Discovery and preclinical evaluations of TQB3616, a novel CDK4-biased inhibitor.
Bioorg Med Chem Lett
; 107: 129769, 2024 Jul 15.
Article
de En
| MEDLINE
| ID: mdl-38670537
ABSTRACT
Among small-molecule CDK4/6 inhibitors (palbociclib, ribociclib, and abemaciclib) approved for metastatic breast cancers, abemaciclib has a more tolerable adverse effects in clinic. This is attributable to preferential inhibition of CDK4 over CDK6. In our search for a biased CDK4 inhibitor, we discovered a series of pyrimidine-indazole inhibitors. SAR studies led us to TQB3616 as a preferential CDK4 inhibitor. TQB3616 exhibited improvements in both enzymatic and cellular proliferation inhibitory potency when tested side-by-side with the FDA approved palbociclib and abemaciclib. TQB3616 also possessed favorable PK profile in multiple species. These differentiated properties, together with excellent GLP safety profile warranted TQB3616 moving to clinic. TQB3616 entered into clinical development in 2019 and currently in phase III clinical trials (NCT05375461, NCT05365178).
Mots clés
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Inhibiteurs de protéines kinases
/
Prolifération cellulaire
/
Kinase-4 cycline-dépendante
Limites:
Animals
/
Humans
Langue:
En
Journal:
Bioorg Med Chem Lett
Sujet du journal:
BIOQUIMICA
/
QUIMICA
Année:
2024
Type de document:
Article