3 research outputs found
Discovery of Clinical Development Candidate GDC-0084, a Brain Penetrant Inhibitor of PI3K and mTOR
Inhibition of phosphoinositide 3-kinase
(PI3K) signaling is an appealing approach to treat brain tumors, especially
glioblastoma multiforme (GBM). We previously disclosed our successful
approach to prospectively design potent and blood–brain barrier
(BBB) penetrating PI3K inhibitors. The previously disclosed molecules
were ultimately deemed not suitable for clinical development due to
projected poor metabolic stability in humans. We, therefore, extended
our studies to identify a BBB penetrating inhibitor of PI3K that was
also projected to be metabolically stable in human. These efforts
required identification of a distinct scaffold for PI3K inhibitors
relative to our previous efforts and ultimately resulted in the identification
of GDC-0084 (<b>16</b>). The discovery and preclinical characterization
of this molecule are described within
The Rational Design of Selective Benzoxazepin Inhibitors of the α‑Isoform of Phosphoinositide 3‑Kinase Culminating in the Identification of (<i>S</i>)‑2-((2-(1-Isopropyl‑1<i>H</i>‑1,2,4-triazol-5-yl)-5,6-dihydrobenzo[<i>f</i>]imidazo[1,2‑<i>d</i>][1,4]oxazepin-9-yl)oxy)propanamide (GDC-0326)
Inhibitors of the class I phosphoinositide
3-kinase (PI3K) isoform
PI3Kα have received substantial attention for their potential
use in cancer therapy. Despite the particular attraction of targeting
PI3Kα, achieving selectivity for the inhibition of this isoform
has proved challenging. Herein we report the discovery of inhibitors
of PI3Kα that have selectivity over the other class I isoforms
and all other kinases tested. In GDC-0032 (<b>3</b>, taselisib),
we previously minimized inhibition of PI3Kβ relative to the
other class I insoforms. Subsequently, we extended our efforts to
identify PI3Kα-specific inhibitors using PI3Kα crystal
structures to inform the design of benzoxazepin inhibitors with selectivity
for PI3Kα through interactions with a nonconserved residue.
Several molecules selective for PI3Kα relative to the other
class I isoforms, as well as other kinases, were identified. Optimization
of properties related to drug metabolism then culminated in the identification
of the clinical candidate GDC-0326 (<b>4</b>)
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