Design, Synthesis, and Structure-Activity Relationship of Novel Pyridazinone-Based PARP7/HDACs Dual Inhibitors for Elucidating the Relationship between Antitumor Immunity and HDACs Inhibition
Histone deacetylases (HDACs) inhibitors such as vorinostat (SAHA) has been used to treat hematologic malignancies (rather than solid tumors) and have been found to suppress the JAK/STAT, a critical signal pathway for antitumor immunity, while PARP7 inhibitor RBN-2397 could activate the type I interferons (IFN-I) pathway, facilitating downstream effects such as STAT1 phosphorylation and immune activation. To elucidate whether simultaneous inhibition of these two targets could interfere with these two signal pathways, a series of pyridazinone-based PARP7/HDACs dual inhibitors have been designed, synthesized, and evaluated in vitro and in vivo experiments. Compound 9l was identified as a potent and balanced dual inhibitor for the first time, exhibiting excellent antitumor capabilities both in vitro and in vivo. This suggests that 9l can be used as a valuable tool molecule for investigating the relationship between anticancer immunity and HDAC inhibition.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:67 |
|---|---|
| Enthalten in: |
Journal of medicinal chemistry - 67(2024), 6 vom: 28. März, Seite 4950-4976 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Duan, Ji-Long [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
58IFB293JI |
|---|
| Anmerkungen: |
Date Completed 29.03.2024 Date Revised 29.03.2024 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1021/acs.jmedchem.4c00090 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM369463560 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM369463560 | ||
| 003 | DE-627 | ||
| 005 | 20240330001159.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 240308s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1021/acs.jmedchem.4c00090 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1355.xml |
| 035 | |a (DE-627)NLM369463560 | ||
| 035 | |a (NLM)38456618 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Duan, Ji-Long |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Design, Synthesis, and Structure-Activity Relationship of Novel Pyridazinone-Based PARP7/HDACs Dual Inhibitors for Elucidating the Relationship between Antitumor Immunity and HDACs Inhibition |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 29.03.2024 | ||
| 500 | |a Date Revised 29.03.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Histone deacetylases (HDACs) inhibitors such as vorinostat (SAHA) has been used to treat hematologic malignancies (rather than solid tumors) and have been found to suppress the JAK/STAT, a critical signal pathway for antitumor immunity, while PARP7 inhibitor RBN-2397 could activate the type I interferons (IFN-I) pathway, facilitating downstream effects such as STAT1 phosphorylation and immune activation. To elucidate whether simultaneous inhibition of these two targets could interfere with these two signal pathways, a series of pyridazinone-based PARP7/HDACs dual inhibitors have been designed, synthesized, and evaluated in vitro and in vivo experiments. Compound 9l was identified as a potent and balanced dual inhibitor for the first time, exhibiting excellent antitumor capabilities both in vitro and in vivo. This suggests that 9l can be used as a valuable tool molecule for investigating the relationship between anticancer immunity and HDAC inhibition | ||
| 650 | 4 | |a Journal Article | |
| 650 | 7 | |a Histone Deacetylase Inhibitors |2 NLM | |
| 650 | 7 | |a Histone Deacetylases |2 NLM | |
| 650 | 7 | |a EC 3.5.1.98 |2 NLM | |
| 650 | 7 | |a Vorinostat |2 NLM | |
| 650 | 7 | |a 58IFB293JI |2 NLM | |
| 650 | 7 | |a Antineoplastic Agents |2 NLM | |
| 700 | 1 | |a Wang, Chen-Chen |e verfasserin |4 aut | |
| 700 | 1 | |a Yuan, Yinghui |e verfasserin |4 aut | |
| 700 | 1 | |a Hui, Zi |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Hang |e verfasserin |4 aut | |
| 700 | 1 | |a Mao, Nian-Dong |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Pengpeng |e verfasserin |4 aut | |
| 700 | 1 | |a Sun, Bowen |e verfasserin |4 aut | |
| 700 | 1 | |a Lin, Jing |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Zishuo |e verfasserin |4 aut | |
| 700 | 1 | |a Gao, Yuan |e verfasserin |4 aut | |
| 700 | 1 | |a Xie, Tian |e verfasserin |4 aut | |
| 700 | 1 | |a Ye, Xiang-Yang |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Journal of medicinal chemistry |d 1963 |g 67(2024), 6 vom: 28. März, Seite 4950-4976 |w (DE-627)NLM000006602 |x 1520-4804 |7 nnns |
| 773 | 1 | 8 | |g volume:67 |g year:2024 |g number:6 |g day:28 |g month:03 |g pages:4950-4976 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1021/acs.jmedchem.4c00090 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 67 |j 2024 |e 6 |b 28 |c 03 |h 4950-4976 | ||