9 research outputs found
4-Bromo-2H-1,3-oxazine-2,6(3H)-dione
The title compound, C4H2BrNO3, is one of a series of three substituted oxauracils prepared as precursors in the preparation of 1-aza-1,3-butadienes. Although each structure has identical potential for N—H⋯O intermolecular hydrogen bonds, each forms a distinctive intermolecular network. In the title compound, there are two independent molecules in the asymmetric unit, with a non-crystallographic twofold screw-like relationship between them. The two indpendent molecules are linked by an intermolecular N—H⋯O hydrogen bond. In the crystal structure, this hydrogen-bonded pair is linked to translationally related molecules through further intermolecular N—H⋯O hydrogen bonds, forming one-dimensional chains along [100]. The crystal structure also has short Br⋯O=C intermolecular contacts with distances of 2.843 (4) and 2.852 (4) Å
Fragment-Based Drug Design of Novel Pyranopyridones as Cell Active and Orally Bioavailable Tankyrase Inhibitors
Tankyrase
activity has been linked to the regulation of intracellular axin levels,
which have been shown to be crucial for the Wnt pathway. Deregulated
Wnt signaling is important for the genesis of many diseases including
cancer. We describe herein the discovery and development of a new
series of tankyrase inhibitors. These pyranopyridones are highly active
in various cell-based assays. A fragment/structure based optimization
strategy led to a compound with good pharmacokinetic properties that
is suitable for in vivo studies and further development
Total Synthesis of 6‑Deoxypladienolide D and Assessment of Splicing Inhibitory Activity in a Mutant SF3B1 Cancer Cell Line
A total
synthesis of the natural product 6-deoxypladienolide D
(<b>1</b>) has been achieved. Two noteworthy attributes of the
synthesis are (1) a late-stage allylic oxidation which proceeds with
full chemo-, regio-, and diastereoselectivity and (2) the development
of a scalable and cost-effective synthetic route to support drug discovery
efforts. 6-Deoxypladienolide D (<b>1</b>) demonstrates potent
growth inhibition in a mutant SF3B1 cancer cell line, high binding
affinity to the SF3b complex, and inhibition of pre-mRNA splicing
Total Synthesis of 6‑Deoxypladienolide D and Assessment of Splicing Inhibitory Activity in a Mutant SF3B1 Cancer Cell Line
A total
synthesis of the natural product 6-deoxypladienolide D
(<b>1</b>) has been achieved. Two noteworthy attributes of the
synthesis are (1) a late-stage allylic oxidation which proceeds with
full chemo-, regio-, and diastereoselectivity and (2) the development
of a scalable and cost-effective synthetic route to support drug discovery
efforts. 6-Deoxypladienolide D (<b>1</b>) demonstrates potent
growth inhibition in a mutant SF3B1 cancer cell line, high binding
affinity to the SF3b complex, and inhibition of pre-mRNA splicing
Potent GCN2 Inhibitor Capable of Reversing MDSC-Driven T Cell Suppression Demonstrates In Vivo Efficacy as a Single Agent and in Combination with Anti-Angiogenesis Therapy
General
control nonderepressible 2 (GCN2) protein kinase is a cellular
stress sensor within the tumor microenvironment (TME), whose signaling
cascade has been proposed to contribute to immune escape in tumors.
Herein, we report the discovery of cell-potent GCN2 inhibitors with
excellent selectivity against its closely related Integrated Stress
Response (ISR) family members heme-regulated inhibitor kinase (HRI),
protein kinase R (PKR), and (PKR)-like endoplasmic reticulum kinase
(PERK), as well as good kinome-wide selectivity and favorable PK.
In mice, compound 39 engages GCN2 at levels ≥80%
with an oral dose of 15 mg/kg BID. We also demonstrate the ability
of compound 39 to alleviate MDSC-related T cell suppression
and restore T cell proliferation, similar to the effect seen in MDSCs
from GCN2 knockout mice. In the LL2 syngeneic mouse model, compound 39 demonstrates significant tumor growth inhibition (TGI)
as a single agent. Furthermore, TGI mediated by anti-VEGFR was enhanced
by treatment with compound 39 demonstrating the complementarity
of these two mechanisms
Potent GCN2 Inhibitor Capable of Reversing MDSC-Driven T Cell Suppression Demonstrates In Vivo Efficacy as a Single Agent and in Combination with Anti-Angiogenesis Therapy
General
control nonderepressible 2 (GCN2) protein kinase is a cellular
stress sensor within the tumor microenvironment (TME), whose signaling
cascade has been proposed to contribute to immune escape in tumors.
Herein, we report the discovery of cell-potent GCN2 inhibitors with
excellent selectivity against its closely related Integrated Stress
Response (ISR) family members heme-regulated inhibitor kinase (HRI),
protein kinase R (PKR), and (PKR)-like endoplasmic reticulum kinase
(PERK), as well as good kinome-wide selectivity and favorable PK.
In mice, compound 39 engages GCN2 at levels ≥80%
with an oral dose of 15 mg/kg BID. We also demonstrate the ability
of compound 39 to alleviate MDSC-related T cell suppression
and restore T cell proliferation, similar to the effect seen in MDSCs
from GCN2 knockout mice. In the LL2 syngeneic mouse model, compound 39 demonstrates significant tumor growth inhibition (TGI)
as a single agent. Furthermore, TGI mediated by anti-VEGFR was enhanced
by treatment with compound 39 demonstrating the complementarity
of these two mechanisms
Discovery of Novel PI3-Kinase δ Specific Inhibitors for the Treatment of Rheumatoid Arthritis: Taming CYP3A4 Time-Dependent Inhibition
PI3Kδ is a lipid kinase and a member of a larger
family of enzymes, PI3K class IA(α, β, δ) and IB
(γ), which catalyze the phosphorylation of PIP2 to PIP3. PI3Kδ
is mainly expressed in leukocytes, where it plays a critical, nonredundant
role in B cell receptor mediated signaling and provides an attractive
opportunity to treat diseases where B cell activity is essential,
e.g., rheumatoid arthritis. We report the discovery of novel, potent,
and selective PI3Kδ inhibitors and describe a structural hypothesis
for isoform (α, β, γ) selectivity gained from interactions
in the affinity pocket. The critical component of our initial pharmacophore
for isoform selectivity was strongly associated with CYP3A4 time-dependent
inhibition (TDI). We describe a variety of strategies and methods
for monitoring and attenuating TDI. Ultimately, a structure-based
design approach was employed to identify a suitable structural replacement
for further optimization