9 research outputs found
AI is a viable alternative to high throughput screening: a 318-target study
: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery
Structural Basis of Selective Inhibition of Human Tankyrases
Tankyrases are poly(ADP-ribose) polymerases that have
many cellular
functions. They play pharmaceutically important roles, at least in
telomere homeostasis and Wnt signaling, by covalently ADP-ribosylating
target proteins and consequently regulating their functions. These
features make tankyrases potential targets for treatment of cancer.
We report here crystal structures of human tankyrase 2 catalytic fragment
in complex with a byproduct, nicotinamide, and with selective inhibitors
of tankyrases (IWR-1) and PARPs 1 and 2 (olaparib). Binding of these
inhibitors to tankyrase 2 induces specific conformational changes.
The crystal structures explain the selectivity of the inhibitors,
reveal the flexibility of a substrate binding loop, and explain existing
structure–activity relationship data. The first crystal structure
of a PARP enzyme in complex with a potent inhibitor, IWR-1, that does
not bind to the widely utilized nicotinamide-binding site makes the
structure valuable for development of PARP inhibitors in general
Evaluation and Structural Basis for the Inhibition of Tankyrases by PARP Inhibitors
Tankyrases, an enzyme subfamily of
human poly(ADP-ribosyl)polymerases,
are potential drug targets especially against cancer. We have evaluated
inhibition of tankyrases by known PARP inhibitors and report five
cocrystal structures of the most potent compounds in complex with
human tankyrase 2. The inhibitors include the small general PARP inhibitors
Phenanthridinone, PJ-34, and TIQ-A as well as the more advanced inhibitors
EB-47 and rucaparib. The compounds anchor to the nicotinamide subsite
of tankyrase 2. Crystal structures reveal flexibility of the ligand
binding site with implications for drug development against tankyrases
and other ADP-ribosyltransferases. EB-47 mimics the substrate NAD<sup>+</sup> and extends from the nicotinamide to the adenosine subsite.
The clinical ARTD1 inhibitor candidate rucaparib was the most potent
tankyrase inhibitor identified (24 and 14 nM for tankyrases), which
indicates that inhibition of tankyrases would affect the cellular
responses of this compound
Derivatives of a PARP inhibitor TIQ-A through the synthesis of 8-alkoxythieno[2,3-c]isoquinolin-5(4H)-ones
Abstract
Thieno[2,3-c]isoquinolin-5(4H)-one is known for its potential as an anti-ischemic agent through the inhibition of poly(ADP-ribose) polymerase 1 (PARP1). However, the compound also inhibits many other enzymes of the PARP family, potentially limiting its usability. The broad inhibition profile, on the other hand, indicates that this molecule backbone could be potentially used as a scaffold for the development of specific inhibitors for certain PARP enzymes. These efforts call for novel synthetic strategies for substituted thieno[2,3-c]isoquinolin-5(4H)-one that could provide the needed selectivity. In this article, an efficient synthetic strategy for 8-alkoxythieno[2,3-c]isoquinolin-5(4H)-ones through eight steps is presented and other tested synthetic pathways are discussed in detail. Synthesis of 7-methoxythieno[2,3-c]isoquinolin-5(4H)-one is also demonstrated to show that the strategy can be applied widely in the syntheses of substituted alkoxythieno[2,3-c]isoquinolin-5(4H)-ones
Discovery of Tankyrase Inhibiting Flavones with Increased Potency and Isoenzyme Selectivity
Tankyrases
are ADP-ribosyltransferases that play key roles in various
cellular pathways, including the regulation of cell proliferation,
and thus, they are promising drug targets for the treatment of cancer.
Flavones have been shown to inhibit tankyrases and we report here
the discovery of more potent and selective flavone derivatives. Commercially
available flavones with single substitutions were used for structure–activity
relationship studies, and cocrystal structures of the 18 hit compounds
were analyzed to explain their potency and selectivity. The most potent
inhibitors were also tested in a cell-based assay, which demonstrated
that they effectively antagonize Wnt signaling. To assess selectivity,
they were further tested against a panel of homologous human ADP-ribosyltransferases.
The most effective compound, <b>22</b> (MN-64), showed 6 nM
potency against tankyrase 1, isoenzyme selectivity, and Wnt signaling
inhibition. This work forms a basis for rational development of flavones
as tankyrase inhibitors and guides the development of other structurally
related inhibitors
[1,2,4]Triazolo[3,4‑<i>b</i>]benzothiazole Scaffold as Versatile Nicotinamide Mimic Allowing Nanomolar Inhibition of Different PARP Enzymes
We report [1,2,4]triazolo[3,4-b]benzothiazole
(TBT) as a new inhibitor scaffold, which competes with nicotinamide
in the binding pocket of human poly- and mono-ADP-ribosylating enzymes.
The binding mode was studied through analogues and cocrystal structures
with TNKS2, PARP2, PARP14, and PARP15. Based on the substitution pattern,
we were able to identify 3-amino derivatives 21 (OUL243)
and 27 (OUL232) as inhibitors of mono-ARTs PARP7, PARP10,
PARP11, PARP12, PARP14, and PARP15 at nM potencies, with 27 being the most potent PARP10 inhibitor described to date (IC50 of 7.8 nM) and the first PARP12 inhibitor ever reported.
On the contrary, hydroxy derivative 16 (OUL245) inhibits
poly-ARTs with a selectivity toward PARP2. The scaffold does not possess
inherent cell toxicity, and the inhibitors can enter cells and engage
with the target protein. This, together with favorable ADME properties,
demonstrates the potential of TBT scaffold for future drug development
efforts toward selective inhibitors against specific enzymes
Discovery of a Novel Series of Tankyrase Inhibitors by a Hybridization Approach
A structure-guided hybridization
approach using two privileged
substructures gave instant access to a new series of tankyrase inhibitors.
The identified inhibitor <b>16</b> displays high target affinity
on tankyrase 1 and 2 with biochemical and cellular IC<sub>50</sub> values of 29 nM, 6.3 nM and 19 nM, respectively, and high selectivity
toward other poly (ADP-ribose) polymerase enzymes. The identified
inhibitor shows a favorable in vitro ADME profile as well as good
oral bioavailability in mice, rats, and dogs. Critical for the approach
was the utilization of an appropriate linker between 1,2,4-triazole
and benzimidazolone moieties, whereby a cyclobutyl linker displayed
superior affinity compared to a cyclohexane and phenyl linker
Discovery of a Novel Series of Tankyrase Inhibitors by a Hybridization Approach
A structure-guided hybridization
approach using two privileged
substructures gave instant access to a new series of tankyrase inhibitors.
The identified inhibitor <b>16</b> displays high target affinity
on tankyrase 1 and 2 with biochemical and cellular IC<sub>50</sub> values of 29 nM, 6.3 nM and 19 nM, respectively, and high selectivity
toward other poly (ADP-ribose) polymerase enzymes. The identified
inhibitor shows a favorable in vitro ADME profile as well as good
oral bioavailability in mice, rats, and dogs. Critical for the approach
was the utilization of an appropriate linker between 1,2,4-triazole
and benzimidazolone moieties, whereby a cyclobutyl linker displayed
superior affinity compared to a cyclohexane and phenyl linker
[1,2,4]Triazolo[3,4‑<i>b</i>]benzothiazole Scaffold as Versatile Nicotinamide Mimic Allowing Nanomolar Inhibition of Different PARP Enzymes
We report [1,2,4]triazolo[3,4-b]benzothiazole
(TBT) as a new inhibitor scaffold, which competes with nicotinamide
in the binding pocket of human poly- and mono-ADP-ribosylating enzymes.
The binding mode was studied through analogues and cocrystal structures
with TNKS2, PARP2, PARP14, and PARP15. Based on the substitution pattern,
we were able to identify 3-amino derivatives 21 (OUL243)
and 27 (OUL232) as inhibitors of mono-ARTs PARP7, PARP10,
PARP11, PARP12, PARP14, and PARP15 at nM potencies, with 27 being the most potent PARP10 inhibitor described to date (IC50 of 7.8 nM) and the first PARP12 inhibitor ever reported.
On the contrary, hydroxy derivative 16 (OUL245) inhibits
poly-ARTs with a selectivity toward PARP2. The scaffold does not possess
inherent cell toxicity, and the inhibitors can enter cells and engage
with the target protein. This, together with favorable ADME properties,
demonstrates the potential of TBT scaffold for future drug development
efforts toward selective inhibitors against specific enzymes