6P3P

Crystal structure of Mcl-1 in complex with compound 65

Summary for 6P3P

• Entry DOI: 10.2210/pdb6p3p/pdb
• Descriptor: Induced myeloid leukemia cell differentiation protein Mcl-1, methyl N-(5-{[2-chloro-5-(trifluoromethyl)phenyl]sulfamoyl}-4-methylthiophene-2-carbonyl)-D-phenylalaninate (3 entities in total)
• Functional Keywords: mcl-1, biaryl sulfonamide inhibitor, apoptosis-apoptosis inhibitor complex, apoptosis/apoptosis inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 18441.30

Authors

Toms, A.V.,Follows, B. (deposition date: 2019-05-24, release date: 2019-07-03, Last modification date: 2023-10-11)

Primary citation

Follows, B.,Fessler, S.,Baumeister, T.,Campbell, A.M.,Zablocki, M.M.,Li, H.,Gotur, D.,Wang, Z.,Zheng, X.,Molz, L.,Nguyen, C.,Herbertz, T.,Wang, L.,Bair, K.
Discovery of novel biaryl sulfonamide based Mcl-1 inhibitors.
Bioorg.Med.Chem.Lett., 29:2375-2382, 2019

PubMed 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.

PubMed: 31235261
DOI: 10.1016/j.bmcl.2019.06.008

Experimental method

X-RAY DIFFRACTION (1.61 Å)