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PDBsum entry 6vwc
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Apoptosis/apoptosis inhibitor
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PDB id
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6vwc
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PDB id:
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| Name: |
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Apoptosis/apoptosis inhibitor
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Title:
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Crystal structure of bcl-xl in complex with tetrahydroisoquinoline- pyridine based inhibitors
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Structure:
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Bcl-2-like protein 1. Chain: a, b. Synonym: bcl2-l-1,apoptosis regulator bcl-x. Engineered: yes. Mutation: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: bcl2l1, bcl2l, bclx. Expressed in: escherichia coli. Expression_system_taxid: 562
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Resolution:
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1.60Å
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R-factor:
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0.180
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R-free:
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0.200
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Authors:
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R.A.Judge,A.S.Judd
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Key ref:
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L.Wang
et al.
(2020).
Discovery of A-1331852, a First-in-Class, Potent, and Orally-Bioavailable BCL-XL Inhibitor.
ACS Med Chem Lett,
11,
1829-1836.
PubMed id:
DOI:
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Date:
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19-Feb-20
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Release date:
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21-Oct-20
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PROCHECK
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Headers
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References
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Q07817
(B2CL1_HUMAN) -
Bcl-2-like protein 1 from Homo sapiens
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Seq:
Struc:
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233 a.a.
139 a.a.*
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Key: |
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PfamA domain |
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Secondary structure |
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*
PDB and UniProt seqs differ
at 3 residue positions (black
crosses)
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DOI no:
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ACS Med Chem Lett
11:1829-1836
(2020)
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PubMed id:
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Discovery of A-1331852, a First-in-Class, Potent, and Orally-Bioavailable BCL-XL Inhibitor.
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L.Wang,
G.A.Doherty,
A.S.Judd,
Z.F.Tao,
T.M.Hansen,
R.R.Frey,
X.Song,
M.Bruncko,
A.R.Kunzer,
X.Wang,
M.D.Wendt,
J.A.Flygare,
N.D.Catron,
R.A.Judge,
C.H.Park,
S.Shekhar,
D.C.Phillips,
P.Nimmer,
M.L.Smith,
S.K.Tahir,
Y.Xiao,
J.Xue,
H.Zhang,
P.N.Le,
M.J.Mitten,
E.R.Boghaert,
W.Gao,
P.Kovar,
E.F.Choo,
D.Diaz,
W.J.Fairbrother,
S.W.Elmore,
D.Sampath,
J.D.Leverson,
A.J.Souers.
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ABSTRACT
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Herein we describe the discovery of A-1331852, a first-in-class orally active
BCL-XL inhibitor that selectively and potently induces apoptosis in
BCL-XL-dependent tumor cells. This molecule was generated by
re-engineering our previously reported BCL-XL inhibitor A-1155463
using structure-based drug design. Key design elements included rigidification
of the A-1155463 pharmacophore and introduction of sp3-rich moieties
capable of generating highly productive interactions within the key P4 pocket of
BCL-XL. A-1331852 has since been used as a critical tool molecule for
further exploring BCL-2 family protein biology, while also representing an
attractive entry into a drug discovery program.
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