8SVY

MBP-Mcl1 in complex with ligand 10

Summary for 8SVY

• Entry DOI: 10.2210/pdb8svy/pdb
• Related PRD ID: PRD_900001
• Descriptor: Maltose/maltodextrin-binding periplasmic protein, Induced myeloid leukemia cell differentiation protein Mcl-1 chimera, alpha-D-glucopyranose-(1-4)-alpha-D-glucopyranose, 1,2-ETHANEDIOL, ... (6 entities in total)
• Functional Keywords: myeloid cell leukemia 1, mcl-1, b-cell lymphoma 2, bcl-2, bh3 mimetic, protein-protein interaction, modulator, apoptosis, cancer, leukemia, myeloma, lymphoma, signaling protein
• Biological source: Escherichia coli; More
• Total number of polymer chains: 1
• Total formula weight: 58739.84

Authors

Miller, B.R.,Shaffer, P. (deposition date: 2023-05-17, release date: 2023-08-09, Last modification date: 2024-05-22)

Primary citation

Demin, S.,Peschiulli, A.,Velter, A.I.,Vos, A.,De Boeck, B.,Miller, B.,Rombouts, F.J.R.,Reuillon, T.,Lento, W.,Blanco, M.D.,Jouffroy, M.,Steyvers, H.,Bekkers, M.,Altrocchi, C.,Pietrak, B.,Koo, S.J.,Szewczuk, L.,Attar, R.,Philippar, U.
Macrocyclic Carbon-Linked Pyrazoles As Novel Inhibitors of MCL-1.
Acs Med.Chem.Lett., 14:955-961, 2023

PubMed Abstract: Myeloid cell leukemia-1 (MCL-1) is a member of the antiapoptotic BCL-2 proteins family and a key regulator of mitochondrial homeostasis. Overexpression of MCL-1 is found in many cancer cells and contributes to tumor progression, which makes it an attractive therapeutic target. Pursuing our previous study of macrocyclic indoles for the inhibition of MCL-1, we report herein the impact of both pyrazole and indole isomerism on the potency and overall properties of this family of compounds. We demonstrated that the incorporation of a fluorine atom on the naphthalene moiety was a necessary step to improve cellular potency and that, combined with the introduction of various side chains on the pyrazole, it enhanced solubility significantly. This exploration culminated in the discovery of compounds ()- and ()-, possessing remarkable cellular potency and properties.

PubMed: 37465311
DOI: 10.1021/acsmedchemlett.3c00141

Experimental method

X-RAY DIFFRACTION (1.47 Å)