15 research outputs found
Structure of the Catalytic Domain of Human Protein Kinase C β II Complexed with a Bisindolylmaleimide Inhibitor ‡
Preclinical Characterization of PF-00868554, a Potent Nonnucleoside Inhibitor of the Hepatitis C Virus RNA-Dependent RNA Polymeraseâ–¿ â€
PF-00868554 is a nonnucleoside inhibitor of the hepatitis C virus (HCV) RNA polymerase, which exerts its inhibitory effect by binding to the thumb base domain of the protein. It is a potent and selective inhibitor, with a mean 50% inhibitory concentration of 0.019 μM against genotype 1 polymerases and a mean 50% effective concentration (EC50) of 0.075 μM against the genotype 1b-Con1 replicon. To determine the in vitro antiviral activity of PF-00868554 against various HCV strains, a panel of chimeric replicons was generated, in which polymerase sequences derived from genotype 1a and 1b clinical isolates were cloned into the 1b-Con1 subgenomic reporter replicon. Our results indicate that PF-00868554 has potent in vitro antiviral activity against a majority (95.8%) of genotype 1a and 1b replicons, with an overall mean EC50 of 0.059 μM. PF-00868554 showed no cytotoxic effect in several human cell lines, up to the highest concentration evaluated (320 μM). Furthermore, the antiviral activity of PF-00868554 was retained in the presence of human serum proteins. An in vitro resistance study of PF-00868554 identified M423T as the predominant resistance mutation, resulting in a 761-fold reduction in susceptibility to PF-00868554 but no change in susceptibility to alpha interferon and a polymerase inhibitor that binds to a different region. PF-00868554 also showed good pharmacokinetic properties in preclinical animal species. Our results demonstrate that PF-00868554 has potent and broad-spectrum antiviral activity against genotype 1 HCV strains, supporting its use as an oral antiviral agent in HCV-infected patients
Design of Selective Benzoxazepin PI3Kδ Inhibitors Through Control of Dihedral Angles
A novel selective benzoxazepin inhibitor
of PI3Kδ has been discovered. Beginning from compound <b>3</b>, an αPI3K inhibitor, we utilized structure-based drug
design and computational analysis of dihedral torsion angles to optimize
for PI3Kδ isoform potency and isoform selectivity. Further medicinal
chemistry optimization of the series led to the identification of <b>24</b>, a highly potent and selective inhibitor of PI3Kδ
Discovery of a potent, selective, and orally available class I phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) kinase inhibitor (GDC-0980) for the treatment of cancer
The discovery of 2 (GDC-0980), a class I PI3K and mTOR kinase inhibitor for oncology indications, is described. mTOR inhibition was added to the class I PI3K inhibitor 1 (GDC-0941) scaffold primarily through the substitution of the indazole in 1 for a 2-aminopyrimidine. This substitution also increased the microsomal stability and the free fraction of compounds as evidenced through a pairwise comparison of molecules that were otherwise identical. Highlighted in detail are analogues of an advanced compound 4 that were designed to improve solubility, resulting in 2. This compound, is potent across PI3K class I isoforms with IC(50)s of 5, 27, 7, and 14 nM for PI3Kα, β, δ, and γ, respectively, inhibits mTOR with a K(i) of 17 nM yet is highly selective versus a large panel of kinases including others in the PIKK family. On the basis of the cell potency, low clearance in mouse, and high free fraction, 2 demonstrated significant efficacy in mouse xenografts when dosed as low as 1 mg/kg orally and is currently in phase I clinical trials for cancer
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
Pyrimidoaminotropanes as Potent, Selective, and Efficacious Small Molecule Kinase Inhibitors of the Mammalian Target of Rapamycin (mTOR)
We
have recently reported a series of tetrahydroquinazoline (THQ)
mTOR inhibitors that produced a clinical candidate <b>1</b> (GDC-0349).
Through insightful design, we hoped to discover and synthesize a new
series of small molecule inhibitors that could attenuate CYP3A4 time-dependent
inhibition commonly observed with the THQ scaffold, maintain or improve
aqueous solubility and oral absorption, reduce free drug clearance,
and selectively increase mTOR potency. Through key in vitro and in
vivo studies, we demonstrate that a pyrimidoaminotropane based core
was able to address each of these goals. This effort culminated in
the discovery of <b>20</b> (GNE-555), a highly potent, selective,
metabolically stable, and efficacious mTOR inhibitor
Structure-Based Design of GNE-495, a Potent and Selective MAP4K4 Inhibitor with Efficacy in Retinal Angiogenesis
Diverse
biological roles for mitogen-activated protein kinase kinase
kinase kinase 4 (MAP4K4) have necessitated the identification of potent
inhibitors in order to study its function in various disease contexts.
In particular, compounds that can be used to carry out such studies
in vivo would be critical for elucidating the potential for therapeutic
intervention. A structure-based design effort coupled with property-guided
optimization directed at minimizing the ability of the inhibitors
to cross into the CNS led to an advanced compound <b>13</b> (GNE-495)
that showed excellent potency and good PK and was used to demonstrate
in vivo efficacy in a retinal angiogenesis model recapitulating effects
that were observed in the inducible <i>Map4k4</i> knockout
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
The Design and Identification of Brain Penetrant Inhibitors of Phosphoinositide 3-Kinase α
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>)