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PDBsum entry 4ymj
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Transferase/transferase inhibitor
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PDB id
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4ymj
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References listed in PDB file
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Key reference
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Title
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(R)-2-Phenylpyrrolidine substituted imidazopyridazines: a new class of potent and selective pan-Trk inhibitors.
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Authors
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H.S.Choi,
P.V.Rucker,
Z.Wang,
Y.Fan,
P.Albaugh,
G.Chopiuk,
F.Gessier,
F.Sun,
F.Adrian,
G.Liu,
T.Hood,
N.Li,
Y.Jia,
J.Che,
S.Mccormack,
A.Li,
J.Li,
A.Steffy,
A.Culazzo,
C.Tompkins,
V.Phung,
A.Kreusch,
M.Lu,
B.Hu,
A.Chaudhary,
M.Prashad,
T.Tuntland,
B.Liu,
J.Harris,
H.M.Seidel,
J.Loren,
V.Molteni.
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Ref.
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Acs Med Chem Lett, 2015,
6,
562-567.
[DOI no: ]
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PubMed id
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Abstract
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Deregulated kinase activities of tropomyosin receptor kinase (TRK) family
members have been shown to be associated with tumorigenesis and poor prognosis
in a variety of cancer types. In particular, several chromosomal rearrangements
involving TRKA have been reported in colorectal, papillary thyroid,
glioblastoma, melanoma, and lung tissue that are believed to be the key
oncogenic driver in these tumors. By screening the Novartis compound collection,
a novel imidazopyridazine TRK inhibitor was identified that served as a
launching point for drug optimization. Structure guided drug design led to the
identification of (R)-2-phenylpyrrolidine substituted imidazopyridazines as a
series of potent, selective, orally bioavailable pan-TRK inhibitors achieving
tumor regression in rats bearing KM12 xenografts. From this work the
(R)-2-phenylpyrrolidine has emerged as an ideal moiety to incorporate in
bicyclic TRK inhibitors by virtue of its shape complementarity to the
hydrophobic pocket of TRKs.
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