TY  - JOUR
AU  - Bulut, Ipek
AU  - Lee, Adam
AU  - Cevatemre, Buse
AU  - Ružić, Dušan
AU  - Belle, Roman
AU  - Kawamura, Akane
AU  - Gul, Sheraz
AU  - Nikolić, Katarina
AU  - Ganesan, A.
AU  - Acilan, Ceyda
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4340
AB  - Defects in epigenetic pathways are key drivers of oncogenic cell proliferation. We developed a LSD1/HDAC6 multitargeting inhibitor (iDual), a hydroxamic acid analogue of the clinical candidate LSD1 inhibitor GSK2879552. iDual inhibits both targets with IC50 values of 540, 110, and 290 nM, respectively, against LSD1, HDAC6, and HDAC8. We compared its activity to structurally similar control probes that act by HDAC or LSD1 inhibition alone, as well as an inactive null compound. iDual inhibited the growth of leukemia cell lines at a higher level than GSK2879552 with micromolar IC50 values. Dual engagement with LSD1 and HDAC6 was supported by dose dependent increases in substrate levels, biomarkers, and cellular thermal shift assay. Both histone methylation and acetylation of tubulin were increased, while acetylated histone levels were only mildly affected, indicating selectivity for HDAC6. Downstream gene expression (CD11b, CD86, p21) was also elevated in response to iDual treatment. Remarkably, iDual synergized with doxorubicin, triggering significant levels of apoptosis with a sublethal concentration of the drug. While mechanistic studies did not reveal changes in DNA repair or drug efflux pathways, the expression of AGPAT9, ALOX5, BTG1, HIPK2, IFI44L, and LRP1, previously implicated in doxorubicin sensitivity, was significantly elevated.
PB  - MDPI
T2  - Cancers
T1  - Dual LSD1 and HDAC6 Inhibition Induces Doxorubicin Sensitivity in Acute Myeloid Leukemia Cells
VL  - 14
IS  - 23
DO  - 10.3390/cancers14236014
ER  - 

@article{
author = "Bulut, Ipek and Lee, Adam and Cevatemre, Buse and Ružić, Dušan and Belle, Roman and Kawamura, Akane and Gul, Sheraz and Nikolić, Katarina and Ganesan, A. and Acilan, Ceyda",
year = "2022",
abstract = "Defects in epigenetic pathways are key drivers of oncogenic cell proliferation. We developed a LSD1/HDAC6 multitargeting inhibitor (iDual), a hydroxamic acid analogue of the clinical candidate LSD1 inhibitor GSK2879552. iDual inhibits both targets with IC50 values of 540, 110, and 290 nM, respectively, against LSD1, HDAC6, and HDAC8. We compared its activity to structurally similar control probes that act by HDAC or LSD1 inhibition alone, as well as an inactive null compound. iDual inhibited the growth of leukemia cell lines at a higher level than GSK2879552 with micromolar IC50 values. Dual engagement with LSD1 and HDAC6 was supported by dose dependent increases in substrate levels, biomarkers, and cellular thermal shift assay. Both histone methylation and acetylation of tubulin were increased, while acetylated histone levels were only mildly affected, indicating selectivity for HDAC6. Downstream gene expression (CD11b, CD86, p21) was also elevated in response to iDual treatment. Remarkably, iDual synergized with doxorubicin, triggering significant levels of apoptosis with a sublethal concentration of the drug. While mechanistic studies did not reveal changes in DNA repair or drug efflux pathways, the expression of AGPAT9, ALOX5, BTG1, HIPK2, IFI44L, and LRP1, previously implicated in doxorubicin sensitivity, was significantly elevated.",
publisher = "MDPI",
journal = "Cancers",
title = "Dual LSD1 and HDAC6 Inhibition Induces Doxorubicin Sensitivity in Acute Myeloid Leukemia Cells",
volume = "14",
number = "23",
doi = "10.3390/cancers14236014"
}

Bulut, I., Lee, A., Cevatemre, B., Ružić, D., Belle, R., Kawamura, A., Gul, S., Nikolić, K., Ganesan, A.,& Acilan, C.. (2022). Dual LSD1 and HDAC6 Inhibition Induces Doxorubicin Sensitivity in Acute Myeloid Leukemia Cells. in Cancers
MDPI., 14(23).
https://doi.org/10.3390/cancers14236014

Bulut I, Lee A, Cevatemre B, Ružić D, Belle R, Kawamura A, Gul S, Nikolić K, Ganesan A, Acilan C. Dual LSD1 and HDAC6 Inhibition Induces Doxorubicin Sensitivity in Acute Myeloid Leukemia Cells. in Cancers. 2022;14(23).
doi:10.3390/cancers14236014 .

Bulut, Ipek, Lee, Adam, Cevatemre, Buse, Ružić, Dušan, Belle, Roman, Kawamura, Akane, Gul, Sheraz, Nikolić, Katarina, Ganesan, A., Acilan, Ceyda, "Dual LSD1 and HDAC6 Inhibition Induces Doxorubicin Sensitivity in Acute Myeloid Leukemia Cells" in Cancers, 14, no. 23 (2022),
https://doi.org/10.3390/cancers14236014 . .

TY  - CONF
AU  - Lee, Adam
AU  - Ganesan, A.
AU  - Bulut, İpek
AU  - Açılan Ayhan, Ceyda
AU  - Ružić, Dušan
AU  - Nikolić, Katarina
AU  - Gul, Sheraz
PY  - 2020
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4872
AB  - Epigenetic therapy is now a clinical reality with eight approved drugs that target
DNA methyltransferases, histone deacetylases (HDACs) and lysine
methyltransferases. A further recent development is the concept of epigenetic
multitargeting through the rational design of novel agents that combine the
inhibition of an epigenetic pathway with a second non-epigenetic target and five
such compounds have advanced to clinical development.
We are investigating the even newer concept of „epi-epi‟ drugs that inhibit two
separate epigenetic pathways. Such dual targeting agents have the potential to
achieve higher efficacy against proliferating cancer cells while reducing tunor
resistance. In this presentation, we report a selective dual histone deacetylase and
demethylase inhibitor with an IC50
LSD1 respectively. The compound was biologically profiled together with control
compounds that were either single inhibitors or inactive against either enzyme. The
dua inhibitor was active against a panel of leukemia cell lines at a micromolar level
and induced apoptosis. Target engagement asays such as CETSA were employed
to confirm the inhibition of HDAC6 and LSD1 in cells. Further experiments were
carried out to identify synergistic effects with clinically approved agents and
promising results were observed with doxorubicin.
PB  - COST Action 17104 (STRATAGEM)
C3  - COST Action 17104 (STRATAGEM) WG2 Meeting and International Online Symposium on “Synthesis and nanodelivery strategies for new therapeutic tools against Multidrug Resistant Tumours”, 15th December 2020, Abstract Boook
T1  - Multitargeting epi-epi drugs for multidrug reistance
SP  - 12
EP  - 12
UR  - https://hdl.handle.net/21.15107/rcub_farfar_4872
ER  - 

@conference{
author = "Lee, Adam and Ganesan, A. and Bulut, İpek and Açılan Ayhan, Ceyda and Ružić, Dušan and Nikolić, Katarina and Gul, Sheraz",
year = "2020",
abstract = "Epigenetic therapy is now a clinical reality with eight approved drugs that target
DNA methyltransferases, histone deacetylases (HDACs) and lysine
methyltransferases. A further recent development is the concept of epigenetic
multitargeting through the rational design of novel agents that combine the
inhibition of an epigenetic pathway with a second non-epigenetic target and five
such compounds have advanced to clinical development.
We are investigating the even newer concept of „epi-epi‟ drugs that inhibit two
separate epigenetic pathways. Such dual targeting agents have the potential to
achieve higher efficacy against proliferating cancer cells while reducing tunor
resistance. In this presentation, we report a selective dual histone deacetylase and
demethylase inhibitor with an IC50
LSD1 respectively. The compound was biologically profiled together with control
compounds that were either single inhibitors or inactive against either enzyme. The
dua inhibitor was active against a panel of leukemia cell lines at a micromolar level
and induced apoptosis. Target engagement asays such as CETSA were employed
to confirm the inhibition of HDAC6 and LSD1 in cells. Further experiments were
carried out to identify synergistic effects with clinically approved agents and
promising results were observed with doxorubicin.",
publisher = "COST Action 17104 (STRATAGEM)",
journal = "COST Action 17104 (STRATAGEM) WG2 Meeting and International Online Symposium on “Synthesis and nanodelivery strategies for new therapeutic tools against Multidrug Resistant Tumours”, 15th December 2020, Abstract Boook",
title = "Multitargeting epi-epi drugs for multidrug reistance",
pages = "12-12",
url = "https://hdl.handle.net/21.15107/rcub_farfar_4872"
}

Lee, A., Ganesan, A., Bulut, İ., Açılan Ayhan, C., Ružić, D., Nikolić, K.,& Gul, S.. (2020). Multitargeting epi-epi drugs for multidrug reistance. in COST Action 17104 (STRATAGEM) WG2 Meeting and International Online Symposium on “Synthesis and nanodelivery strategies for new therapeutic tools against Multidrug Resistant Tumours”, 15th December 2020, Abstract Boook
COST Action 17104 (STRATAGEM)., 12-12.
https://hdl.handle.net/21.15107/rcub_farfar_4872

Lee A, Ganesan A, Bulut İ, Açılan Ayhan C, Ružić D, Nikolić K, Gul S. Multitargeting epi-epi drugs for multidrug reistance. in COST Action 17104 (STRATAGEM) WG2 Meeting and International Online Symposium on “Synthesis and nanodelivery strategies for new therapeutic tools against Multidrug Resistant Tumours”, 15th December 2020, Abstract Boook. 2020;:12-12.
https://hdl.handle.net/21.15107/rcub_farfar_4872 .

Lee, Adam, Ganesan, A., Bulut, İpek, Açılan Ayhan, Ceyda, Ružić, Dušan, Nikolić, Katarina, Gul, Sheraz, "Multitargeting epi-epi drugs for multidrug reistance" in COST Action 17104 (STRATAGEM) WG2 Meeting and International Online Symposium on “Synthesis and nanodelivery strategies for new therapeutic tools against Multidrug Resistant Tumours”, 15th December 2020, Abstract Boook (2020):12-12,
https://hdl.handle.net/21.15107/rcub_farfar_4872 .