4HW3

Discovery of potent Mcl-1 inhibitors using fragment-based methods and structure-based design

Summary for 4HW3

• Entry DOI: 10.2210/pdb4hw3/pdb
• Related: 4HW2 4HW4
• Descriptor: Induced myeloid leukemia cell differentiation protein Mcl-1, 3-[3-(4-chloro-3,5-dimethylphenoxy)propyl]-1-benzothiophene-2-carboxylic acid (3 entities in total)
• Functional Keywords: regulation of apoptosis, maintenance of viability, apoptosis, apoptosis-inhibitor complex, apoptosis/inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Membrane; Single-pass membrane protein (Potential): Q07820
• Total number of polymer chains: 12
• Total formula weight: 214425.44

Authors

Zhao, B. (deposition date: 2012-11-07, release date: 2013-01-09, Last modification date: 2024-02-28)

Primary citation

Friberg, A.,Vigil, D.,Zhao, B.,Daniels, R.N.,Burke, J.P.,Garcia-Barrantes, P.M.,Camper, D.,Chauder, B.A.,Lee, T.,Olejniczak, E.T.,Fesik, S.W.
Discovery of potent myeloid cell leukemia 1 (Mcl-1) inhibitors using fragment-based methods and structure-based design.
J.Med.Chem., 56:15-30, 2013

PubMed Abstract: Myeloid cell leukemia 1 (Mcl-1), a member of the Bcl-2 family of proteins, is overexpressed and amplified in various cancers and promotes the aberrant survival of tumor cells that otherwise would undergo apoptosis. Here we describe the discovery of potent and selective Mcl-1 inhibitors using fragment-based methods and structure-based design. NMR-based screening of a large fragment library identified two chemically distinct hit series that bind to different sites on Mcl-1. Members of the two fragment classes were merged together to produce lead compounds that bind to Mcl-1 with a dissociation constant of <100 nM with selectivity for Mcl-1 over Bcl-xL and Bcl-2. Structures of merged compounds when complexed to Mcl-1 were obtained by X-ray crystallography and provide detailed information about the molecular recognition of small-molecule ligands binding Mcl-1. The compounds represent starting points for the discovery of clinically useful Mcl-1 inhibitors for the treatment of a wide variety of cancers.

PubMed: 23244564
DOI: 10.1021/jm301448p

Experimental method

X-RAY DIFFRACTION (2.4 Å)