61073-01-6Relevant academic research and scientific papers
Discovery of novel biaryl sulfonamide based Mcl-1 inhibitors
Follows,Fessler,Baumeister, Timm,Campbell, Ann-Marie,Zablocki, Mary Margaret,Li, Hongbin,Gotur, Deepali,Wang, Zhongguo,Zheng, Xiaozhang,Molz, Lisa,Nguyen,Herbertz, Torsten,Wang,Bair, Kenneth
, p. 2375 - 2382 (2019)
Mcl-1 is an anti-apoptotic protein overexpressed in hematological malignancies and several human solid tumors. Small molecule inhibition of Mcl-1 would offer an effective therapy to Mcl-1 mediated resistance. Subsequently, it has been the target of extensive research in the pharmaceutical industry. The discovery of a novel class of Mcl-1 small molecule inhibitors is described beginning with a simple biaryl sulfonamide hit derived from a high through put screen. A medicinal chemistry effort aided by SBDD generated compounds capable of disrupting the Mcl-1/Bid protein-protein interaction in vitro. The crystal structure of the Mcl-1 bound ligand represents a unique binding mode to the BH3 binding pocket where binding affinity is achieved, in part, through a sulfonamide oxygen/Arg263 interaction. The work highlights the some of the key challenges in designing effective protein-protein inhibitors for the Bcl-2 class of proteins.
