4 research outputs found
The Role of the Acidity of NâHeteroaryl Sulfonamides as Inhibitors of Bclâ2 Family ProteinâProtein Interactions
Overexpression of the antiapoptotic members of the Bcl-2
family
of proteins is commonly associated with cancer cell survival and resistance
to chemotherapeutics. Here, we describe the structure-based optimization
of a series of N-heteroaryl sulfonamides that demonstrate potent mechanism-based
cell death. The role of the acidic nature of the sulfonamide moiety
as it relates to potency, solubility, and clearance is examined. This
has led to the discovery of novel heterocyclic replacements for the
acylsulfonamide core of ABT-737 and ABT-263
Design, Synthesis, and Properties of a Potent Inhibitor of <i>Pseudomonas aeruginosa</i> Deacetylase LpxC
Over the past several decades, the
frequency of antibacterial resistance
in hospitals, including multidrug resistance (MDR) and its association
with serious infectious diseases, has increased at alarming rates. <i>Pseudomonas aeruginosa</i> is a leading cause of nosocomial
infections, and resistance to virtually all approved antibacterial
agents is emerging in this pathogen. To address the need for new agents
to treat MDR <i>P. aeruginosa</i>, we focused on inhibiting
the first committed step in the biosynthesis of lipid A, the deacetylation
of uridyldiphospho-3-<i>O</i>-(<i>R</i>-hydroxydecanoyl)-<i>N</i>-acetylglucosamine by the enzyme LpxC. We approached this
through the design, synthesis, and biological evaluation of novel
hydroxamic acid LpxC inhibitors, exemplified by <b>1</b>, where
cytotoxicity against mammalian cell lines was reduced, solubility
and plasma-protein binding were improved while retaining potent anti-pseudomonal
activity in vitro and in vivo
Identification of NVP-TNKS656: The Use of StructureâEfficiency Relationships To Generate a Highly Potent, Selective, and Orally Active Tankyrase Inhibitor
Tankyrase
1 and 2 have been shown to be redundant, druggable nodes
in the Wnt pathway. As such, there has been intense interest in developing
agents suitable for modulating the Wnt pathway in vivo by targeting
this enzyme pair. By utilizing a combination of structure-based design
and LipE-based structure efficiency relationships, the core of XAV939
was optimized into a more stable, more efficient, but less potent
dihydropyran motif <b>7</b>. This core was combined with elements
of screening hits <b>2</b>, <b>19</b>, and <b>33</b> and resulted in highly potent, selective tankyrase inhibitors that
are novel three pocket binders. NVP-TNKS656 (<b>43</b>) was
identified as an orally active antagonist of Wnt pathway activity
in the MMTV-Wnt1 mouse xenograft model. With an enthalpy-driven thermodynamic
signature of binding, highly favorable physicochemical properties,
and high lipophilic efficiency, NVP-TNKS656 is a novel tankyrase inhibitor
that is well suited for further in vivo validation studies
Allosteric Inhibition of SHP2: Identification of a Potent, Selective, and Orally Efficacious Phosphatase Inhibitor
SHP2
is a nonreceptor protein tyrosine phosphatase (PTP) encoded by the <i>PTPN11</i> gene involved in cell growth and differentiation
via the MAPK signaling pathway. SHP2 also purportedly plays an important
role in the programmed cell death pathway (PD-1/PD-L1). Because it
is an oncoprotein associated with multiple cancer-related diseases,
as well as a potential immunomodulator, controlling SHP2 activity
is of significant therapeutic interest. Recently in our laboratories,
a small molecule inhibitor of SHP2 was identified as an allosteric
modulator that stabilizes the autoinhibited conformation of SHP2.
A high throughput screen was performed to identify progressable chemical
matter, and X-ray crystallography revealed the location of binding
in a previously undisclosed allosteric binding pocket. Structure-based
drug design was employed to optimize for SHP2 inhibition, and several
new proteinâligand interactions were characterized. These studies
culminated in the discovery of 6-(4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)Âpyrazin-2-amine
(SHP099, <b>1</b>), a potent, selective, orally bioavailable,
and efficacious SHP2 inhibitor