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.

Basic information

Original name

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

Authors

KHIRSARIYA, PrashantKumar (356 India, belonging to the institution), Patrik POSPÍŠIL (203 Czech Republic, belonging to the institution), Lukáš MAIER (203 Czech Republic, belonging to the institution), Miroslav BOUDNÝ (203 Czech Republic, belonging to the institution), Martin BABÁŠ (203 Czech Republic, belonging to the institution), Ondřej KROUTIL (203 Czech Republic, belonging to the institution), Marek MRÁZ (203 Czech Republic, belonging to the institution), Robert VÁCHA (203 Czech Republic, belonging to the institution) and Kamil PARUCH (203 Czech Republic, guarantor, belonging to the institution)

Edition

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

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

30104 Pharmacology and pharmacy

Country of publisher

United States of America

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Impact factor

Impact factor: 7.300

RIV identification code

RIV/00216224:14310/22:00125850

Organization unit

Faculty of Science

DOI

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

UT WoS

000792282200030

Keywords in English

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

Abstract

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.

Links

EF16_025/0007381, research and development project

Name: Preklinická progrese nových organických sloučenin s cílenou biologickou aktivitou

GA20-20152S, research and development project

Name: Proteinová přitažlivost a selektivita pro buněčné membrány

Investor: Czech Science Foundation

LM2015085, research and development project

Name: CERIT Scientific Cloud (Acronym: CERIT-SC)

Investor: Ministry of Education, Youth and Sports of the CR, CERIT Scientific Cloud

LM2018130, research and development project

Name: Národní infrastruktura chemické biologie (Acronym: CZ-OPENSCREEN)

Investor: Ministry of Education, Youth and Sports of the CR

90042, large research infrastructures

Name: CESNET II

Citovat

KHIRSARIYA, PrashantKumar, Patrik POSPÍŠIL, Lukáš MAIER, Miroslav BOUDNÝ, Martin BABÁŠ, Ondřej KROUTIL, Marek MRÁZ, Robert VÁCHA and 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, vol. 65, No 7, p. 5701-5723. ISSN 0022-2623. Available from: 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 and 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, vol.~65, No~7, p.~5701-5723. ISSN~0022-2623. Available from: https://dx.doi.org/10.1021/acs.jmedchem.1c02228.

Detailed Information on Publication Record