3,5,7-Substituted Pyrazolo[4,3- d]Pyrimidine Inhibitors of Cyclin-Dependent Kinases and Cyclin K Degraders

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F22%3A00562052" target="_blank" >RIV/61388963:_____/22:00562052 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/61389030:_____/22:00562052 RIV/00216208:11110/22:10445238 RIV/61989592:15310/22:73616092 RIV/00064165:_____/22:10445238

Výsledek na webu

<a href="https://doi.org/10.1021/acs.jmedchem.1c02184" target="_blank" >https://doi.org/10.1021/acs.jmedchem.1c02184</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1021/acs.jmedchem.1c02184" target="_blank" >10.1021/acs.jmedchem.1c02184</a>

Jazyk výsledku

angličtina

Název v původním jazyce

3,5,7-Substituted Pyrazolo[4,3- d]Pyrimidine Inhibitors of Cyclin-Dependent Kinases and Cyclin K Degraders

Popis výsledku v původním jazyce

3,5,7-Trisubstituted pyrazolo[4,3-d]pyrimidines have been identified as potent inhibitors of cyclin-dependent kinases (CDKs), which are established drug targets. Herein, we describe their further structural modifications leading to novel nanomolar inhibitors with strong antiproliferative activity. We determined the crystal structure of fully active CDK2/A2 with 5-(2-amino-1-ethyl)thio-3-cyclobutyl-7-[4-(pyrazol-1-yl)benzyl]amino-1(2)H-pyrazolo[4,3-d]pyrimidine (24) at 1.7 Å resolution, confirming the competitive mode of inhibition. Biochemical and cellular assays in lymphoma cell lines confirmed the expected mechanism of action through dephosphorylation of retinoblastoma protein and RNA polymerase II, leading to induction of apoptosis. Importantly, we also revealed an interesting ability of compound 24 to induce proteasome-dependent degradation of cyclin K both in vitro and in a patient-derived xenograft in vivo. We propose that 24 has a dual mechanism of action, acting as a kinase inhibitor and as a molecular glue inducing an interaction between CDK12 and DDB1 that leads to polyubiquitination of cyclin K and its subsequent degradation.

Název v anglickém jazyce

3,5,7-Substituted Pyrazolo[4,3- d]Pyrimidine Inhibitors of Cyclin-Dependent Kinases and Cyclin K Degraders

Popis výsledku anglicky

3,5,7-Trisubstituted pyrazolo[4,3-d]pyrimidines have been identified as potent inhibitors of cyclin-dependent kinases (CDKs), which are established drug targets. Herein, we describe their further structural modifications leading to novel nanomolar inhibitors with strong antiproliferative activity. We determined the crystal structure of fully active CDK2/A2 with 5-(2-amino-1-ethyl)thio-3-cyclobutyl-7-[4-(pyrazol-1-yl)benzyl]amino-1(2)H-pyrazolo[4,3-d]pyrimidine (24) at 1.7 Å resolution, confirming the competitive mode of inhibition. Biochemical and cellular assays in lymphoma cell lines confirmed the expected mechanism of action through dephosphorylation of retinoblastoma protein and RNA polymerase II, leading to induction of apoptosis. Importantly, we also revealed an interesting ability of compound 24 to induce proteasome-dependent degradation of cyclin K both in vitro and in a patient-derived xenograft in vivo. We propose that 24 has a dual mechanism of action, acting as a kinase inhibitor and as a molecular glue inducing an interaction between CDK12 and DDB1 that leads to polyubiquitination of cyclin K and its subsequent degradation.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10401 - Organic chemistry

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2022

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Journal of Medicinal Chemistry

ISSN

0022-2623

e-ISSN

1520-4804

Svazek periodika

65

Číslo periodika v rámci svazku

13

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

16

Strana od-do

8881-8896

Kód UT WoS článku

000821678600001

EID výsledku v databázi Scopus

2-s2.0-85134433935