5LOF

Crystal structure of the MBP-MCL1 complex with highly selective and potent inhibitor of MCL1

Summary for 5LOF

• Entry DOI: 10.2210/pdb5lof/pdb
• Related PRD ID: PRD_900001
• Descriptor: Maltose-binding periplasmic protein,Induced myeloid leukemia cell differentiation protein Mcl-1, alpha-D-glucopyranose-(1-4)-alpha-D-glucopyranose, (2~{R})-2-[5-[3-chloranyl-2-methyl-4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl]-6-(5-fluoranylfuran-2-yl)thieno[2,3-d]pyrimidin-4-yl]oxy-3-[2-[[2-[2,2,2-tris(fluoranyl)ethyl]pyrazol-3-yl]methoxy]phenyl]propanoic acid, ... (4 entities in total)
• Functional Keywords: apoptosis-inhibitor complex, mcl-1, s s63845, mbp, apoptosis/inhibitor
• Biological source: Escherichia coli O157:H7; More
• Total number of polymer chains: 1
• Total formula weight: 58397.42

Authors

Dokurno, P.,Kotschy, A.,Szlavik, Z.,Murray, J.,Davidson, J.,Csekei, M.,Paczal, A.,Szabo, Z.,Sipos, S.,Radics, G.,Proszenyak, A.,Balint, B.,Ondi, L.,Blasko, G.,Robertson, A.,Surgenor, A.,Chen, I.,Matassova, N.,Smith, J.,Pedder, C.,Graham, C.,Geneste, O. (deposition date: 2016-08-09, release date: 2016-10-26, Last modification date: 2024-01-10)

Primary citation

Kotschy, A.,Szlavik, Z.,Murray, J.,Davidson, J.,Maragno, A.L.,Le Toumelin-Braizat, G.,Chanrion, M.,Kelly, G.L.,Gong, J.N.,Moujalled, D.M.,Bruno, A.,Csekei, M.,Paczal, A.,Szabo, Z.B.,Sipos, S.,Radics, G.,Proszenyak, A.,Balint, B.,Ondi, L.,Blasko, G.,Robertson, A.,Surgenor, A.,Dokurno, P.,Chen, I.,Matassova, N.,Smith, J.,Pedder, C.,Graham, C.,Studeny, A.,Lysiak-Auvity, G.,Girard, A.M.,Grave, F.,Segal, D.,Riffkin, C.D.,Pomilio, G.,Galbraith, L.C.,Aubrey, B.J.,Brennan, M.S.,Herold, M.J.,Chang, C.,Guasconi, G.,Cauquil, N.,Melchiore, F.,Guigal-Stephan, N.,Lockhart, B.,Colland, F.,Hickman, J.A.,Roberts, A.W.,Huang, D.C.,Wei, A.H.,Strasser, A.,Lessene, G.,Geneste, O.
The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models.
Nature, 538:477-482, 2016

PubMed Abstract: Avoidance of apoptosis is critical for the development and sustained growth of tumours. The pro-survival protein myeloid cell leukemia 1 (MCL1) is overexpressed in many cancers, but the development of small molecules targeting this protein that are amenable for clinical testing has been challenging. Here we describe S63845, a small molecule that specifically binds with high affinity to the BH3-binding groove of MCL1. Our mechanistic studies demonstrate that S63845 potently kills MCL1-dependent cancer cells, including multiple myeloma, leukaemia and lymphoma cells, by activating the BAX/BAK-dependent mitochondrial apoptotic pathway. In vivo, S63845 shows potent anti-tumour activity with an acceptable safety margin as a single agent in several cancers. Moreover, MCL1 inhibition, either alone or in combination with other anti-cancer drugs, proved effective against several solid cancer-derived cell lines. These results point towards MCL1 as a target for the treatment of a wide range of tumours.

PubMed: 27760111
DOI: 10.1038/nature19830

Experimental method

X-RAY DIFFRACTION (2.2 Å)