9 research outputs found
Discovery of Selective LRRK2 Inhibitors Guided by Computational Analysis and Molecular Modeling
Mutations in the genetic sequence of leucine-rich repeat
kinase
2 (LRRK2) have been linked to increased LRRK2 activity and risk for
the development of Parkinson’s disease (PD). Potent and selective
small molecules capable of inhibiting the kinase activity of LRRK2
will be important tools for establishing a link between the kinase
activity of LRRK2 and PD. In the absence of LRRK2 kinase domain crystal
structures, a LRRK2 homology model was developed that provided robust
guidance in the hit-to-lead optimization of small molecule LRRK2 inhibitors.
Through a combination of molecular modeling, sequence analysis, and
matched molecular pair (MMP) activity cliff analysis, a potent and
selective lead inhibitor was discovered. The selectivity of this compound
could be understood using the LRRK2 homology model, and application
of this learning to a series of 2,4-diaminopyrimidine inhibitors in
a scaffold hopping exercise led to the identification of highly potent
and selective LRRK2 inhibitors that were also brain penetrable
Minimizing CYP2C9 Inhibition of Exposed-Pyridine NAMPT (Nicotinamide Phosphoribosyltransferase) Inhibitors
NAMPT
inhibitors may show potential as therapeutics for oncology. Throughout
our NAMPT inhibitor program, we found that exposed pyridines or related
heterocyclic systems in the left-hand portion of the inhibitors are
necessary pharmacophores for potent cellular NAMPT inhibition. However,
when combined with a benzyl group in the center of the inhibitors,
such pyridine-like moieties also led to consistent and potent inhibition
of CYP2C9. In an attempt to reduce CYP2C9 inhibition, a parallel synthesis
approach was used to identify central benzyl group replacements with
increased Fsp3. A spirocyclic central motif was thus discovered that
was combined with left-hand pyridines (or pyridine-like systems) to
provide cellularly potent NAMPT inhibitors with minimal CYP2C9 inhibition.
Further optimization of potency and ADME properties led to the discovery
of compound <b>68</b>, a highly potent NAMPT inhibitor with
outstanding efficacy in a mouse tumor xenograft model and lacking
measurable CYP2C9 inhibition at the concentrations tested
Structure-Based Identification of Ureas as Novel Nicotinamide Phosphoribosyltransferase (Nampt) Inhibitors
Nicotinamide
phosphoribosyltransferase (Nampt) is a promising anticancer
target. Virtual screening identified a thiourea analogue, compound <b>5</b>, as a novel highly potent Nampt inhibitor. Guided by the
cocrystal structure of <b>5</b>, SAR exploration revealed that
the corresponding urea compound <b>7</b> exhibited similar potency
with an improved solubility profile. These studies also indicated
that a 3-pyridyl group was the preferred substituent at one inhibitor
terminus and also identified a urea moiety as the optimal linker to
the remainder of the inhibitor structure. Further SAR optimization
of the other inhibitor terminus ultimately yielded compound <b>50</b> as a urea-containing Nampt inhibitor which exhibited excellent
biochemical and cellular potency (enzyme IC<sub>50</sub> = 0.007 μM;
A2780 IC<sub>50</sub> = 0.032 μM). Compound <b>50</b> also
showed excellent in vivo antitumor efficacy when dosed orally in an
A2780 ovarian tumor xenograft model (TGI of 97% was observed on day
17)
Fragment-Based Identification of Amides Derived from <i>trans</i>-2-(Pyridin-3-yl)cyclopropanecarboxylic Acid as Potent Inhibitors of Human Nicotinamide Phosphoribosyltransferase (NAMPT)
Potent, <i>trans</i>-2-(pyridin-3-yl)ÂcyclopropaneÂcarboxamide-containing
inhibitors of the human nicotinamide phosphoribosylÂtransferase
(NAMPT) enzyme were identified using fragment-based screening and
structure-based design techniques. Multiple crystal structures were
obtained of initial fragment leads, and this structural information
was utilized to improve the biochemical and cell-based potency of
the associated molecules. Many of the optimized compounds exhibited
nanomolar antiproliferative activities against human tumor lines in
in vitro cell culture experiments.
In a key example, a fragment lead (<b>13</b>, <i>K</i><sub>D</sub> = 51 μM) was elaborated into a potent NAMPT inhibitor
(<b>39</b>, NAMPT IC<sub>50</sub> = 0.0051 μM, A2780 cell
culture IC<sub>50</sub> = 0.000 49 μM) which demonstrated
encouraging in vivo efficacy in an HT-1080 mouse xenograft tumor model
Structure-Based Discovery of Novel Amide-Containing Nicotinamide Phosphoribosyltransferase (Nampt) Inhibitors
Crystal structures of several urea-
and thiourea-derived compounds
in complex with the nicotinamide phosphoribosyltransferase (Nampt)
protein were utilized to design a potent amide-containing inhibitor
bearing an aza-indole moiety (<b>7</b>, Nampt BC IC<sub>50</sub> = 9.0 nM, A2780 cell proliferation IC<sub>50</sub> = 10 nM). The
Nampt–<b>7</b> cocrystal structure was subsequently obtained
and enabled the design of additional amide-containing inhibitors which
incorporated various other fused 6,5-heterocyclic moieties and biaryl
sulfone or sulfonamide motifs. Additional modifications of these molecules
afforded many potent biaryl sulfone-containing Nampt inhibitors which
also exhibited favorable in vitro ADME properties (microsomal and
hepatocyte stability, MDCK permeability, plasma protein binding).
An optimized compound (<b>58</b>) was a potent inhibitor of
multiple cancer cell lines (IC<sub>50</sub> <10 nM vs U251, HT1080,
PC3, MiaPaCa2, and HCT116 lines), displayed acceptable mouse PK properties
(F = 41%, CL = 52.4 mL/min/kg), and exhibited robust efficacy in a
U251 mouse xenograft model
Discovery of Peptidomimetic Antibody–Drug Conjugate Linkers with Enhanced Protease Specificity
Antibody–drug
conjugates (ADCs) have become an important
therapeutic modality for oncology, with three approved by the FDA
and over 60 others in clinical trials. Despite the progress, improvements
in ADC therapeutic index are desired. Peptide-based ADC linkers that
are cleaved by lysosomal proteases have shown sufficient stability
in serum and effective payload-release in targeted cells. If the linker
can be preferentially hydrolyzed by tumor-specific proteases, safety
margin may improve. However, the use of peptide-based linkers limits
our ability to modulate protease specificity. Here we report the structure-guided
discovery of novel, nonpeptidic ADC linkers. We show that a cyclobutane-1,1-dicarboxamide-containing
linker is hydrolyzed predominantly by cathepsin B while the valine–citrulline
dipeptide linker is not. ADCs bearing the nonpeptidic linker are as
efficacious and stable in vivo as those with the dipeptide linker.
Our results strongly support the application of the peptidomimetic
linker and present new opportunities for improving the selectivity
of ADCs
Discovery of Peptidomimetic Antibody–Drug Conjugate Linkers with Enhanced Protease Specificity
Antibody–drug
conjugates (ADCs) have become an important
therapeutic modality for oncology, with three approved by the FDA
and over 60 others in clinical trials. Despite the progress, improvements
in ADC therapeutic index are desired. Peptide-based ADC linkers that
are cleaved by lysosomal proteases have shown sufficient stability
in serum and effective payload-release in targeted cells. If the linker
can be preferentially hydrolyzed by tumor-specific proteases, safety
margin may improve. However, the use of peptide-based linkers limits
our ability to modulate protease specificity. Here we report the structure-guided
discovery of novel, nonpeptidic ADC linkers. We show that a cyclobutane-1,1-dicarboxamide-containing
linker is hydrolyzed predominantly by cathepsin B while the valine–citrulline
dipeptide linker is not. ADCs bearing the nonpeptidic linker are as
efficacious and stable in vivo as those with the dipeptide linker.
Our results strongly support the application of the peptidomimetic
linker and present new opportunities for improving the selectivity
of ADCs
Discovery of Peptidomimetic Antibody–Drug Conjugate Linkers with Enhanced Protease Specificity
Antibody–drug
conjugates (ADCs) have become an important
therapeutic modality for oncology, with three approved by the FDA
and over 60 others in clinical trials. Despite the progress, improvements
in ADC therapeutic index are desired. Peptide-based ADC linkers that
are cleaved by lysosomal proteases have shown sufficient stability
in serum and effective payload-release in targeted cells. If the linker
can be preferentially hydrolyzed by tumor-specific proteases, safety
margin may improve. However, the use of peptide-based linkers limits
our ability to modulate protease specificity. Here we report the structure-guided
discovery of novel, nonpeptidic ADC linkers. We show that a cyclobutane-1,1-dicarboxamide-containing
linker is hydrolyzed predominantly by cathepsin B while the valine–citrulline
dipeptide linker is not. ADCs bearing the nonpeptidic linker are as
efficacious and stable in vivo as those with the dipeptide linker.
Our results strongly support the application of the peptidomimetic
linker and present new opportunities for improving the selectivity
of ADCs
Discovery of Highly Potent, Selective, and Brain-Penetrable Leucine-Rich Repeat Kinase 2 (LRRK2) Small Molecule Inhibitors
There is a high demand for potent, selective, and brain-penetrant
small molecule inhibitors of leucine-rich repeat kinase 2 (LRRK2)
to test whether inhibition of LRRK2 kinase activity is a potentially
viable treatment option for Parkinson’s disease patients. Herein
we disclose the use of property and structure-based drug design for
the optimization of highly ligand efficient aminopyrimidine lead compounds.
High throughput in vivo rodent cassette pharmacokinetic studies enabled
rapid validation of in vitro–in vivo correlations. Guided by
this data, optimal design parameters were established. Effective incorporation
of these guidelines into our molecular design process resulted in
the discovery of small molecule inhibitors such as <b>GNE-7915</b> (<b>18</b>) and <b>19</b>, which possess an ideal balance
of LRRK2 cellular potency, broad kinase selectivity, metabolic stability,
and brain penetration across multiple species. Advancement of <b>GNE-7915</b> into rodent and higher species toxicity studies enabled
risk assessment for early development