5 research outputs found
Property- and Structure-Guided Discovery of a Tetrahydroindazole Series of Interleukin‑2 Inducible T‑Cell Kinase Inhibitors
Interleukin-2
inducible T-cell kinase (ITK), a member of the Tec
family of tyrosine kinases, plays a major role in T-cell signaling
downstream of the T-cell receptor (TCR), and considerable efforts
have been directed toward discovery of ITK-selective inhibitors as
potential treatments of inflammatory disorders such as asthma. Using
a previously disclosed indazole series of inhibitors as a starting
point, and using X-ray crystallography and solubility forecast index
(SFI) as guides, we evolved a series of tetrahydroindazole inhibitors
with improved potency, selectivity, and pharmaceutical properties.
Highlights include identification of a selectivity pocket above the
ligand plane, and identification of appropriate lipophilic substituents
to occupy this space. This effort culminated in identification of
a potent and selective ITK inhibitor (GNE-9822) with good ADME properties
in preclinical species
Tetrahydroindazoles as Interleukin‑2 Inducible T‑Cell Kinase Inhibitors. Part II. Second-Generation Analogues with Enhanced Potency, Selectivity, and Pharmacodynamic Modulation in Vivo
The medicinal chemistry community
has directed considerable efforts
toward the discovery of selective inhibitors of interleukin-2 inducible
T-cell kinase (ITK), given its role in T-cell signaling downstream
of the T-cell receptor (TCR) and the implications of this target for
inflammatory disorders such as asthma. We have previously disclosed
a structure- and property-guided lead optimization effort which resulted
in the discovery of a new series of tetrahydroindazole-containing
selective ITK inhibitors. Herein we disclose further optimization
of this series that resulted in further potency improvements, reduced
off-target receptor binding liabilities, and reduced cytotoxicity.
Specifically, we have identified a correlation between the basicity
of solubilizing elements in the ITK inhibitors and off-target antiproliferative
effects, which was exploited to reduce cytotoxicity while maintaining
kinase selectivity. Optimized analogues were shown to reduce IL-2
and IL-13 production in vivo following oral or intraperitoneal dosing
in mice
Tetrahydroindazoles as Interleukin‑2 Inducible T‑Cell Kinase Inhibitors. Part II. Second-Generation Analogues with Enhanced Potency, Selectivity, and Pharmacodynamic Modulation in Vivo
The medicinal chemistry community
has directed considerable efforts
toward the discovery of selective inhibitors of interleukin-2 inducible
T-cell kinase (ITK), given its role in T-cell signaling downstream
of the T-cell receptor (TCR) and the implications of this target for
inflammatory disorders such as asthma. We have previously disclosed
a structure- and property-guided lead optimization effort which resulted
in the discovery of a new series of tetrahydroindazole-containing
selective ITK inhibitors. Herein we disclose further optimization
of this series that resulted in further potency improvements, reduced
off-target receptor binding liabilities, and reduced cytotoxicity.
Specifically, we have identified a correlation between the basicity
of solubilizing elements in the ITK inhibitors and off-target antiproliferative
effects, which was exploited to reduce cytotoxicity while maintaining
kinase selectivity. Optimized analogues were shown to reduce IL-2
and IL-13 production in vivo following oral or intraperitoneal dosing
in mice
Discovery and Biological Profiling of Potent and Selective mTOR Inhibitor GDC-0349
Aberrant activation of the PI3K-Akt-mTOR signaling pathway
has
been observed in human tumors and tumor cell lines, indicating that
these protein kinases may be attractive therapeutic targets for treating
cancer. Optimization of advanced lead <b>1</b> culminated in
the discovery of clinical development candidate <b>8h</b>, GDC-0349,
a potent and selective ATP-competitive inhibitor of mTOR. GDC-0349
demonstrates pathway modulation and dose-dependent efficacy in mouse
xenograft cancer models
Structure-Guided Rescaffolding of Selective Antagonists of BCL‑X<sub>L</sub>
Because
of the promise of BCL-2 antagonists in combating chronic
lymphocytic leukemia (CLL) and non-Hodgkin’s lymphoma (NHL),
interest in additional selective antagonists of antiapoptotic proteins
has grown. Beginning with a series of selective, potent BCL-X<sub>L</sub> antagonists containing an undesirable hydrazone functionality,
in silico design and X-ray crystallography were utilized to develop
alternative scaffolds that retained the selectivity and potency of
the starting compounds