In:
Organic & Biomolecular Chemistry, Royal Society of Chemistry (RSC), Vol. 19, No. 41 ( 2021), p. 8968-8987
Abstract:
In the area of cancer research, the development of new and potent inhibitors of anti-apoptotic proteins is a very active and promising topic. The small molecule MIM1 has been reported earlier as one of the first selective inhibitors of the anti-apoptotic protein Mcl-1. In the present paper, we first revised the structure of this molecule based on extensive physicochemical analyses. Then we designed and synthesized a focused library of analogues for the corrected structure of MIM1. Next, these molecules were subjected to a panel of in cellulo biological studies, allowing the identification of dual Bcl-x L /Mcl-1 inhibitors, as well as selective Mcl-1 inhibitors. These results have been complemented by fluorescence polarization assays with the Mcl-1 protein. Preliminary structure–activity relationships were discussed and extensive molecular modelling studies allowed us to propose a rationale for the biological activity of this series of new inhibitors, in particular for the selectivity of inhibition of Mcl-1 versus Bcl-x L .
Type of Medium:
Online Resource
ISSN:
1477-0520
,
1477-0539
Language:
English
Publisher:
Royal Society of Chemistry (RSC)
Publication Date:
2021
detail.hit.zdb_id:
2097583-1