6GL8

Crystal structure of Bcl-2 in complex with the novel orally active inhibitor S55746

Summary for 6GL8

• Entry DOI: 10.2210/pdb6gl8/pdb
• Descriptor: Apoptosis regulator Bcl-2,Apoptosis regulator Bcl-2,Apoptosis regulator Bcl-2,Bcl-2-like protein 1,Apoptosis regulator Bcl-2,Apoptosis regulator Bcl-2,Apoptosis regulator Bcl-2, ~{N}-(4-hydroxyphenyl)-3-[6-[[(3~{S})-3-(morpholin-4-ylmethyl)-3,4-dihydro-1~{H}-isoquinolin-2-yl]carbonyl]-1,3-benzodioxol-5-yl]-~{N}-phenyl-5,6,7,8-tetrahydroindolizine-1-carboxamide (3 entities in total)
• Functional Keywords: apoptosis-inhibitor complex, bcl-2, bh3-mimetics, apoptosis
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 1
• Total formula weight: 20947.37

Authors

Casara, P.,Davidson, J.,Claperon, A.,Le Toumelin-Braizat, G.,Vogler, M.,Bruno, A.,Chanrion, M.,Lysiak-Auvity, G.,Le Diguarher, T.,Starck, J.B.,Chen, I.,Whitehead, N.,Graham, C.,Matassova, N.,Dokurno, P.,Pedder, C.,Wang, Y.,Qiu, S.,Girard, A.M.,Schneider, E.,Grave, F.,Studeny, A.,Guasconi, G.,Rocchetti, F.,Maiga, S.,Henlin, J.M.,Colland, F.,Kraus-Berthier, L.,Le Gouill, S.,Dyer, M.J.S.,Hubbard, R.,Wood, M.,Amiot, M.,Cohen, G.M.,Hickman, J.A.,Morris, E.,Murray, J.,Geneste, O. (deposition date: 2018-05-23, release date: 2018-11-07, Last modification date: 2024-01-17)

Primary citation

Casara, P.,Davidson, J.,Claperon, A.,Le Toumelin-Braizat, G.,Vogler, M.,Bruno, A.,Chanrion, M.,Lysiak-Auvity, G.,Le Diguarher, T.,Starck, J.B.,Chen, I.,Whitehead, N.,Graham, C.,Matassova, N.,Dokurno, P.,Pedder, C.,Wang, Y.,Qiu, S.,Girard, A.M.,Schneider, E.,Grave, F.,Studeny, A.,Guasconi, G.,Rocchetti, F.,Maiga, S.,Henlin, J.M.,Colland, F.,Kraus-Berthier, L.,Le Gouill, S.,Dyer, M.J.S.,Hubbard, R.,Wood, M.,Amiot, M.,Cohen, G.M.,Hickman, J.A.,Morris, E.,Murray, J.,Geneste, O.
S55746 is a novel orally active BCL-2 selective and potent inhibitor that impairs hematological tumor growth.
Oncotarget, 9:20075-20088, 2018

PubMed Abstract: Escape from apoptosis is one of the major hallmarks of cancer cells. The B-cell Lymphoma 2 (BCL-2) gene family encodes pro-apoptotic and anti-apoptotic proteins that are key regulators of the apoptotic process. Overexpression of the pro-survival member BCL-2 is a well-established mechanism contributing to oncogenesis and chemoresistance in several cancers, including lymphoma and leukemia. Thus, BCL-2 has become an attractive target for therapeutic strategy in cancer, as demonstrated by the recent approval of ABT-199 (Venclexta™) in relapsed or refractory Chronic Lymphocytic Leukemia with 17p deletion. Here, we describe a novel orally bioavailable BCL-2 selective and potent inhibitor called S55746 (also known as BCL201). S55746 occupies the hydrophobic groove of BCL-2. Its selectivity profile demonstrates no significant binding to MCL-1, BFL-1 (BCL2A1/A1) and poor affinity for BCL-XL. Accordingly, S55746 has no cytotoxic activity on BCL-XL-dependent cells, such as platelets. In a panel of hematological cell lines, S55746 induces hallmarks of apoptosis including externalization of phosphatidylserine, caspase-3 activation and PARP cleavage. , S55746 induces apoptosis in the low nanomolar range in primary Chronic Lymphocytic Leukemia and Mantle Cell Lymphoma patient samples. Finally, S55746 administered by oral route daily in mice demonstrated robust anti-tumor efficacy in two hematological xenograft models with no weight lost and no change in behavior. Taken together, these data demonstrate that S55746 is a novel, well-tolerated BH3-mimetic targeting selectively and potently the BCL-2 protein.

PubMed: 29732004
DOI: 10.18632/oncotarget.24744

Experimental method

X-RAY DIFFRACTION (1.4 Å)