3 research outputs found
Discovery and Optimization of Allosteric Inhibitors of Mutant Isocitrate Dehydrogenase 1 (R132H IDH1) Displaying Activity in Human Acute Myeloid Leukemia Cells
A collaborative
high throughput screen of 1.35 million compounds
against mutant (R132H) isocitrate dehydrogenase IDH1 led to the identification
of a novel series of inhibitors. Elucidation of the bound ligand crystal
structure showed that the inhibitors exhibited a novel binding mode
in a previously identified allosteric site of IDH1 (R132H). This information
guided the optimization of the series yielding submicromolar enzyme
inhibitors with promising cellular activity. Encouragingly, one compound
from this series was found to induce myeloid differentiation in primary
human IDH1 R132H AML cells <i>in vitro</i>
Identification of Imidazo-Pyrrolopyridines as Novel and Potent JAK1 Inhibitors
A therapeutic rationale is proposed for the treatment
of inflammatory diseases, such as rheumatoid arthritis (RA), by specific
targeting of the JAK1 pathway. Examination of the preferred binding
conformation of clinically effective, pan-JAK inhibitor <b>1</b> led to identification of a novel, tricyclic hinge binding scaffold <b>3</b>. Exploration of SAR through a series of cycloamino and cycloalkylamino
analogues demonstrated this template to be highly tolerant of substitution,
with a predisposition to moderate selectivity for the JAK1 isoform
over JAK2. This study culminated in the identification of subnanomolar
JAK1 inhibitors such as <b>22</b> and <b>49</b>, having
excellent cell potency, good rat pharmacokinetic characteristics,
and excellent kinase selectivity. Determination of the binding modes
of the series in JAK1 and JAK2 by X-ray crystallography supported
the design of analogues to enhance affinity and selectivity
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 IAÂ(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