Structure-based design, synthesis, and evaluation of Bcl-2/Mcl-1 dual inhibitors.
Arch Pharm (Weinheim)
; 353(5): e2000005, 2020 May.
Article
in En
| MEDLINE
| ID: mdl-32175625
ABSTRACT
Based on our previously reported Bcl-2/Mcl-1 dual inhibitor 4-thiomorpholinyl-2-cyano-3-amidinophenalenone (A1) that simultaneously occupies the p2 and p4 hydrophobic pockets of Bcl-2 and Mcl-1, we optimized molecules with different bond angles of the groups extending to the p4 pocket and bulky hydrophobic groups to explore p2. Research on structure-activity relationship resulted in a new derivative B4 that is capable of occupying both the p2 and p4 more deeply and completely than A1, with Ki values determined by fluorescence polarization assay (FPAs) improving to 0.31 µM for Bcl-2 and 0.16 µM for Mcl-1. Furthermore, B4 exhibited selective lethality on cancer cells over normal cells. It showed stronger apoptosis induction than (-)-gossypol on a Bcl-2/Mcl-1-dependent cancer cell line and killed an Mcl-1-dependent cell line which is resistant to ABT-199 treatment.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Drug Design
/
Proto-Oncogene Proteins c-bcl-2
/
Phenalenes
/
Myeloid Cell Leukemia Sequence 1 Protein
/
Antineoplastic Agents
Type of study:
Prognostic_studies
Limits:
Humans
Language:
En
Journal:
Arch Pharm (Weinheim)
Year:
2020
Document type:
Article
Affiliation country:
China