6UD2

co-crystal structure of compound 1 bound to human Mcl-1

Summary for 6UD2

• Entry DOI: 10.2210/pdb6ud2/pdb
• Descriptor: Induced myeloid leukemia cell differentiation protein Mcl-1, (4S,7aR,9aR,10S,11E,18R)-6'-chloro-10-[2-(3,3-difluoroazetidin-1-yl)ethoxy]-N-(dimethylsulfamoyl)-18-hydroxy-15-methyl-16-oxo-3',4',7,7a,8,9,9a,10,13,14,15,16,17,18-tetradecahydro-2'H,3H,5H-spiro[1,19-(ethanediylidene)cyclobuta[n][1,4]oxazepino[4,3-a][1,8]diazacyclohexadecine-4,1'-naphthalene]-18-carboxamide (3 entities in total)
• Functional Keywords: inhibitor, apoptosis, protein-protein interaction, apoptosis-inhibitor complex, apoptosis/inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 18742.73

Authors

Huang, X.,Whittington, D. (deposition date: 2019-09-18, release date: 2019-12-04, Last modification date: 2024-03-13)

Primary citation

Rescourio, G.,Gonzalez, A.Z.,Jabri, S.,Belmontes, B.,Moody, G.,Whittington, D.,Huang, X.,Caenepeel, S.,Cardozo, M.,Cheng, A.C.,Chow, D.,Dou, H.,Jones, A.,Kelly, R.C.,Li, Y.,Lizarzaburu, M.,Lo, M.C.,Mallari, R.,Meleza, C.,Rew, Y.,Simonovich, S.,Sun, D.,Turcotte, S.,Yan, X.,Wong, S.G.,Yanez, E.,Zancanella, M.,Houze, J.,Medina, J.C.,Hughes, P.E.,Brown, S.P.
Discovery and in Vivo Evaluation of Macrocyclic Mcl-1 Inhibitors Featuring an alpha-Hydroxy Phenylacetic Acid Pharmacophore or Bioisostere.
J.Med.Chem., 62:10258-10271, 2019

PubMed Abstract: Overexpression of the antiapoptotic protein Mcl-1 provides a survival advantage to some cancer cells, making inhibition of this protein an attractive therapeutic target for the treatment of certain types of tumors. Herein, we report our efforts toward the identification of a novel series of macrocyclic Mcl-1 inhibitors featuring an α-hydroxy phenylacetic acid pharmacophore or bioisostere. This work led to the discovery of , a potent Mcl-1 inhibitor (IC = 19 nM in an OPM-2 cell viability assay) with good pharmacokinetic properties and excellent in vivo efficacy in an OPM-2 multiple myeloma xenograft model.

PubMed: 31736296
DOI: 10.1021/acs.jmedchem.9b01310

Experimental method

X-RAY DIFFRACTION (1.7 Å)