12 research outputs found
Discovery of Small-Molecule Inhibitors of Ubiquitin Specific Protease 7 (USP7) Using Integrated NMR and in Silico Techniques
USP7
is a deubiquitinase implicated in destabilizing the tumor
suppressor p53, and for this reason it has gained increasing attention
as a potential oncology target for small molecule inhibitors. Herein
we describe the biophysical, biochemical, and computational approaches
that led to the identification of 4-(2-aminopyridin-3-yl)Āphenol compounds
described by Kategaya (Nature 2017, 550, 534ā538) as specific inhibitors of
USP7. Fragment based lead discovery (FBLD) by NMR combined with virtual
screening and re-mining of biochemical high-throughput screening (HTS)
hits led to the discovery of a series of ligands that bind in the
āpalmā region of the catalytic domain of USP7 and inhibit
its catalytic activity. These ligands were then optimized by structure-based
design to yield cell-active molecules with reasonable physical properties.
This discovery process not only involved multiple techniques working
in concert but also illustrated a unique way in which hits from orthogonal
screening approaches complemented each other for lead identification
Discovery of Small-Molecule Inhibitors of Ubiquitin Specific Protease 7 (USP7) Using Integrated NMR and in Silico Techniques
USP7
is a deubiquitinase implicated in destabilizing the tumor
suppressor p53, and for this reason it has gained increasing attention
as a potential oncology target for small molecule inhibitors. Herein
we describe the biophysical, biochemical, and computational approaches
that led to the identification of 4-(2-aminopyridin-3-yl)Āphenol compounds
described by Kategaya (Nature 2017, 550, 534ā538) as specific inhibitors of
USP7. Fragment based lead discovery (FBLD) by NMR combined with virtual
screening and re-mining of biochemical high-throughput screening (HTS)
hits led to the discovery of a series of ligands that bind in the
āpalmā region of the catalytic domain of USP7 and inhibit
its catalytic activity. These ligands were then optimized by structure-based
design to yield cell-active molecules with reasonable physical properties.
This discovery process not only involved multiple techniques working
in concert but also illustrated a unique way in which hits from orthogonal
screening approaches complemented each other for lead identification
A Unique Approach to Design Potent and Selective Cyclic Adenosine Monophosphate Response Element Binding Protein, Binding Protein (CBP) Inhibitors
The
epigenetic regulator CBP/P300 presents a novel therapeutic
target for oncology. Previously, we disclosed the development of potent
and selective CBP bromodomain inhibitors by first identifying pharmacophores
that bind the KAc region and then building into the LPF shelf. Herein,
we report the āhybridizationā of a variety of KAc-binding
fragments with a tetrahydroquinoline scaffold that makes optimal interactions
with the LPF shelf, imparting enhanced potency and selectivity to
the hybridized ligand. To demonstrate the utility of our hybridization
approach, two analogues containing unique Asn binders and the optimized
tetrahydroquinoline moiety were rapidly optimized to yield single-digit
nanomolar inhibitors of CBP with exquisite selectivity over BRD4(1)
and the broader bromodomain family
The Rational Design of Selective Benzoxazepin Inhibitors of the Ī±āIsoform of Phosphoinositide 3āKinase Culminating in the Identification of (<i>S</i>)ā2-((2-(1-Isopropylā1<i>H</i>ā1,2,4-triazol-5-yl)-5,6-dihydrobenzo[<i>f</i>]imidazo[1,2ā<i>d</i>][1,4]oxazepin-9-yl)oxy)propanamide (GDC-0326)
Inhibitors of the class I phosphoinositide
3-kinase (PI3K) isoform
PI3KĪ± have received substantial attention for their potential
use in cancer therapy. Despite the particular attraction of targeting
PI3KĪ±, achieving selectivity for the inhibition of this isoform
has proved challenging. Herein we report the discovery of inhibitors
of PI3KĪ± 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 PI3KĪ² relative to the
other class I insoforms. Subsequently, we extended our efforts to
identify PI3KĪ±-specific inhibitors using PI3KĪ± crystal
structures to inform the design of benzoxazepin inhibitors with selectivity
for PI3KĪ± through interactions with a nonconserved residue.
Several molecules selective for PI3KĪ± 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>)
GNE-886: A Potent and Selective Inhibitor of the Cat Eye Syndrome Chromosome Region Candidate 2 Bromodomain (CECR2)
The
biological function of bromodomains, epigenetic readers of
acetylated lysine residues, remains largely unknown. Herein we report
our efforts to discover a potent and selective inhibitor of the bromodomain
of cat eye syndrome chromosome region candidate 2 (CECR2). Screening
of our internal medicinal chemistry collection led to the identification
of a pyrrolopyridone chemical lead, and subsequent structure-based
drug design led to a potent and selective CECR2 bromodomain inhibitor
(GNE-886) suitable for use as an in vitro tool compound
GNE-886: A Potent and Selective Inhibitor of the Cat Eye Syndrome Chromosome Region Candidate 2 Bromodomain (CECR2)
The
biological function of bromodomains, epigenetic readers of
acetylated lysine residues, remains largely unknown. Herein we report
our efforts to discover a potent and selective inhibitor of the bromodomain
of cat eye syndrome chromosome region candidate 2 (CECR2). Screening
of our internal medicinal chemistry collection led to the identification
of a pyrrolopyridone chemical lead, and subsequent structure-based
drug design led to a potent and selective CECR2 bromodomain inhibitor
(GNE-886) suitable for use as an in vitro tool compound
Diving into the Water: Inducible Binding Conformations for BRD4, TAF1(2), BRD9, and CECR2 Bromodomains
The
biological role played by non-BET bromodomains remains poorly understood,
and it is therefore imperative to identify potent and highly selective
inhibitors to effectively explore the biology of individual bromodomain
proteins. A ligand-efficient nonselective bromodomain inhibitor was
identified from a 6-methyl pyrrolopyridone fragment. Small hydrophobic
substituents replacing the <i>N</i>-methyl group were designed
directing toward the conserved bromodomain water pocket, and two distinct
binding conformations were then observed. The substituents either
directly displaced and rearranged the conserved solvent network, as
in BRD4(1) and TAF1(2), or induced a narrow hydrophobic channel adjacent
to the lipophilic shelf, as in BRD9 and CECR2. The preference of distinct
substituents for individual bromodomains provided selectivity handles
useful for future lead optimization efforts for selective BRD9, CECR2,
and TAF1(2) inhibitors
Discovery of a Potent Small-Molecule Antagonist of Inhibitor of Apoptosis (IAP) Proteins and Clinical Candidate for the Treatment of Cancer (GDC-0152)
A series of compounds were designed and synthesized as
antagonists of cIAP1/2, ML-IAP, and XIAP based on the N-terminus,
AVPI, of mature Smac. Compound <b>1</b> (GDC-0152) has the best
profile of these compounds; it binds to the XIAP BIR3 domain, the
BIR domain of ML-IAP, and the BIR3 domains of cIAP1 and cIAP2 with <i>K</i><sub><i>i</i></sub> values of 28, 14, 17, and
43 nM, respectively. These compounds promote degradation of cIAP1,
induce activation of caspase-3/7, and lead to decreased viability
of breast cancer cells without affecting normal mammary epithelial
cells. Compound <b>1</b> inhibits tumor growth when dosed orally
in the MDA-MB-231 breast cancer xenograft model. Compound <b>1</b> was advanced to human clinical trials, and it exhibited linear pharmacokinetics
over the dose range (0.049 to 1.48 mg/kg) tested. Mean plasma clearance
in humans was 9 Ā± 3 mL/min/kg, and the volume of distribution
was 0.6 Ā± 0.2 L/kg
GNE-781, A Highly Advanced Potent and Selective Bromodomain Inhibitor of Cyclic Adenosine Monophosphate Response Element Binding Protein, Binding Protein (CBP)
Inhibition of the bromodomain of
the transcriptional regulator
CBP/P300 is an especially interesting new therapeutic approach in
oncology. We recently disclosed in vivo chemical tool <b>1</b> (GNE-272) for the bromodomain of CBP that was moderately potent
and selective over BRD4(1). In pursuit of a more potent and selective
CBP inhibitor, we used structure-based design. Constraining the aniline
of <b>1</b> into a tetrahydroquinoline motif maintained potency
and increased selectivity 2-fold. Structureāactivity relationship
studies coupled with further structure-based design targeting the
LPF shelf, BC loop, and KAc regions allowed us to significantly increase
potency and selectivity, resulting in the identification of non-CNS
penetrant <b>19</b> (GNE-781, TR-FRET IC<sub>50</sub> = 0.94
nM, BRET IC<sub>50</sub> = 6.2 nM; BRD4(1) IC<sub>50</sub> = 5100
nĪ) that maintained good in vivo PK properties in multiple species.
Compound <b>19</b> displays antitumor activity in an AML tumor
model and was also shown to decrease Foxp3 transcript levels in a
dose dependent manner