Discovery of novel biaryl sulfonamide based Mcl-1 inhibitors.
Basic Information
ID: ALA4387763
Journal: Bioorg Med Chem Lett
Title: Discovery of novel biaryl sulfonamide based Mcl-1 inhibitors.
Authors: Follows B, Fessler S, Baumeister T, Campbell AM, Zablocki MM, Li H, Gotur D, Wang Z, Zheng X, Molz L, Nguyen C, Herbertz T, Wang L, Bair K.
Abstract: 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.
CiteXplore: 31235261
DOI: 10.1016/j.bmcl.2019.06.008
Patent ID: ┄