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uc cell lines ht1197  (ATCC)


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    ATCC uc cell lines ht1197
    (a) Overview of medicinal chemistry strategy for covalent PPARG inverse agonist optimization resulting in FTX-6746. (b) Crystal structure of FTX-6746 covalent adduct with PPARG LBD. The PPARG LBD (gray) adopts a similar conformation to that observed with T0070907 (PDB 6ONI) with H12 (orange) inserted into the ligand binding pocket with the C-terminal carboxylate forming a key H-bond with the quinolone nitrogen of the FTX-6746 adduct (yellow dashes). (c) Dose-dependent recruitment of NCOR1 ID2 to RXRA S427F :PPARG heterodimers, demonstrating the superiority of FTX-6746 for countering the activation bias driven by this mutation over T0070907 and SR10221. Representative curves from ≥ 3 biological replicates are shown. Data points indicate the average of technical duplicates from a representative biological replicate. The 95% confidence interval for EC 50 values of SR10221, T0070907 and FTX-6746, respectively, were determined to be: 109 nM ± 30 nM, 60.5 ± nM, 197.5 ± 8.5 nM. The 95% confidence interval for the E max values relative to T0070907 for SR10221 and FTX- 6746, respectively, were determined to be: 6.2 ± 0.6% and 170.5 ± 2%. Rosiglitazone was not present for these experiments. (d) Comparison of SR10221, T007097 and FTX-6746 ability to suppress PPARG target gene ANGPTL4 in RXRA WT (blue, 5637 cell line) and RXRA S427F (orange, <t>HT1197</t> cell line) contexts. Data indicate the activation bias observed biochemically reduces T0070907 and SR10221 efficacy and the superior repressive biasing of FTX-6746 enables it to achieve similar repressive effects in both contexts. Data is representative of two separate biological experiments.
    Uc Cell Lines Ht1197, supplied by ATCC, used in various techniques. Bioz Stars score: 95/100, based on 217 PubMed citations. ZERO BIAS - scores, article reviews, protocol conditions and more
    https://www.bioz.com/product/uc+cell+lines+ht1197/bio_rxiv__2025__05__08__652848-251-1-21?v=ATCC
    Average 95 stars, based on 217 article reviews
    uc cell lines ht1197 - by Bioz Stars, 2026-08
    95/100 stars

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    1) Product Images from "Discovery and characterization of FX-909, a covalent inverse agonist of PPARG rationally designed to impose a powerful repressive bias in PPARG for the treatment of PPARG/RXRA-activated muscle-invasive urothelial cancers"

    Article Title: Discovery and characterization of FX-909, a covalent inverse agonist of PPARG rationally designed to impose a powerful repressive bias in PPARG for the treatment of PPARG/RXRA-activated muscle-invasive urothelial cancers

    Journal: bioRxiv

    doi: 10.1101/2025.05.08.652848

    (a) Overview of medicinal chemistry strategy for covalent PPARG inverse agonist optimization resulting in FTX-6746. (b) Crystal structure of FTX-6746 covalent adduct with PPARG LBD. The PPARG LBD (gray) adopts a similar conformation to that observed with T0070907 (PDB 6ONI) with H12 (orange) inserted into the ligand binding pocket with the C-terminal carboxylate forming a key H-bond with the quinolone nitrogen of the FTX-6746 adduct (yellow dashes). (c) Dose-dependent recruitment of NCOR1 ID2 to RXRA S427F :PPARG heterodimers, demonstrating the superiority of FTX-6746 for countering the activation bias driven by this mutation over T0070907 and SR10221. Representative curves from ≥ 3 biological replicates are shown. Data points indicate the average of technical duplicates from a representative biological replicate. The 95% confidence interval for EC 50 values of SR10221, T0070907 and FTX-6746, respectively, were determined to be: 109 nM ± 30 nM, 60.5 ± nM, 197.5 ± 8.5 nM. The 95% confidence interval for the E max values relative to T0070907 for SR10221 and FTX- 6746, respectively, were determined to be: 6.2 ± 0.6% and 170.5 ± 2%. Rosiglitazone was not present for these experiments. (d) Comparison of SR10221, T007097 and FTX-6746 ability to suppress PPARG target gene ANGPTL4 in RXRA WT (blue, 5637 cell line) and RXRA S427F (orange, HT1197 cell line) contexts. Data indicate the activation bias observed biochemically reduces T0070907 and SR10221 efficacy and the superior repressive biasing of FTX-6746 enables it to achieve similar repressive effects in both contexts. Data is representative of two separate biological experiments.
    Figure Legend Snippet: (a) Overview of medicinal chemistry strategy for covalent PPARG inverse agonist optimization resulting in FTX-6746. (b) Crystal structure of FTX-6746 covalent adduct with PPARG LBD. The PPARG LBD (gray) adopts a similar conformation to that observed with T0070907 (PDB 6ONI) with H12 (orange) inserted into the ligand binding pocket with the C-terminal carboxylate forming a key H-bond with the quinolone nitrogen of the FTX-6746 adduct (yellow dashes). (c) Dose-dependent recruitment of NCOR1 ID2 to RXRA S427F :PPARG heterodimers, demonstrating the superiority of FTX-6746 for countering the activation bias driven by this mutation over T0070907 and SR10221. Representative curves from ≥ 3 biological replicates are shown. Data points indicate the average of technical duplicates from a representative biological replicate. The 95% confidence interval for EC 50 values of SR10221, T0070907 and FTX-6746, respectively, were determined to be: 109 nM ± 30 nM, 60.5 ± nM, 197.5 ± 8.5 nM. The 95% confidence interval for the E max values relative to T0070907 for SR10221 and FTX- 6746, respectively, were determined to be: 6.2 ± 0.6% and 170.5 ± 2%. Rosiglitazone was not present for these experiments. (d) Comparison of SR10221, T007097 and FTX-6746 ability to suppress PPARG target gene ANGPTL4 in RXRA WT (blue, 5637 cell line) and RXRA S427F (orange, HT1197 cell line) contexts. Data indicate the activation bias observed biochemically reduces T0070907 and SR10221 efficacy and the superior repressive biasing of FTX-6746 enables it to achieve similar repressive effects in both contexts. Data is representative of two separate biological experiments.

    Techniques Used: Ligand Binding Assay, Activation Assay, Mutagenesis, Comparison

    (A) Selective engagement of FX-909 across urothelial carcinoma cell lines. Global cysteine profiling and engagement of FX-909 in UMUC9, HT1197 and 5637 cell lines following 30 min treatment. PPARG C313 was the only significantly engaged target (orange). Competition ratio (CR) was calculated dividing the control channel (DMSO) by the electrophile treated channel. The blue dotted line indicates a CR of 3. (B) Cellular potency of FX-909. (top) Dose-dependent suppression of IL1B expression by FX-909 in the urothelial carcinoma line UMUC9. Relative IL1B expression and IC 50 value are indicated. (bottom) Dose-dependent suppression of ANGPTL4 expression by FX-909 in the urothelial carcinoma line HT1197. Relative ANGPTL4 expression and IC 50 value are indicated. (C) Transcriptional changes induced by PPARG inverse agonists in UMUC9, HT1197 and 5637 cell lines following 24 hr treatment. (top) Heatmap showing the effect of T0070907, FTX-6746 and FX-909 on the genes that are differentially up- or down-regulated by FX-909 (see ). (bottom) Comparison of gene expression changes induced by FX-909 vs T0070907. Each dot corresponds to a gene that showed statistically significant change in response to T0070907, FTX- 6746 or FX-909 (n=6,759 genes; FDR < 0.05) as assessed from a mixed effect model where cell lines are treated as a random effect. Red line corresponds to a linear regression model with a slope of β=1.8, indicating that on average FX-909 induces 3.5=fold (2^1.8) times greater fold changes in gene expression. Dashed black line shows where data would fall if FX-909 and T0070907 induced effects of the same magnitude. The lack of gene expression changes in the bottom right and top left quadrants of the plot indicates that FX-909 does not regulate different genes from T0070907.
    Figure Legend Snippet: (A) Selective engagement of FX-909 across urothelial carcinoma cell lines. Global cysteine profiling and engagement of FX-909 in UMUC9, HT1197 and 5637 cell lines following 30 min treatment. PPARG C313 was the only significantly engaged target (orange). Competition ratio (CR) was calculated dividing the control channel (DMSO) by the electrophile treated channel. The blue dotted line indicates a CR of 3. (B) Cellular potency of FX-909. (top) Dose-dependent suppression of IL1B expression by FX-909 in the urothelial carcinoma line UMUC9. Relative IL1B expression and IC 50 value are indicated. (bottom) Dose-dependent suppression of ANGPTL4 expression by FX-909 in the urothelial carcinoma line HT1197. Relative ANGPTL4 expression and IC 50 value are indicated. (C) Transcriptional changes induced by PPARG inverse agonists in UMUC9, HT1197 and 5637 cell lines following 24 hr treatment. (top) Heatmap showing the effect of T0070907, FTX-6746 and FX-909 on the genes that are differentially up- or down-regulated by FX-909 (see ). (bottom) Comparison of gene expression changes induced by FX-909 vs T0070907. Each dot corresponds to a gene that showed statistically significant change in response to T0070907, FTX- 6746 or FX-909 (n=6,759 genes; FDR < 0.05) as assessed from a mixed effect model where cell lines are treated as a random effect. Red line corresponds to a linear regression model with a slope of β=1.8, indicating that on average FX-909 induces 3.5=fold (2^1.8) times greater fold changes in gene expression. Dashed black line shows where data would fall if FX-909 and T0070907 induced effects of the same magnitude. The lack of gene expression changes in the bottom right and top left quadrants of the plot indicates that FX-909 does not regulate different genes from T0070907.

    Techniques Used: Control, Expressing, Comparison, Gene Expression

    Selective engagement of FTX-6746 across urothelial carcinoma cell lines. Global cysteine profiling and engagement of FTX-6746 in UMUC9, HT1197 and 5637 cell lines following 30 min treatment. PPARG C313 was the only significantly engaged target (green). Competition ratio (CR) was calculated dividing the control channel (DMSO) by the electrophile treated channel. The blue dotted line indicates a CR of 3.
    Figure Legend Snippet: Selective engagement of FTX-6746 across urothelial carcinoma cell lines. Global cysteine profiling and engagement of FTX-6746 in UMUC9, HT1197 and 5637 cell lines following 30 min treatment. PPARG C313 was the only significantly engaged target (green). Competition ratio (CR) was calculated dividing the control channel (DMSO) by the electrophile treated channel. The blue dotted line indicates a CR of 3.

    Techniques Used: Control

    (A) Principal component analysis (PCA) of genome-wide expression changes (on log2 scale) induced by PPARG inverse agonists in UMUC9, HT1197 and 5637 cell lines after 24 hr treatment. (B) Consensus FX-909 induced differential gene expression was assessed using a mixed effect model where Treatment was a fixed effect and Cell Line was a random effect. Differentially expressed genes were determined by contrasting the FX-909 treatment with DMSO and using the cutoffs of FDR < 0.05 and absolute log2(fold change) > 0.6.
    Figure Legend Snippet: (A) Principal component analysis (PCA) of genome-wide expression changes (on log2 scale) induced by PPARG inverse agonists in UMUC9, HT1197 and 5637 cell lines after 24 hr treatment. (B) Consensus FX-909 induced differential gene expression was assessed using a mixed effect model where Treatment was a fixed effect and Cell Line was a random effect. Differentially expressed genes were determined by contrasting the FX-909 treatment with DMSO and using the cutoffs of FDR < 0.05 and absolute log2(fold change) > 0.6.

    Techniques Used: Genome Wide, Expressing, Gene Expression

    (A) Phenotypic potency of PPARG inverse agonists. GI 50 values of UC cell lines treated with T0070907, FTX-6746 or FX-909 for 11-14 days. GI 50 values were calculated relative to the DMSO treated cells using a crystal violet stain quantitation. GI 50 values greater than the maximum dose tested - 500 nM (FX-909) or 1500 nM (T0070907 and FTX-6746) - were graphed as 500 nM and 1500 nM, respectively. * = PPARG/RXRA mutant or PPARG amplified lines. Data are a representative of multiple individual experiments performed. (B) Phenotypic potency of FX-909 in WT or C313A isogenic HT1197 cell lines. Treatment of parental and C313A HT1997 cells lines for 14 days with FX-909 resulted in potent growth inhibition only in parental line, growth curve on left and images of clonogenic assay on right.
    Figure Legend Snippet: (A) Phenotypic potency of PPARG inverse agonists. GI 50 values of UC cell lines treated with T0070907, FTX-6746 or FX-909 for 11-14 days. GI 50 values were calculated relative to the DMSO treated cells using a crystal violet stain quantitation. GI 50 values greater than the maximum dose tested - 500 nM (FX-909) or 1500 nM (T0070907 and FTX-6746) - were graphed as 500 nM and 1500 nM, respectively. * = PPARG/RXRA mutant or PPARG amplified lines. Data are a representative of multiple individual experiments performed. (B) Phenotypic potency of FX-909 in WT or C313A isogenic HT1197 cell lines. Treatment of parental and C313A HT1997 cells lines for 14 days with FX-909 resulted in potent growth inhibition only in parental line, growth curve on left and images of clonogenic assay on right.

    Techniques Used: Staining, Quantitation Assay, Mutagenesis, Amplification, Inhibition, Clonogenic Assay

    Clonogenic growth assay of HT1197 cells treated with FTX-6746, FX-909 or T0070907. Percent cell density relative to DMSO control well shown, data are representative of three independent experiments.
    Figure Legend Snippet: Clonogenic growth assay of HT1197 cells treated with FTX-6746, FX-909 or T0070907. Percent cell density relative to DMSO control well shown, data are representative of three independent experiments.

    Techniques Used: Growth Assay, Control

    – (A) UMUC9 xenograft efficacy study shows FX-909 elicits durable tumor regression at all doses, while FTX-6746 elicits tumor regression that is not durable upon drug cessation. (B) HT1197 xenograft efficacy study shows tumor regression for both FX-909 and FTX-6746. (C) PK/PD relationship for FTX-6746 and FX-909. (D) H&E staining of adipose tissue from mice in study shown in (A).
    Figure Legend Snippet: – (A) UMUC9 xenograft efficacy study shows FX-909 elicits durable tumor regression at all doses, while FTX-6746 elicits tumor regression that is not durable upon drug cessation. (B) HT1197 xenograft efficacy study shows tumor regression for both FX-909 and FTX-6746. (C) PK/PD relationship for FTX-6746 and FX-909. (D) H&E staining of adipose tissue from mice in study shown in (A).

    Techniques Used: Staining



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    uc cell lines ht1197  (ATCC)
    95
    ATCC uc cell lines ht1197
    (a) Overview of medicinal chemistry strategy for covalent PPARG inverse agonist optimization resulting in FTX-6746. (b) Crystal structure of FTX-6746 covalent adduct with PPARG LBD. The PPARG LBD (gray) adopts a similar conformation to that observed with T0070907 (PDB 6ONI) with H12 (orange) inserted into the ligand binding pocket with the C-terminal carboxylate forming a key H-bond with the quinolone nitrogen of the FTX-6746 adduct (yellow dashes). (c) Dose-dependent recruitment of NCOR1 ID2 to RXRA S427F :PPARG heterodimers, demonstrating the superiority of FTX-6746 for countering the activation bias driven by this mutation over T0070907 and SR10221. Representative curves from ≥ 3 biological replicates are shown. Data points indicate the average of technical duplicates from a representative biological replicate. The 95% confidence interval for EC 50 values of SR10221, T0070907 and FTX-6746, respectively, were determined to be: 109 nM ± 30 nM, 60.5 ± nM, 197.5 ± 8.5 nM. The 95% confidence interval for the E max values relative to T0070907 for SR10221 and FTX- 6746, respectively, were determined to be: 6.2 ± 0.6% and 170.5 ± 2%. Rosiglitazone was not present for these experiments. (d) Comparison of SR10221, T007097 and FTX-6746 ability to suppress PPARG target gene ANGPTL4 in RXRA WT (blue, 5637 cell line) and RXRA S427F (orange, <t>HT1197</t> cell line) contexts. Data indicate the activation bias observed biochemically reduces T0070907 and SR10221 efficacy and the superior repressive biasing of FTX-6746 enables it to achieve similar repressive effects in both contexts. Data is representative of two separate biological experiments.
    Uc Cell Lines Ht1197, supplied by ATCC, used in various techniques. Bioz Stars score: 95/100, based on 1 PubMed citations. ZERO BIAS - scores, article reviews, protocol conditions and more
    https://www.bioz.com/product/uc+cell+lines+ht1197/bio_rxiv__2025__05__08__652848-251-1-21?v=ATCC
    Average 95 stars, based on 1 article reviews
    uc cell lines ht1197 - by Bioz Stars, 2026-08
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    5637  (ATCC)
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    ATCC 5637
    (a) Overview of medicinal chemistry strategy for covalent PPARG inverse agonist optimization resulting in FTX-6746. (b) Crystal structure of FTX-6746 covalent adduct with PPARG LBD. The PPARG LBD (gray) adopts a similar conformation to that observed with T0070907 (PDB 6ONI) with H12 (orange) inserted into the ligand binding pocket with the C-terminal carboxylate forming a key H-bond with the quinolone nitrogen of the FTX-6746 adduct (yellow dashes). (c) Dose-dependent recruitment of NCOR1 ID2 to RXRA S427F :PPARG heterodimers, demonstrating the superiority of FTX-6746 for countering the activation bias driven by this mutation over T0070907 and SR10221. Representative curves from ≥ 3 biological replicates are shown. Data points indicate the average of technical duplicates from a representative biological replicate. The 95% confidence interval for EC 50 values of SR10221, T0070907 and FTX-6746, respectively, were determined to be: 109 nM ± 30 nM, 60.5 ± nM, 197.5 ± 8.5 nM. The 95% confidence interval for the E max values relative to T0070907 for SR10221 and FTX- 6746, respectively, were determined to be: 6.2 ± 0.6% and 170.5 ± 2%. Rosiglitazone was not present for these experiments. (d) Comparison of SR10221, T007097 and FTX-6746 ability to suppress PPARG target gene ANGPTL4 in RXRA WT (blue, 5637 cell line) and RXRA S427F (orange, <t>HT1197</t> cell line) contexts. Data indicate the activation bias observed biochemically reduces T0070907 and SR10221 efficacy and the superior repressive biasing of FTX-6746 enables it to achieve similar repressive effects in both contexts. Data is representative of two separate biological experiments.
    5637, supplied by ATCC, used in various techniques. Bioz Stars score: 97/100, based on 1 PubMed citations. ZERO BIAS - scores, article reviews, protocol conditions and more
    https://www.bioz.com/product/uc+cell+lines+ht1197/custom%40htb-9%4040314887?v=ATCC
    Average 97 stars, based on 1 article reviews
    5637 - by Bioz Stars, 2026-08
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    (a) Overview of medicinal chemistry strategy for covalent PPARG inverse agonist optimization resulting in FTX-6746. (b) Crystal structure of FTX-6746 covalent adduct with PPARG LBD. The PPARG LBD (gray) adopts a similar conformation to that observed with T0070907 (PDB 6ONI) with H12 (orange) inserted into the ligand binding pocket with the C-terminal carboxylate forming a key H-bond with the quinolone nitrogen of the FTX-6746 adduct (yellow dashes). (c) Dose-dependent recruitment of NCOR1 ID2 to RXRA S427F :PPARG heterodimers, demonstrating the superiority of FTX-6746 for countering the activation bias driven by this mutation over T0070907 and SR10221. Representative curves from ≥ 3 biological replicates are shown. Data points indicate the average of technical duplicates from a representative biological replicate. The 95% confidence interval for EC 50 values of SR10221, T0070907 and FTX-6746, respectively, were determined to be: 109 nM ± 30 nM, 60.5 ± nM, 197.5 ± 8.5 nM. The 95% confidence interval for the E max values relative to T0070907 for SR10221 and FTX- 6746, respectively, were determined to be: 6.2 ± 0.6% and 170.5 ± 2%. Rosiglitazone was not present for these experiments. (d) Comparison of SR10221, T007097 and FTX-6746 ability to suppress PPARG target gene ANGPTL4 in RXRA WT (blue, 5637 cell line) and RXRA S427F (orange, HT1197 cell line) contexts. Data indicate the activation bias observed biochemically reduces T0070907 and SR10221 efficacy and the superior repressive biasing of FTX-6746 enables it to achieve similar repressive effects in both contexts. Data is representative of two separate biological experiments.

    Journal: bioRxiv

    Article Title: Discovery and characterization of FX-909, a covalent inverse agonist of PPARG rationally designed to impose a powerful repressive bias in PPARG for the treatment of PPARG/RXRA-activated muscle-invasive urothelial cancers

    doi: 10.1101/2025.05.08.652848

    Figure Lengend Snippet: (a) Overview of medicinal chemistry strategy for covalent PPARG inverse agonist optimization resulting in FTX-6746. (b) Crystal structure of FTX-6746 covalent adduct with PPARG LBD. The PPARG LBD (gray) adopts a similar conformation to that observed with T0070907 (PDB 6ONI) with H12 (orange) inserted into the ligand binding pocket with the C-terminal carboxylate forming a key H-bond with the quinolone nitrogen of the FTX-6746 adduct (yellow dashes). (c) Dose-dependent recruitment of NCOR1 ID2 to RXRA S427F :PPARG heterodimers, demonstrating the superiority of FTX-6746 for countering the activation bias driven by this mutation over T0070907 and SR10221. Representative curves from ≥ 3 biological replicates are shown. Data points indicate the average of technical duplicates from a representative biological replicate. The 95% confidence interval for EC 50 values of SR10221, T0070907 and FTX-6746, respectively, were determined to be: 109 nM ± 30 nM, 60.5 ± nM, 197.5 ± 8.5 nM. The 95% confidence interval for the E max values relative to T0070907 for SR10221 and FTX- 6746, respectively, were determined to be: 6.2 ± 0.6% and 170.5 ± 2%. Rosiglitazone was not present for these experiments. (d) Comparison of SR10221, T007097 and FTX-6746 ability to suppress PPARG target gene ANGPTL4 in RXRA WT (blue, 5637 cell line) and RXRA S427F (orange, HT1197 cell line) contexts. Data indicate the activation bias observed biochemically reduces T0070907 and SR10221 efficacy and the superior repressive biasing of FTX-6746 enables it to achieve similar repressive effects in both contexts. Data is representative of two separate biological experiments.

    Article Snippet: The UC cell lines HT1197 (CRL1473), 5637 (HTB-9), HT1376 (CRL-1472), J82 (HTB- 1), RT4 (HTB-2) and SW780 (CRL-2169) were purchased from ATCC.

    Techniques: Ligand Binding Assay, Activation Assay, Mutagenesis, Comparison

    (A) Selective engagement of FX-909 across urothelial carcinoma cell lines. Global cysteine profiling and engagement of FX-909 in UMUC9, HT1197 and 5637 cell lines following 30 min treatment. PPARG C313 was the only significantly engaged target (orange). Competition ratio (CR) was calculated dividing the control channel (DMSO) by the electrophile treated channel. The blue dotted line indicates a CR of 3. (B) Cellular potency of FX-909. (top) Dose-dependent suppression of IL1B expression by FX-909 in the urothelial carcinoma line UMUC9. Relative IL1B expression and IC 50 value are indicated. (bottom) Dose-dependent suppression of ANGPTL4 expression by FX-909 in the urothelial carcinoma line HT1197. Relative ANGPTL4 expression and IC 50 value are indicated. (C) Transcriptional changes induced by PPARG inverse agonists in UMUC9, HT1197 and 5637 cell lines following 24 hr treatment. (top) Heatmap showing the effect of T0070907, FTX-6746 and FX-909 on the genes that are differentially up- or down-regulated by FX-909 (see ). (bottom) Comparison of gene expression changes induced by FX-909 vs T0070907. Each dot corresponds to a gene that showed statistically significant change in response to T0070907, FTX- 6746 or FX-909 (n=6,759 genes; FDR < 0.05) as assessed from a mixed effect model where cell lines are treated as a random effect. Red line corresponds to a linear regression model with a slope of β=1.8, indicating that on average FX-909 induces 3.5=fold (2^1.8) times greater fold changes in gene expression. Dashed black line shows where data would fall if FX-909 and T0070907 induced effects of the same magnitude. The lack of gene expression changes in the bottom right and top left quadrants of the plot indicates that FX-909 does not regulate different genes from T0070907.

    Journal: bioRxiv

    Article Title: Discovery and characterization of FX-909, a covalent inverse agonist of PPARG rationally designed to impose a powerful repressive bias in PPARG for the treatment of PPARG/RXRA-activated muscle-invasive urothelial cancers

    doi: 10.1101/2025.05.08.652848

    Figure Lengend Snippet: (A) Selective engagement of FX-909 across urothelial carcinoma cell lines. Global cysteine profiling and engagement of FX-909 in UMUC9, HT1197 and 5637 cell lines following 30 min treatment. PPARG C313 was the only significantly engaged target (orange). Competition ratio (CR) was calculated dividing the control channel (DMSO) by the electrophile treated channel. The blue dotted line indicates a CR of 3. (B) Cellular potency of FX-909. (top) Dose-dependent suppression of IL1B expression by FX-909 in the urothelial carcinoma line UMUC9. Relative IL1B expression and IC 50 value are indicated. (bottom) Dose-dependent suppression of ANGPTL4 expression by FX-909 in the urothelial carcinoma line HT1197. Relative ANGPTL4 expression and IC 50 value are indicated. (C) Transcriptional changes induced by PPARG inverse agonists in UMUC9, HT1197 and 5637 cell lines following 24 hr treatment. (top) Heatmap showing the effect of T0070907, FTX-6746 and FX-909 on the genes that are differentially up- or down-regulated by FX-909 (see ). (bottom) Comparison of gene expression changes induced by FX-909 vs T0070907. Each dot corresponds to a gene that showed statistically significant change in response to T0070907, FTX- 6746 or FX-909 (n=6,759 genes; FDR < 0.05) as assessed from a mixed effect model where cell lines are treated as a random effect. Red line corresponds to a linear regression model with a slope of β=1.8, indicating that on average FX-909 induces 3.5=fold (2^1.8) times greater fold changes in gene expression. Dashed black line shows where data would fall if FX-909 and T0070907 induced effects of the same magnitude. The lack of gene expression changes in the bottom right and top left quadrants of the plot indicates that FX-909 does not regulate different genes from T0070907.

    Article Snippet: The UC cell lines HT1197 (CRL1473), 5637 (HTB-9), HT1376 (CRL-1472), J82 (HTB- 1), RT4 (HTB-2) and SW780 (CRL-2169) were purchased from ATCC.

    Techniques: Control, Expressing, Comparison, Gene Expression

    Selective engagement of FTX-6746 across urothelial carcinoma cell lines. Global cysteine profiling and engagement of FTX-6746 in UMUC9, HT1197 and 5637 cell lines following 30 min treatment. PPARG C313 was the only significantly engaged target (green). Competition ratio (CR) was calculated dividing the control channel (DMSO) by the electrophile treated channel. The blue dotted line indicates a CR of 3.

    Journal: bioRxiv

    Article Title: Discovery and characterization of FX-909, a covalent inverse agonist of PPARG rationally designed to impose a powerful repressive bias in PPARG for the treatment of PPARG/RXRA-activated muscle-invasive urothelial cancers

    doi: 10.1101/2025.05.08.652848

    Figure Lengend Snippet: Selective engagement of FTX-6746 across urothelial carcinoma cell lines. Global cysteine profiling and engagement of FTX-6746 in UMUC9, HT1197 and 5637 cell lines following 30 min treatment. PPARG C313 was the only significantly engaged target (green). Competition ratio (CR) was calculated dividing the control channel (DMSO) by the electrophile treated channel. The blue dotted line indicates a CR of 3.

    Article Snippet: The UC cell lines HT1197 (CRL1473), 5637 (HTB-9), HT1376 (CRL-1472), J82 (HTB- 1), RT4 (HTB-2) and SW780 (CRL-2169) were purchased from ATCC.

    Techniques: Control

    (A) Principal component analysis (PCA) of genome-wide expression changes (on log2 scale) induced by PPARG inverse agonists in UMUC9, HT1197 and 5637 cell lines after 24 hr treatment. (B) Consensus FX-909 induced differential gene expression was assessed using a mixed effect model where Treatment was a fixed effect and Cell Line was a random effect. Differentially expressed genes were determined by contrasting the FX-909 treatment with DMSO and using the cutoffs of FDR < 0.05 and absolute log2(fold change) > 0.6.

    Journal: bioRxiv

    Article Title: Discovery and characterization of FX-909, a covalent inverse agonist of PPARG rationally designed to impose a powerful repressive bias in PPARG for the treatment of PPARG/RXRA-activated muscle-invasive urothelial cancers

    doi: 10.1101/2025.05.08.652848

    Figure Lengend Snippet: (A) Principal component analysis (PCA) of genome-wide expression changes (on log2 scale) induced by PPARG inverse agonists in UMUC9, HT1197 and 5637 cell lines after 24 hr treatment. (B) Consensus FX-909 induced differential gene expression was assessed using a mixed effect model where Treatment was a fixed effect and Cell Line was a random effect. Differentially expressed genes were determined by contrasting the FX-909 treatment with DMSO and using the cutoffs of FDR < 0.05 and absolute log2(fold change) > 0.6.

    Article Snippet: The UC cell lines HT1197 (CRL1473), 5637 (HTB-9), HT1376 (CRL-1472), J82 (HTB- 1), RT4 (HTB-2) and SW780 (CRL-2169) were purchased from ATCC.

    Techniques: Genome Wide, Expressing, Gene Expression

    (A) Phenotypic potency of PPARG inverse agonists. GI 50 values of UC cell lines treated with T0070907, FTX-6746 or FX-909 for 11-14 days. GI 50 values were calculated relative to the DMSO treated cells using a crystal violet stain quantitation. GI 50 values greater than the maximum dose tested - 500 nM (FX-909) or 1500 nM (T0070907 and FTX-6746) - were graphed as 500 nM and 1500 nM, respectively. * = PPARG/RXRA mutant or PPARG amplified lines. Data are a representative of multiple individual experiments performed. (B) Phenotypic potency of FX-909 in WT or C313A isogenic HT1197 cell lines. Treatment of parental and C313A HT1997 cells lines for 14 days with FX-909 resulted in potent growth inhibition only in parental line, growth curve on left and images of clonogenic assay on right.

    Journal: bioRxiv

    Article Title: Discovery and characterization of FX-909, a covalent inverse agonist of PPARG rationally designed to impose a powerful repressive bias in PPARG for the treatment of PPARG/RXRA-activated muscle-invasive urothelial cancers

    doi: 10.1101/2025.05.08.652848

    Figure Lengend Snippet: (A) Phenotypic potency of PPARG inverse agonists. GI 50 values of UC cell lines treated with T0070907, FTX-6746 or FX-909 for 11-14 days. GI 50 values were calculated relative to the DMSO treated cells using a crystal violet stain quantitation. GI 50 values greater than the maximum dose tested - 500 nM (FX-909) or 1500 nM (T0070907 and FTX-6746) - were graphed as 500 nM and 1500 nM, respectively. * = PPARG/RXRA mutant or PPARG amplified lines. Data are a representative of multiple individual experiments performed. (B) Phenotypic potency of FX-909 in WT or C313A isogenic HT1197 cell lines. Treatment of parental and C313A HT1997 cells lines for 14 days with FX-909 resulted in potent growth inhibition only in parental line, growth curve on left and images of clonogenic assay on right.

    Article Snippet: The UC cell lines HT1197 (CRL1473), 5637 (HTB-9), HT1376 (CRL-1472), J82 (HTB- 1), RT4 (HTB-2) and SW780 (CRL-2169) were purchased from ATCC.

    Techniques: Staining, Quantitation Assay, Mutagenesis, Amplification, Inhibition, Clonogenic Assay

    Clonogenic growth assay of HT1197 cells treated with FTX-6746, FX-909 or T0070907. Percent cell density relative to DMSO control well shown, data are representative of three independent experiments.

    Journal: bioRxiv

    Article Title: Discovery and characterization of FX-909, a covalent inverse agonist of PPARG rationally designed to impose a powerful repressive bias in PPARG for the treatment of PPARG/RXRA-activated muscle-invasive urothelial cancers

    doi: 10.1101/2025.05.08.652848

    Figure Lengend Snippet: Clonogenic growth assay of HT1197 cells treated with FTX-6746, FX-909 or T0070907. Percent cell density relative to DMSO control well shown, data are representative of three independent experiments.

    Article Snippet: The UC cell lines HT1197 (CRL1473), 5637 (HTB-9), HT1376 (CRL-1472), J82 (HTB- 1), RT4 (HTB-2) and SW780 (CRL-2169) were purchased from ATCC.

    Techniques: Growth Assay, Control

    – (A) UMUC9 xenograft efficacy study shows FX-909 elicits durable tumor regression at all doses, while FTX-6746 elicits tumor regression that is not durable upon drug cessation. (B) HT1197 xenograft efficacy study shows tumor regression for both FX-909 and FTX-6746. (C) PK/PD relationship for FTX-6746 and FX-909. (D) H&E staining of adipose tissue from mice in study shown in (A).

    Journal: bioRxiv

    Article Title: Discovery and characterization of FX-909, a covalent inverse agonist of PPARG rationally designed to impose a powerful repressive bias in PPARG for the treatment of PPARG/RXRA-activated muscle-invasive urothelial cancers

    doi: 10.1101/2025.05.08.652848

    Figure Lengend Snippet: – (A) UMUC9 xenograft efficacy study shows FX-909 elicits durable tumor regression at all doses, while FTX-6746 elicits tumor regression that is not durable upon drug cessation. (B) HT1197 xenograft efficacy study shows tumor regression for both FX-909 and FTX-6746. (C) PK/PD relationship for FTX-6746 and FX-909. (D) H&E staining of adipose tissue from mice in study shown in (A).

    Article Snippet: The UC cell lines HT1197 (CRL1473), 5637 (HTB-9), HT1376 (CRL-1472), J82 (HTB- 1), RT4 (HTB-2) and SW780 (CRL-2169) were purchased from ATCC.

    Techniques: Staining