31 research outputs found
The thiirane-based selective MT1-MMP/MMP2 inhibitor ND-322 reduces melanoma tumor growth and delays metastatic dissemination
MT1-MMP and MMP2 have been implicated as pro-tumorigenic and pro-metastatic factors in a wide variety of cancers including melanoma. We have previously demonstrated that MT1-MMP is highly expressed in melanoma where it promotes melanoma cell invasion and metastasis in part through the activation of its target MMP2. Given the accessibility of MMPs, as they are either secreted (e.g. MMP2) or membrane-tethered (e.g. MT1-MMP), they represent ideal targets for specific inhibition via small molecules. Here we show that the novel small-molecule inhibitor ND-322 with high selectivity for MT1- MMP and MMP2, effectively inhibits MT1-MMP and MMP2 activity resulting in reduced in vitro melanoma cell growth, migration and invasion. Importantly, these inhibitory effects lead to significant reduction of melanoma tumor growth and metastasis. We further show that while cell migration and invasion could be similarly hampered by specific inhibition of either MT1-MMP or MMP2 via shRNAs, the growth inhibitory activity of ND-322 could only be mirrored by specific inhibition of MT1-MMP. These data support ND-322 as a novel effective inhibitor capable of counteracting both MT1-MMP and MMP2, two key proteases involved in melanoma growth and metastasis. ND-322 may therefore represent a new inhibitor in the repertoire of treatments against melanoma
Onchocerca volvulus Molting Inhibitors Identified through Scaffold Hopping
The
anthelmintic closantel has shown promise in abrogating the L3 molting
of Onchocerca volvulus, the causative
agent of the infectious disease onchocerciasis. In our search for
alternative scaffolds, we utilized a fragment replacement/modification
approach to generate novel chemotypes with improved chitinase inhibitory
properties. Further evaluation of the compounds unveiled the potential
of urea-tropolones as potent inhibitors of <i>O. volvulus</i> L3 molting
Influencing Antibody-Mediated Attenuation of Methamphetamine CNS Distribution through Vaccine Linker Design
Active
vaccination examining a single hapten engendered with a series of
peptidic linkers has resulted in the production of antimethamphetamine
antibodies. Given the limited chemical complexity of methamphetamine,
the structure of the linker species embedded within the hapten could
have a substantial effect on the ultimate efficacy of the resulting
vaccines. Herein, we investigate linker effects by generating a series
of methamphetamine haptens that harbor a linker with varying amino
acid identity, peptide length, and associated carrier protein. Independent
changes in each of these parameters were found to result in alterations
in both the quantity and quality of the antibodies induced by vaccination.
Although it was found that the consequence of the linker design was
also dependent on the identity of the carrier protein, we demonstrate
overall that the inclusion of a short, structurally simple, amino
acid linker benefits the efficacy of a methamphetamine vaccine in
limiting brain penetration of the free drug
Selective Gelatinase Inhibitor Neuroprotective Agents Cross the Blood-Brain Barrier
SB-3CT, a potent and selective inhibitor of matrix metalloproteinase-2
and -9, has shown efficacy in several animal models of neurological
diseases. One of the greatest challenges in the development of therapeutics
for neurological diseases is the inability of drugs to cross the blood-brain
barrier. A sensitive bioanalytical method based on ultraperformance
liquid chromatography with multiple-reaction monitoring detection
was developed to measure levels of SB-3CT, its active metabolite,
the α-methyl analogue, and its <i>p</i>-hydroxy metabolite
in plasma and brain. The compounds are rapidly absorbed and are readily
distributed to the brain. The pharmacokinetic properties of these
gelatinase inhibitors and the efficacy shown by SB-3CT in animal models
of stroke, subarachnoid hemorrhage, and spinal cord injury indicate
that this class of compounds holds considerable promise in the treatment
of diseases of the central nervous system
Substituted 4-hydroxy-1,2,3-triazoles:synthesis, characterization and first drug design applications through bioisosteric modulation and scaffold hopping approaches
Acceleration of diabetic wound healing using a novel protease–anti-protease combination therapy
Early Gelatinase Activity Is Not a Determinant of Long-Term Recovery after Traumatic Brain Injury in the Immature Mouse.
The gelatinases, matrix metalloproteinases (MMP)-2 and MMP-9, are thought to be key mediators of secondary damage in adult animal models of brain injury. Moreover, an acute increase in these proteases in plasma and brain extracellular fluid of adult patients with moderate-to-severe traumatic brain injuries (TBIs) is associated with poorer clinical outcomes and mortality. Nonetheless, their involvement after TBI in the pediatric brain remains understudied. Using a murine model of TBI at postnatal day 21 (p21), approximating a toddler-aged child, we saw upregulation of active and pro-MMP-9 and MMP-2 by gelatin zymography at 48 h post-injury. We therefore investigated the role of gelatinases on long-term structural and behavioral outcomes after injury after acute inhibition with a selective gelatinase inhibitor, p-OH SB-3CT. After systemic administration, p-OH SB-3CT crossed the blood-brain barrier at therapeutically-relevant concentrations. TBI at p21 induced hyperactivity, deficits in spatial learning and memory, and reduced sociability when mice were assessed at adulthood, alongside pronounced tissue loss in key neuroanatomical regions. Acute and short-term post-injury treatment with p-OH SB-3CT did not ameliorate these long-term behavioral, cognitive, or neuropathological deficits as compared to vehicle-treated controls, suggesting that these deficits were independent of MMP-9 and MMP-2 upregulation. These findings emphasize the vulnerability of the immature brain to the consequences of traumatic injuries. However, early upregulation of gelatinases do not appear to be key determinants of long-term recovery after an early-life injury
Water-Soluble MMP-9 Inhibitor Prodrug Generates Active Metabolites That Cross the Blood–Brain Barrier
Water-Soluble MMP‑9 Inhibitor Prodrug Generates Active Metabolites That Cross the Blood–Brain Barrier
MMP-9
plays a detrimental role in the pathology of several neurological
diseases and, thus, represents an important target for intervention.
The water-soluble prodrug ND-478 is hydrolyzed to the active MMP-9
inhibitor ND-322, which in turn is <i>N</i>-acetylated to
the even more potent metabolite ND-364. We used a sensitive bioanalytical
method based on ultraperformance liquid chromatography with multiple-reaction
monitoring detection to measure levels of ND-478, ND-322, and ND-364
in plasma and brain after administration of ND-478 and the metabolites.
ND-478 did not cross the blood–brain barrier, as was expected;
however the active metabolites ND-322 and ND-364 distributed to the
brain. The active compound after administration of either ND-478 or
ND-322 is likely ND-364. ND-322 is <i>N</i>-acetylated in
both brain and liver, but it is so metabolized preferentially in liver.
Since <i>N</i>-acetyltransferases involved in the metabolism
of ND-322 to ND-364 are polymorphic, direct administration of the <i>N</i>-acetylated ND-364 would achieve the requisite therapeutic
levels in the brain