TY  - JOUR
AU  - Koravović, Mladen
AU  - Mayasundari, Anand
AU  - Tasić, Gordana
AU  - Keramatnia, F.
AU  - Stachowski, Timothy R.
AU  - Cui, Huarui
AU  - Chai, Sergio C.
AU  - Jonchere, Barbara
AU  - Yang, Lei
AU  - Li, Yong
AU  - Fu, Xiang
AU  - Hiltenbrand, Ryan
AU  - Paul, Leena
AU  - Mishra, Vibhor
AU  - Klco, Jeffery M.
AU  - Roussel, Martine F.
AU  - Pomerantz, William CK.
AU  - Fischer, Marcus
AU  - Ranković, Zoran
AU  - Savić, Vladimir
PY  - 2023
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4513
AB  - An X-ray structure of a CLICK chemistry-based BET PROTAC bound to BRD2(BD2) inspired synthesis of JQ1 derived heterocyclic amides. This effort led to the discovery of potent BET inhibitors displaying overall improved profiles when compared to JQ1 and birabresib. A thiadiazole derived 1q (SJ1461) displayed excellent BRD4 and BRD2 affinity and high potency in the panel of acute leukaemia and medulloblastoma cell lines. A structure of 1q co-crystalised with BRD4-BD1 revealed polar interactions with the AZ/BC loops, in particular with Asn140 and Tyr139, rationalising the observed affinity improvements. In addition, exploration of pharmacokinetic properties of this class of compounds suggest that the heterocyclic amide moiety improves drug-like features. Our study led to the discovery of potent and orally bioavailable BET inhibitor 1q (SJ1461) as a promising candidate for further development.
PB  - Elsevier
T2  - European Journal of Medicinal Chemistry
T1  - From PROTAC to inhibitor: Structure-guided discovery of potent and orally bioavailable BET inhibitors
VL  - 251
DO  - 10.1016/j.ejmech.2023.115246
ER  - 

@article{
author = "Koravović, Mladen and Mayasundari, Anand and Tasić, Gordana and Keramatnia, F. and Stachowski, Timothy R. and Cui, Huarui and Chai, Sergio C. and Jonchere, Barbara and Yang, Lei and Li, Yong and Fu, Xiang and Hiltenbrand, Ryan and Paul, Leena and Mishra, Vibhor and Klco, Jeffery M. and Roussel, Martine F. and Pomerantz, William CK. and Fischer, Marcus and Ranković, Zoran and Savić, Vladimir",
year = "2023",
abstract = "An X-ray structure of a CLICK chemistry-based BET PROTAC bound to BRD2(BD2) inspired synthesis of JQ1 derived heterocyclic amides. This effort led to the discovery of potent BET inhibitors displaying overall improved profiles when compared to JQ1 and birabresib. A thiadiazole derived 1q (SJ1461) displayed excellent BRD4 and BRD2 affinity and high potency in the panel of acute leukaemia and medulloblastoma cell lines. A structure of 1q co-crystalised with BRD4-BD1 revealed polar interactions with the AZ/BC loops, in particular with Asn140 and Tyr139, rationalising the observed affinity improvements. In addition, exploration of pharmacokinetic properties of this class of compounds suggest that the heterocyclic amide moiety improves drug-like features. Our study led to the discovery of potent and orally bioavailable BET inhibitor 1q (SJ1461) as a promising candidate for further development.",
publisher = "Elsevier",
journal = "European Journal of Medicinal Chemistry",
title = "From PROTAC to inhibitor: Structure-guided discovery of potent and orally bioavailable BET inhibitors",
volume = "251",
doi = "10.1016/j.ejmech.2023.115246"
}

Koravović, M., Mayasundari, A., Tasić, G., Keramatnia, F., Stachowski, T. R., Cui, H., Chai, S. C., Jonchere, B., Yang, L., Li, Y., Fu, X., Hiltenbrand, R., Paul, L., Mishra, V., Klco, J. M., Roussel, M. F., Pomerantz, W. CK., Fischer, M., Ranković, Z.,& Savić, V.. (2023). From PROTAC to inhibitor: Structure-guided discovery of potent and orally bioavailable BET inhibitors. in European Journal of Medicinal Chemistry
Elsevier., 251.
https://doi.org/10.1016/j.ejmech.2023.115246

Koravović M, Mayasundari A, Tasić G, Keramatnia F, Stachowski TR, Cui H, Chai SC, Jonchere B, Yang L, Li Y, Fu X, Hiltenbrand R, Paul L, Mishra V, Klco JM, Roussel MF, Pomerantz WC, Fischer M, Ranković Z, Savić V. From PROTAC to inhibitor: Structure-guided discovery of potent and orally bioavailable BET inhibitors. in European Journal of Medicinal Chemistry. 2023;251.
doi:10.1016/j.ejmech.2023.115246 .

Koravović, Mladen, Mayasundari, Anand, Tasić, Gordana, Keramatnia, F., Stachowski, Timothy R., Cui, Huarui, Chai, Sergio C., Jonchere, Barbara, Yang, Lei, Li, Yong, Fu, Xiang, Hiltenbrand, Ryan, Paul, Leena, Mishra, Vibhor, Klco, Jeffery M., Roussel, Martine F., Pomerantz, William CK., Fischer, Marcus, Ranković, Zoran, Savić, Vladimir, "From PROTAC to inhibitor: Structure-guided discovery of potent and orally bioavailable BET inhibitors" in European Journal of Medicinal Chemistry, 251 (2023),
https://doi.org/10.1016/j.ejmech.2023.115246 . .

TY  - CONF
AU  - Koravović, Mladen
AU  - Tasić, Gordana
AU  - Mayasundari, Anand
AU  - Keramatnia, Fatemeh
AU  - Fischer, Marcus
AU  - Ranković, Zoran
AU  - Savić, Vladimir
PY  - 2021
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/5385
AB  - BET proteini su epigenetski biološki targeti koji regulišu ekspresiju gena i uključeni su u
patogenezu kancera. Jedan od inhibitora ovih proteina koji je opisan u literaturi je derivat
tienotriazolodiazepina (+)-JQ1. Cilj ovog rada bio je dalje unapređenje osobina (+)-JQ1
derivatizacijom estarske grupe (Shema 1). U toku ovog istraživanja sintetisano je više amidnih
analoga od koji je jedan pokazao 16 puta veću aktivnost u TR-FRET testu u odnosu na (+)-JQ1.
AB  - BET proteins are epigenetic biological targets that regulate gene expression and are involved in
cancer pathogenesis. One of BET inhibitors described in the literature is thienotriazolodiazepine
derivative (+)-JQ1. The aim of this research was to further improve the properties of (+)-JQ1 by
ester group derivatization (Scheme 1). During the research several amide analogs were synthesized
and one of them had 16 fold greater activity in TR-FRET assay compared to (+)-JQ1.
PB  - Srpsko hemijsko društvo, Beograd
C3  - 57. Savetovanje Srpskog hemijskog društva.  Kratki izvodi, Juni 18 i 19, 2021, Kragujevac, Srbija
T1  - Sinteza i biološko profilisanje (+)-JQ1 amida kao BET inhibitora
T1  - Synthesis and biological profiling of (+)-JQ1 amides as BET inhibitors
SP  - 86
EP  - 86
UR  - https://hdl.handle.net/21.15107/rcub_farfar_5385
ER  - 

@conference{
author = "Koravović, Mladen and Tasić, Gordana and Mayasundari, Anand and Keramatnia, Fatemeh and Fischer, Marcus and Ranković, Zoran and Savić, Vladimir",
year = "2021",
abstract = "BET proteini su epigenetski biološki targeti koji regulišu ekspresiju gena i uključeni su u
patogenezu kancera. Jedan od inhibitora ovih proteina koji je opisan u literaturi je derivat
tienotriazolodiazepina (+)-JQ1. Cilj ovog rada bio je dalje unapređenje osobina (+)-JQ1
derivatizacijom estarske grupe (Shema 1). U toku ovog istraživanja sintetisano je više amidnih
analoga od koji je jedan pokazao 16 puta veću aktivnost u TR-FRET testu u odnosu na (+)-JQ1., BET proteins are epigenetic biological targets that regulate gene expression and are involved in
cancer pathogenesis. One of BET inhibitors described in the literature is thienotriazolodiazepine
derivative (+)-JQ1. The aim of this research was to further improve the properties of (+)-JQ1 by
ester group derivatization (Scheme 1). During the research several amide analogs were synthesized
and one of them had 16 fold greater activity in TR-FRET assay compared to (+)-JQ1.",
publisher = "Srpsko hemijsko društvo, Beograd",
journal = "57. Savetovanje Srpskog hemijskog društva.  Kratki izvodi, Juni 18 i 19, 2021, Kragujevac, Srbija",
title = "Sinteza i biološko profilisanje (+)-JQ1 amida kao BET inhibitora, Synthesis and biological profiling of (+)-JQ1 amides as BET inhibitors",
pages = "86-86",
url = "https://hdl.handle.net/21.15107/rcub_farfar_5385"
}

Koravović, M., Tasić, G., Mayasundari, A., Keramatnia, F., Fischer, M., Ranković, Z.,& Savić, V.. (2021). Sinteza i biološko profilisanje (+)-JQ1 amida kao BET inhibitora. in 57. Savetovanje Srpskog hemijskog društva.  Kratki izvodi, Juni 18 i 19, 2021, Kragujevac, Srbija
Srpsko hemijsko društvo, Beograd., 86-86.
https://hdl.handle.net/21.15107/rcub_farfar_5385

Koravović M, Tasić G, Mayasundari A, Keramatnia F, Fischer M, Ranković Z, Savić V. Sinteza i biološko profilisanje (+)-JQ1 amida kao BET inhibitora. in 57. Savetovanje Srpskog hemijskog društva.  Kratki izvodi, Juni 18 i 19, 2021, Kragujevac, Srbija. 2021;:86-86.
https://hdl.handle.net/21.15107/rcub_farfar_5385 .

Koravović, Mladen, Tasić, Gordana, Mayasundari, Anand, Keramatnia, Fatemeh, Fischer, Marcus, Ranković, Zoran, Savić, Vladimir, "Sinteza i biološko profilisanje (+)-JQ1 amida kao BET inhibitora" in 57. Savetovanje Srpskog hemijskog društva.  Kratki izvodi, Juni 18 i 19, 2021, Kragujevac, Srbija (2021):86-86,
https://hdl.handle.net/21.15107/rcub_farfar_5385 .

TY  - CONF
AU  - Koravović, Mladen
AU  - Tasić, Gordana
AU  - Mayasundari, Anand
AU  - Keramatnia, Fatemeh
AU  - Stachowski, Tim
AU  - Fischer, Marcus
AU  - Ranković, Zoran
AU  - Savić, Vladimir
PY  - 2021
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4010
AB  - Histoni su bazni proteini koji interakcijom preko baznih ostataka lizina sa fosfatnim grupama DNK omogućavaju upakivanje DNK molekula i formiranje nukleozoma i hromatina. Jedan od glavnih mehanizama aktivacije hromatina uključuje prepoznavanje Nε-acetilovanih L-lizina na N-terminalnim krajevima histona od strane proteina BET (eng. Bromodomain and Extra-Terminal domain) familije. Opisano je četiri BET proteina označenih kao BRD2, BRD3, BRD4 i BRDT. Strukturu ovih proteina čine dva bromodomena (BD1 i BD2), kao i ekstraterminalni (ET) i C-terminalni domen (CTD). Bromodomeni su, zapravo, hidrofobni regioni sačinjeni od četiri α-heliksa (Z, A, B, C) i dve petlje (ZA i BC) koji prepoznaju Nε-acetilovane L-lizine u histonima i drugim proteinima. Članovi BET familije proteina su epigenetski čitači koji regulišu ekspresiju gena. Uključeni su u brojne fiziološke i patofiziološke procese, pri čemu je markantna njihova uloga u razvoju kancera. Različite klase BET inhibitora su opisane u literaturi. Među prvima je prijavljen (+)-JQ1 molekul koji, farmakološki posmatrano, predstavlja kompetitivni inhibitor BET proteina i danas se veoma često koristi kao alat u proučavanju biologije BET proteina. Međutim, estarska funkcionalna grupa koja uslovljava njegov kratak poluživot je onemogućila sprovođenje širih kliničkih ispitivanja ovog molekula. Suprotno tome, amidni analog (+)-JQ1 molekula, birabresib, ušao je u kliničke studije i pokazao povoljan bezbednosni profil i aktivnost u NMC (eng. NUT Midline Carcinoma). Interesovanje za BET proteine je pokrenulo ovu studiju o amidnim derivatima (+)-JQ1 koji bi imali unapređene fizičko-hemijske i farmakološke profile.
C3  - Konkurs za izbor najboljih naučno-istraživačkih radova studenata doktorskih akademskih studija
T1  - Nove protein-ligand interakcije amidnih BET inhibitora otkrivene derivatizacijom (+)-JQ1 molekula
UR  - https://hdl.handle.net/21.15107/rcub_farfar_4010
ER  - 

@conference{
author = "Koravović, Mladen and Tasić, Gordana and Mayasundari, Anand and Keramatnia, Fatemeh and Stachowski, Tim and Fischer, Marcus and Ranković, Zoran and Savić, Vladimir",
year = "2021",
abstract = "Histoni su bazni proteini koji interakcijom preko baznih ostataka lizina sa fosfatnim grupama DNK omogućavaju upakivanje DNK molekula i formiranje nukleozoma i hromatina. Jedan od glavnih mehanizama aktivacije hromatina uključuje prepoznavanje Nε-acetilovanih L-lizina na N-terminalnim krajevima histona od strane proteina BET (eng. Bromodomain and Extra-Terminal domain) familije. Opisano je četiri BET proteina označenih kao BRD2, BRD3, BRD4 i BRDT. Strukturu ovih proteina čine dva bromodomena (BD1 i BD2), kao i ekstraterminalni (ET) i C-terminalni domen (CTD). Bromodomeni su, zapravo, hidrofobni regioni sačinjeni od četiri α-heliksa (Z, A, B, C) i dve petlje (ZA i BC) koji prepoznaju Nε-acetilovane L-lizine u histonima i drugim proteinima. Članovi BET familije proteina su epigenetski čitači koji regulišu ekspresiju gena. Uključeni su u brojne fiziološke i patofiziološke procese, pri čemu je markantna njihova uloga u razvoju kancera. Različite klase BET inhibitora su opisane u literaturi. Među prvima je prijavljen (+)-JQ1 molekul koji, farmakološki posmatrano, predstavlja kompetitivni inhibitor BET proteina i danas se veoma često koristi kao alat u proučavanju biologije BET proteina. Međutim, estarska funkcionalna grupa koja uslovljava njegov kratak poluživot je onemogućila sprovođenje širih kliničkih ispitivanja ovog molekula. Suprotno tome, amidni analog (+)-JQ1 molekula, birabresib, ušao je u kliničke studije i pokazao povoljan bezbednosni profil i aktivnost u NMC (eng. NUT Midline Carcinoma). Interesovanje za BET proteine je pokrenulo ovu studiju o amidnim derivatima (+)-JQ1 koji bi imali unapređene fizičko-hemijske i farmakološke profile.",
journal = "Konkurs za izbor najboljih naučno-istraživačkih radova studenata doktorskih akademskih studija",
title = "Nove protein-ligand interakcije amidnih BET inhibitora otkrivene derivatizacijom (+)-JQ1 molekula",
url = "https://hdl.handle.net/21.15107/rcub_farfar_4010"
}

Koravović, M., Tasić, G., Mayasundari, A., Keramatnia, F., Stachowski, T., Fischer, M., Ranković, Z.,& Savić, V.. (2021). Nove protein-ligand interakcije amidnih BET inhibitora otkrivene derivatizacijom (+)-JQ1 molekula. in Konkurs za izbor najboljih naučno-istraživačkih radova studenata doktorskih akademskih studija.
https://hdl.handle.net/21.15107/rcub_farfar_4010

Koravović M, Tasić G, Mayasundari A, Keramatnia F, Stachowski T, Fischer M, Ranković Z, Savić V. Nove protein-ligand interakcije amidnih BET inhibitora otkrivene derivatizacijom (+)-JQ1 molekula. in Konkurs za izbor najboljih naučno-istraživačkih radova studenata doktorskih akademskih studija. 2021;.
https://hdl.handle.net/21.15107/rcub_farfar_4010 .

Koravović, Mladen, Tasić, Gordana, Mayasundari, Anand, Keramatnia, Fatemeh, Stachowski, Tim, Fischer, Marcus, Ranković, Zoran, Savić, Vladimir, "Nove protein-ligand interakcije amidnih BET inhibitora otkrivene derivatizacijom (+)-JQ1 molekula" in Konkurs za izbor najboljih naučno-istraživačkih radova studenata doktorskih akademskih studija (2021),
https://hdl.handle.net/21.15107/rcub_farfar_4010 .

TY  - CONF
AU  - Koravović, Mladen
AU  - Tasić, Gordana
AU  - Mayasundari, Anand
AU  - Min, Jaeki
AU  - Keramatnia, Fatemeh
AU  - Fischer, Marcus
AU  - Ranković, Zoran
AU  - Savić, Vladimir
PY  - 2019
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4011
AB  - Hsp90 (Heat Shock Protein 90) is a chaperon protein which plays role in protein folding and maintaining protein structures. It is overexpressed in cancer and stabilizes many oncoproteins and as such represents a good target for developing anticancer drugs. The majority of approved drugs today operate by occupancy-driven pharmacology. The PROTAC approach as a strategy in creating novel drugs utilizes event-driven pharmacology in which target proteins are degraded. In recent years it emerged as very attractive and conceptually novel approach in drug discovery and development. PROTACs are molecules with two warheads connected with a linker with general structure: Ligand(protein of interest)-Linker-Ligand(E3 ligase). One warhead binds the protein of interest (POI) and the other one binds E3 ligase, while the linker brings these two parts in close proximity permitting ubiquitination and subsequent degradation of the protein. Two classes of compounds were studied: pyrrolopyrimidine and thienopyrimidine derivatives. Both classes of compounds were reported in the literature and their structure is modified in order to investigate whether linker introduction deteriorate binding of those molecules to Hsp90.
C3  - Konkurs za izbor najboljih naučno-istraživačkih radova studenata doktorskih akademskih studija
T1  - Design and synthesis of Hsp90 PROTAC degraders as potential anticancer agents
UR  - https://hdl.handle.net/21.15107/rcub_farfar_4011
ER  - 

@conference{
author = "Koravović, Mladen and Tasić, Gordana and Mayasundari, Anand and Min, Jaeki and Keramatnia, Fatemeh and Fischer, Marcus and Ranković, Zoran and Savić, Vladimir",
year = "2019",
abstract = "Hsp90 (Heat Shock Protein 90) is a chaperon protein which plays role in protein folding and maintaining protein structures. It is overexpressed in cancer and stabilizes many oncoproteins and as such represents a good target for developing anticancer drugs. The majority of approved drugs today operate by occupancy-driven pharmacology. The PROTAC approach as a strategy in creating novel drugs utilizes event-driven pharmacology in which target proteins are degraded. In recent years it emerged as very attractive and conceptually novel approach in drug discovery and development. PROTACs are molecules with two warheads connected with a linker with general structure: Ligand(protein of interest)-Linker-Ligand(E3 ligase). One warhead binds the protein of interest (POI) and the other one binds E3 ligase, while the linker brings these two parts in close proximity permitting ubiquitination and subsequent degradation of the protein. Two classes of compounds were studied: pyrrolopyrimidine and thienopyrimidine derivatives. Both classes of compounds were reported in the literature and their structure is modified in order to investigate whether linker introduction deteriorate binding of those molecules to Hsp90.",
journal = "Konkurs za izbor najboljih naučno-istraživačkih radova studenata doktorskih akademskih studija",
title = "Design and synthesis of Hsp90 PROTAC degraders as potential anticancer agents",
url = "https://hdl.handle.net/21.15107/rcub_farfar_4011"
}

Koravović, M., Tasić, G., Mayasundari, A., Min, J., Keramatnia, F., Fischer, M., Ranković, Z.,& Savić, V.. (2019). Design and synthesis of Hsp90 PROTAC degraders as potential anticancer agents. in Konkurs za izbor najboljih naučno-istraživačkih radova studenata doktorskih akademskih studija.
https://hdl.handle.net/21.15107/rcub_farfar_4011

Koravović M, Tasić G, Mayasundari A, Min J, Keramatnia F, Fischer M, Ranković Z, Savić V. Design and synthesis of Hsp90 PROTAC degraders as potential anticancer agents. in Konkurs za izbor najboljih naučno-istraživačkih radova studenata doktorskih akademskih studija. 2019;.
https://hdl.handle.net/21.15107/rcub_farfar_4011 .

Koravović, Mladen, Tasić, Gordana, Mayasundari, Anand, Min, Jaeki, Keramatnia, Fatemeh, Fischer, Marcus, Ranković, Zoran, Savić, Vladimir, "Design and synthesis of Hsp90 PROTAC degraders as potential anticancer agents" in Konkurs za izbor najboljih naučno-istraživačkih radova studenata doktorskih akademskih studija (2019),
https://hdl.handle.net/21.15107/rcub_farfar_4011 .