Synthesis and Profiling of Highly Selective Inhibitors of
Methyltransferase DOT1L Based on Carbocyclic C-Nucleosides

J 2022

Synthesis and Profiling of Highly Selective Inhibitors of Methyltransferase DOT1L Based on Carbocyclic C-Nucleosides

KHIRSARIYA, PrashantKumar, Patrik POSPÍŠIL, Lukáš MAIER, Miroslav BOUDNÝ, Martin BABÁŠ et. al.

Základní údaje

Originální název

Synthesis and Profiling of Highly Selective Inhibitors of Methyltransferase DOT1L Based on Carbocyclic C-Nucleosides

Autoři

KHIRSARIYA, PrashantKumar (356 Indie, domácí), Patrik POSPÍŠIL (203 Česká republika, domácí), Lukáš MAIER (203 Česká republika, domácí), Miroslav BOUDNÝ (203 Česká republika, domácí), Martin BABÁŠ (203 Česká republika, domácí), Ondřej KROUTIL (203 Česká republika, domácí), Marek MRÁZ (203 Česká republika, domácí), Robert VÁCHA (203 Česká republika, domácí) a Kamil PARUCH (203 Česká republika, garant, domácí)

Vydání

Journal of Medicinal Chemistry, Washington, American Chemical Society, 2022, 0022-2623

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

30104 Pharmacology and pharmacy

Stát vydavatele

Spojené státy

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Impakt faktor

Impact factor: 7.300

Kód RIV

RIV/00216224:14310/22:00125850

Organizační jednotka

Přírodovědecká fakulta

DOI

http://dx.doi.org/10.1021/acs.jmedchem.1c02228

UT WoS

000792282200030

Klíčová slova anglicky

Molecular structure; Genetics; Ethanol; Inhibitors; Assays; leukemia; DOT1L

Štítky

14110212, podil, rivok

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 27. 5. 2022 16:00, Mgr. Marie Šípková, DiS.

Anotace

V originále

Histone methyltransferase DOT1L is an attractive therapeutic target for the treatment of hematological malignancies. Here, we report the design, synthesis, and profiling of new DOT1L inhibitors based on nonroutine carbocyclic C-nucleoside scaffolds. The experimentally observed SAR was found to be nontrivial as seemingly minor changes of individual substituents resulted in significant changes in the affinity to DOT1L. Molecular modeling suggested that these trends could be related to significant conformational changes of the protein upon interaction with the inhibitors. The compounds 22 and (−)-53 (MU1656), carbocyclic C-nucleoside analogues of the natural nucleoside derivative EPZ004777, and the clinical candidate EPZ5676 (pinometostat) potently and selectively inhibit DOT1L in vitro as well as in the cell. The most potent compound MU1656 was found to be more metabolically stable and significantly less toxic in vivo than pinometostat itself.

Návaznosti

EF16_025/0007381, projekt VaV

Název: Preklinická progrese nových organických sloučenin s cílenou biologickou aktivitou

GA20-20152S, projekt VaV

Název: Proteinová přitažlivost a selektivita pro buněčné membrány

Investor: Grantová agentura ČR, Protein Affinity and Selectivity to Cellular Membranes

LM2015085, projekt VaV

Název: CERIT Scientific Cloud (Akronym: CERIT-SC)

Investor: Ministerstvo školství, mládeže a tělovýchovy ČR, CERIT Scientific Cloud

LM2018130, projekt VaV

Název: Národní infrastruktura chemické biologie (Akronym: CZ-OPENSCREEN)

Investor: Ministerstvo školství, mládeže a tělovýchovy ČR, CZ-OPENSCREEN: National Infrastructure for Chemical Biology

90042, velká výzkumná infrastruktura

Název: CESNET II

Citovat

KHIRSARIYA, PrashantKumar, Patrik POSPÍŠIL, Lukáš MAIER, Miroslav BOUDNÝ, Martin BABÁŠ, Ondřej KROUTIL, Marek MRÁZ, Robert VÁCHA a Kamil PARUCH. Synthesis and Profiling of Highly Selective Inhibitors of Methyltransferase DOT1L Based on Carbocyclic C-Nucleosides. Journal of Medicinal Chemistry. Washington: American Chemical Society, 2022, roč. 65, č. 7, s. 5701-5723. ISSN 0022-2623. Dostupné z: https://dx.doi.org/10.1021/acs.jmedchem.1c02228.

@article{1854512,
   author = {Khirsariya, PrashantKumar and Pospíšil, Patrik and Maier, Lukáš and Boudný, Miroslav and Babáš, Martin and Kroutil, Ondřej and Mráz, Marek and Vácha, Robert and Paruch, Kamil},
   article_location = {Washington},
   article_number = {7},
   doi = {http://dx.doi.org/10.1021/acs.jmedchem.1c02228},
   keywords = {Molecular structure; Genetics; Ethanol; Inhibitors; Assays; leukemia; DOT1L},
   language = {eng},
   issn = {0022-2623},
   journal = {Journal of Medicinal Chemistry},
   title = {Synthesis and Profiling of Highly Selective Inhibitors of Methyltransferase DOT1L Based on Carbocyclic C-Nucleosides},
   url = {https://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.1c02228},
   volume = {65},
   year = {2022}
}

TY  - JOUR
ID  - 1854512
AU  - Khirsariya, PrashantKumar - Pospíšil, Patrik - Maier, Lukáš - Boudný, Miroslav - Babáš, Martin - Kroutil, Ondřej - Mráz, Marek - Vácha, Robert - Paruch, Kamil
PY  - 2022
TI  - Synthesis and Profiling of Highly Selective Inhibitors of Methyltransferase DOT1L Based on Carbocyclic C-Nucleosides
JF  - Journal of Medicinal Chemistry
VL  - 65
IS  - 7
SP  - 5701-5723
EP  - 5701-5723
PB  - American Chemical Society
SN  - 00222623
KW  - Molecular structure
KW  - Genetics
KW  - Ethanol
KW  - Inhibitors
KW  - Assays
KW  - leukemia
KW  - DOT1L
UR  - https://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.1c02228
N2  - Histone methyltransferase DOT1L is an attractive therapeutic target for the treatment of hematological malignancies. Here, we report the design, synthesis, and profiling of new DOT1L inhibitors based on nonroutine carbocyclic C-nucleoside scaffolds. The experimentally observed SAR was found to be nontrivial as seemingly minor changes of individual substituents resulted in significant changes in the affinity to DOT1L. Molecular modeling suggested that these trends could be related to significant conformational changes of the protein upon interaction with the inhibitors. The compounds 22 and (−)-53 (MU1656), carbocyclic C-nucleoside analogues of the natural nucleoside derivative EPZ004777, and the clinical candidate EPZ5676 (pinometostat) potently and selectively inhibit DOT1L in vitro as well as in the cell. The most potent compound MU1656 was found to be more metabolically stable and significantly less toxic in vivo than pinometostat itself.
ER  -

KHIRSARIYA, PrashantKumar, Patrik POSPÍŠIL, Lukáš MAIER, Miroslav BOUDNÝ, Martin BABÁŠ, Ondřej KROUTIL, Marek MRÁZ, Robert VÁCHA a Kamil PARUCH. Synthesis and Profiling of Highly Selective Inhibitors of Methyltransferase DOT1L Based on Carbocyclic C-Nucleosides. \textit{Journal of Medicinal Chemistry}. Washington: American Chemical Society, 2022, roč.~65, č.~7, s.~5701-5723. ISSN~0022-2623. Dostupné z: https://dx.doi.org/10.1021/acs.jmedchem.1c02228.

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