test whether the effects of THZ-1 were a consequence of CDK12 inhibition, we utilised THZ531; a highly selective covalent inhibitor of CDK12 and CDK13 (IC   158 
1	THZ531	CHEBI:143122	inhibits		UNIPROT:Q9NYV4	Protein	8b340dc6-ae93-11ec-b4ed-0050569a1f61	PMCPMC8267727	THZ531 is a potent inhibitor of CDK12.
1	THZ531	CHEBI:143122	inhibits		UNIPROT:Q9NYV4	Protein	96a9453a-ae94-11ec-89b1-0050569a791b	PMCPMC8210036	The inhibition of CDK12 by THZ531 or its AS form exhibited a gene-length-dependent elongation defect leading to a shortening of transcripts by premature termination in genes with a high number of cryptic polyadenylation sites, especially in DNA repair and core DNA replication genes (39,40).
1	THZ531	CHEBI:143122	inhibits		UNIPROT:Q9NYV4	Protein	3a448798-3546-11e9-8741-001a4a160176	PMC5846483	The authors reported that THZ531 inhibits CDK12 and CDK13 with half maximal inhibitory concentrations (IC50) of 158 and 69 nM, respectively, whereas THZ531 inhibits CDK7 and CDK9 at 8.5 and 10.5 μM, respectively (Zhang et al., 2016).
1	THZ531	CHEBI:143122	inhibits		UNIPROT:Q14004	Protein	3a448798-3546-11e9-8741-001a4a160176	PMC5846483	The authors reported that THZ531 inhibits CDK12 and CDK13 with half maximal inhibitory concentrations (IC50) of 158 and 69 nM, respectively, whereas THZ531 inhibits CDK7 and CDK9 at 8.5 and 10.5 μM, respectively (Zhang et al., 2016).
1	THZ531	CHEBI:143122	inhibits		CHEBI:2509	Chemical	3a448798-3546-11e9-8741-001a4a160176	PMC5846483	In addition, THZ531 increased PARP cleavage and Annexin V+cell populations and decreased anchorage-independent growth in soft agar in Ewing sarcoma cells (Figures S2E–S2G).
1	THZ531	CHEBI:143122	inhibits		GO:0000077	Phenotype	aa2c60a8-f574-11eb-8e09-001a4a160176	32691223	In hepatocellular carcinoma, suppression of CDK12 using THZ531 (CDK12/13 inhibitor) preferentially decreased expression of DNA damage response genes and showed synergistic effects with sorafenib by inducing apoptosis [38].
1	THZ531	CHEBI:143122	activates		GO:0010467	Phenotype	d3b3a8bc-ae94-11ec-ae7b-0050569a1f61	PMCPMC8835885	THZ531 Treatment Represses Genes Involved in DNA Repair and Induces a State of BRCAness Treatment of cells with CDK inhibitors causes a massive change in gene expression profiles [28].
1	THZ531	CHEBI:143122	inhibits		MESH:D012512	Phenotype	3a448798-3546-11e9-8741-001a4a160176	PMC5846483	These previous studies, in addition to our gene expression data identifying that THZ531 preferentially downregulates HR repair genes in Ewing sarcoma, led us to hypothesize that THZ531 would synergize with PARP inhibitors.
1	THZ531	CHEBI:143122	inhibits		GO:0008283	Phenotype	96a9453a-ae94-11ec-89b1-0050569a791b	PMCPMC8210036	Moreover, THZ531 and ATP analogue 3-MB-PP1 inhibited cellular proliferation in various cell lines and engineered AS CDK12 cells, respectively (38,41).
1	THZ531	CHEBI:143122	inhibits		GO:0051320	Phenotype	2e6194d4-950e-11e9-bffb-001a4a160175	PMC6052445	In addition, pharmacological inhibition of CDK12/13 with THZ531, a covalent inhibitor (Zhang et al., 2016), also suppressed the transcriptional activation ofFANCD2in S phase (Figure 7I).
1	THZ531	CHEBI:143122	decreases		GO:0042769	Phenotype	37249f42-c990-11ee-ae05-0050569a1f61	10.1016/j.bbcan.2022.188842	[117,134–136] Analogously, THZ531 significantly suppresses the expression of DDR genes and produces synergistic effects with sorafenib in hepatocellular carcinoma (HCC).
1	THZ531	CHEBI:143122	inhibits		GO:0042769	Phenotype	d3b3a8bc-ae94-11ec-ae7b-0050569a1f61	PMCPMC8835885	Moreover, gene expression data identified that THZ531 preferentially downregulated DDR genes, especially those involved in HR pathway (BRCA1, BRCA2, FANCF, RAD51, and its paralogs RAD51C, RAD51D, and XRCC2).
1	THZ531	CHEBI:143122	inhibits		GO:0006281	Phenotype	4901a042-6faf-11ee-add2-0050569a791b	10.1007/s10565-021-09686-x	THZ531, a CDK12 inhibitor, can inhibit DNA repair–related genes at the protein level and cause strong DNA damage in HCC cells (Wang et al.2020).
1	THZ531	CHEBI:143122	inhibits		GO:0006281	Phenotype	3a448798-3546-11e9-8741-001a4a160176	PMC5846483	THZ531 Treatment Preferentially Represses the Expression of DNA Repair-Related Genes in Ewing Sarcoma Cells We next performed global gene expression profiling to investigate the effects of THZ531 on transcriptional programs in Ewing sarcoma.
1	THZ531	CHEBI:143122	activates		MESH:D004249	Phenotype	624f6428-c75a-11ee-b346-0050569a791b	10.1016/j.mam.2023.101205	The CDK12 inhibitor THZ531 decreases DNA damage repair and increases Dox sensitivity of anaplastic thyroid carcinoma cells (Geng et al., 2019).
1	THZ531	CHEBI:143122	activates		MESH:D004249	Phenotype	3a448798-3546-11e9-8741-001a4a160176	PMC5846483	These data support that inhibition of CDK12 is responsible for the defects in DNA damage repair induced by THZ531.
1	THZ531	CHEBI:143122	inhibits		MESH:D004249	Phenotype	4901a042-6faf-11ee-add2-0050569a791b	10.1007/s10565-021-09686-x	THZ531, a CDK12 inhibitor, can inhibit DNA repair–related genes at the protein level and cause strong DNA damage in HCC cells (Wang et al.2020).
1	THZ531	CHEBI:143122	inhibits		MESH:D007938	Phenotype	0bcd5d9a-c6fa-11ee-ae05-0050569a1f61	10.1016/j.molcel.2023.10.004	The covalent CDK12/13 inhibitor THZ531 induces apoptotic cell death in leukemia cells.69The use of THZ531 in combination with other agents that inhibit DNA damage response or RNA processing could potentially help attenuate the growth of cancers that are “addicted” to CDK12’s effects on DNA damage response and RNA processing.
1	THZ531	CHEBI:143122	activates		MESH:D002945	Phenotype	3a448798-3546-11e9-8741-001a4a160176	PMC5846483	Moreover, we observed that THZ531 strongly synergizes with cisplatin, mitomycin C, the ATR inhibitor VE821, and the ATM inhibitor KU5593, in Ewing sarcoma cells (Figures S4A–S4D).
1	THZ531	CHEBI:143122	inhibits		GO:0090398	Phenotype	1703f948-c7d2-11ee-b346-0050569a791b	10.1016/j.biopha.2023.115002	Wang et al. showed that the specific inhibitor THZ531 of CDK12, by inhibiting genes involved in DNA repair, induced apoptosis and senescence in HCC cells[70].
1	THZ531	CHEBI:143122	inhibits		GO:0006915	Phenotype	2e6194d4-950e-11e9-bffb-001a4a160175	PMC6052445	THZ531 inhibited growth of MLL-r/non-MLL-r leukemia cell lines and induced apoptosis in the MOLM-13 cell line (Figures S7G and S7H).
1	THZ531	CHEBI:143122	inhibits		GO:0006915	Phenotype	1703f948-c7d2-11ee-b346-0050569a791b	10.1016/j.biopha.2023.115002	Wang et al. showed that the specific inhibitor THZ531 of CDK12, by inhibiting genes involved in DNA repair, induced apoptosis and senescence in HCC cells[70].
1	THZ531	CHEBI:143122	activates		GO:0006915	Phenotype	3db5ddbe-351f-11e8-b868-001a4a160176	PMC6141011	Importantly, treatment with THZ531 induced apoptosis in leukemic T cells, coincident with changes in gene expression.
1	THZ531	CHEBI:143122	inhibits		GO:0006915	Phenotype	0bcd5d9a-c6fa-11ee-ae05-0050569a1f61	10.1016/j.molcel.2023.10.004	The covalent CDK12/13 inhibitor THZ531 induces apoptotic cell death in leukemia cells.69The use of THZ531 in combination with other agents that inhibit DNA damage response or RNA processing could potentially help attenuate the growth of cancers that are “addicted” to CDK12’s effects on DNA damage response and RNA processing.
1	THZ531	CHEBI:143122	activates		GO:0006915	Phenotype	aa2c60a8-f574-11eb-8e09-001a4a160176	32691223	THZ531 also induced apoptotic cell death in anaplastic thyroid cancer and enhanced the doxorubicin sensitivity of the cancer cells as well [23].
1	THZ531	CHEBI:143122	activates		GO:0008219	Phenotype	d3b3a8bc-ae94-11ec-ae7b-0050569a1f61	PMCPMC8835885	We observed that THZ531 produced synergistic cell death with the DNA-PK inhibitor KU-0060648.
1	THZ531	CHEBI:143122	activates		MESH:D016685	Phenotype	3a448798-3546-11e9-8741-001a4a160176	PMC5846483	Moreover, we observed that THZ531 strongly synergizes with cisplatin, mitomycin C, the ATR inhibitor VE821, and the ATM inhibitor KU5593, in Ewing sarcoma cells (Figures S4A–S4D).
1	THZ531	CHEBI:143122	inhibits		GO:0016049	Phenotype	d3b3a8bc-ae94-11ec-ae7b-0050569a1f61	PMCPMC8835885	Our study showed that (THZ531) decreased myeloma cell growth especially when combined with other DNA damaging agents, probably by disrupting HR function of MM cells.
1	THZ531	CHEBI:143122	inhibits		MESH:D002470	Phenotype	d3b3a8bc-ae94-11ec-ae7b-0050569a1f61	PMCPMC8835885	Although we found that THZ531 significantly decreases MM cell viability, a synthetic lethal effect ensued when combined with Olaparib, resulting in a significantly greater loss of viability relative to single agent administration.
1	THZ531	CHEBI:143122	inhibits		GO:0000725	Phenotype	3a448798-3546-11e9-8741-001a4a160176	PMC5846483	These previous studies, in addition to our gene expression data identifying that THZ531 preferentially downregulates HR repair genes in Ewing sarcoma, led us to hypothesize that THZ531 would synergize with PARP inhibitors.
1	THZ531	CHEBI:143122	activates		GO:0000725	Phenotype	d3b3a8bc-ae94-11ec-ae7b-0050569a1f61	PMCPMC8835885	Our study showed that (THZ531) decreased myeloma cell growth especially when combined with other DNA damaging agents, probably by disrupting HR function of MM cells.
1	THZ531	CHEBI:143122	activates		MESH:D065646	Phenotype	aa2c60a8-f574-11eb-8e09-001a4a160176	32691223	THZ531 also induced apoptotic cell death in anaplastic thyroid cancer and enhanced the doxorubicin sensitivity of the cancer cells as well [23].