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Macrocyclic Carbon-Linked Pyrazoles As Novel Inhibitors of MCL-1.

Macrocyclic Carbon-Linked Pyrazoles As Novel Inhibitors of MCL-1.

Authors :
Demin S
Peschiulli A
Velter AI
Vos A
De Boeck B
Miller B
Rombouts FJR
Reuillon T
Lento W
Blanco MD
Jouffroy M
Steyvers H
Bekkers M
Altrocchi C
Pietrak B
Koo SJ
Szewczuk L
Attar R
Philippar U
Source :
ACS medicinal chemistry letters [ACS Med Chem Lett] 2023 Jul 03; Vol. 14 (7), pp. 955-961. Date of Electronic Publication: 2023 Jul 03 (Print Publication: 2023).
Publication Year :
2023

Abstract

Myeloid cell leukemia-1 (MCL-1) is a member of the antiapoptotic BCL-2 proteins family and a key regulator of mitochondrial homeostasis. Overexpression of MCL-1 is found in many cancer cells and contributes to tumor progression, which makes it an attractive therapeutic target. Pursuing our previous study of macrocyclic indoles for the inhibition of MCL-1, we report herein the impact of both pyrazole and indole isomerism on the potency and overall properties of this family of compounds. We demonstrated that the incorporation of a fluorine atom on the naphthalene moiety was a necessary step to improve cellular potency and that, combined with the introduction of various side chains on the pyrazole, it enhanced solubility significantly. This exploration culminated in the discovery of compounds ( R <subscript>a</subscript> )- 10 and ( R <subscript>a</subscript> )- 15 , possessing remarkable cellular potency and properties.<br />Competing Interests: The authors declare no competing financial interest.<br /> (© 2023 American Chemical Society.)

Details

Language :
English
ISSN :
1948-5875
Volume :
14
Issue :
7
Database :
MEDLINE
Journal :
ACS medicinal chemistry letters
Publication Type :
Academic Journal
Accession number :
37465311
Full Text :
https://doi.org/10.1021/acsmedchemlett.3c00141