5UJB

Structure of a Mcl-1 Inhibitor Binding to Site 3 of Human Serum Albumin

Summary for 5UJB

• Entry DOI: 10.2210/pdb5ujb/pdb
• Descriptor: Serum albumin, 4-{8-chloro-11-[3-(4-chloro-3,5-dimethylphenoxy)propyl]-1-oxo-7-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-[1,4]diazepino[1,2-a]indol-2(3H)-yl}-1-methyl-1H-indole-6-carboxylic acid, PHOSPHATE ION (3 entities in total)
• Functional Keywords: human serum albumin, free fraction, apoptosis, cancer, mcl-1, drug discovery, transport protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 140554.66

Authors

Zhao, B. (deposition date: 2017-01-17, release date: 2017-05-03, Last modification date: 2024-10-16)

Primary citation

Zhao, B.,Sensintaffar, J.,Bian, Z.,Belmar, J.,Lee, T.,Olejniczak, E.T.,Fesik, S.W.
Structure of a Myeloid cell leukemia-1 (Mcl-1) inhibitor bound to drug site 3 of Human Serum Albumin.
Bioorg. Med. Chem., 25:3087-3092, 2017

PubMed Abstract: Amplification of the gene encoding Myeloid cell leukemia-1 (Mcl-1) is one of the most common genetic aberrations in human cancer and is associated with high tumor grade and poor survival. Recently, we reported on the discovery of high affinity Mcl-1 inhibitors that elicit mechanism-based cell activity. These inhibitors are lipophilic and contain an acidic functionality which is a common chemical profile for compounds that bind to albumin in plasma. Indeed, these Mcl-1 inhibitors exhibited reduced in vitro cell activity in the presence of serum. Here we describe the structure of a lead Mcl-1 inhibitor when bound to Human Serum Albumin (HSA). Unlike many acidic lipophilic compounds that bind to drug site 1 or 2, we found that this Mcl-1 inhibitor binds predominantly to drug site 3. Site 3 of HSA may be able to accommodate larger, more rigid compounds that do not fit into the smaller drug site 1 or 2. Structural studies of molecules that bind to this third site may provide insight into how some higher molecular weight compounds bind to albumin and could be used to aid in the design of compounds with reduced albumin binding.

PubMed: 28428041
DOI: 10.1016/j.bmc.2017.03.060

Experimental method

X-RAY DIFFRACTION (2.7 Å)