Polymer Microparticles Prolong Delivery of the 15-PGDH Inhibitor SW033291

As the prevalence of age-related fibrotic diseases continues to increase, novel antifibrotic therapies are emerging to address clinical needs. However, many novel therapeutics for managing chronic fibrosis are small-molecule drugs that require frequent dosing to attain effective concentrations. Although bolus parenteral administrations have become standard clinical practice, an extended delivery platform would achieve steady-state concentrations over a longer time period with fewer administrations. This study lays the foundation for the development of a sustained release platform for the delivery of (+)SW033291, a potent, small-molecule inhibitor of the 15-hydroxyprostaglandin dehydrogenase (15-PGDH) enzyme, which has previously demonstrated efficacy in a murine model of pulmonary fibrosis. Herein, we leverage fine-tuned cyclodextrin microparticles—specifically, β-CD microparticles (β-CD MPs)—to extend the delivery of the 15-PGDH inhibitor, (+)SW033291, to over one week.

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Polymer microparticles prolong delivery of the 15-PGDH inhibitor SW033291

10.1101/2021.08.15.456403 ◽

2021 ◽

Author(s):

Alan B. Dogan ◽

Nathan A. Rohner ◽

Julianne N.P. Smith ◽

Jessica A. Kilgore ◽

Noelle S. Williams ◽

...

Keyword(s):

Steady State ◽

Small Molecule ◽

Small Molecule Drugs ◽

Standard Clinical Practice ◽

Age Related ◽

Time Period ◽

Molecule Inhibitor ◽

Delivery Platform ◽

Fibrotic Diseases ◽

Polymer Microparticles

As the prevalence of age-related fibrotic diseases continues to increase, novel antifibrotic therapies are emerging to address clinical needs. However, many novel therapeutics for managing chronic fibrosis are small-molecule drugs that require frequent dosing to attain effective concentrations. While bolus parenteral administrations have become standard clinical practice, an extended delivery platform would achieve steady state concentrations over a longer time period with fewer administrations. This study lays the foundation for the development of a sustained release platform for the delivery of (+)SW033291, a potent, small-molecule inhibitor of the 15-hydroxyprostaglandin dehydrogenase (15-PGDH) enzyme, which has previously demonstrated efficacy in a murine model of pulmonary fibrosis. Herein, we leverage fine-tuned cyclodextrin microparticles - specifically β-CD microparticles (β-CD MPs) - to extend the delivery of 15-PGDH inhibitor, (+)SW033291, to over one week.

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Thermostable small-molecule inhibitor of angiogenesis and vascular permeability that suppresses a pERK-FosB/ΔFosB–VCAM-1 axis

Science Advances ◽

10.1126/sciadv.aaz7815 ◽

2020 ◽

Vol 6 (31) ◽

pp. eaaz7815

Author(s):

Yue Li ◽

Ahmad M. N. Alhendi ◽

Mei-Chun Yeh ◽

Mina Elahy ◽

Fernando S. Santiago ◽

...

Keyword(s):

Vascular Permeability ◽

Small Molecule ◽

Wound Repair ◽

Network Formation ◽

Small Molecule Inhibitor ◽

Age Related Macular Degeneration ◽

Endothelial Cell Proliferation ◽

Age Related ◽

Molecule Inhibitor

Vascular permeability and angiogenesis underpin neovascular age-related macular degeneration and diabetic retinopathy. While anti-VEGF therapies are widely used clinically, many patients do not respond optimally, or at all, and small-molecule therapies are lacking. Here, we identified a dibenzoxazepinone BT2 that inhibits endothelial cell proliferation, migration, wound repair in vitro, network formation, and angiogenesis in mice bearing Matrigel plugs. BT2 interacts with MEK1 and inhibits ERK phosphorylation and the expression of FosB/ΔFosB, VCAM-1, and many genes involved in proliferation, migration, angiogenesis, and inflammation. BT2 reduced retinal vascular leakage following rat choroidal laser trauma and rabbit intravitreal VEGF-A165 administration. BT2 suppressed retinal CD31, pERK, VCAM-1, and VEGF-A165 expression. BT2 reduced retinal leakage in rats at least as effectively as aflibercept, a first-line therapy for nAMD/DR. BT2 withstands boiling or autoclaving and several months’ storage at 22°C. BT2 is a new small-molecule inhibitor of vascular permeability and angiogenesis.

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Phase I and Pharmacokinetic Study of YM155, a Small-Molecule Inhibitor of Survivin

Journal of Clinical Oncology ◽

10.1200/jco.2008.17.2064 ◽

2008 ◽

Vol 26 (32) ◽

pp. 5198-5203 ◽

Cited By ~ 169

Author(s):

Anthony W. Tolcher ◽

Alain Mita ◽

Lionel D. Lewis ◽

Christopher R. Garrett ◽

Elizabeth Till ◽

...

Keyword(s):

Steady State ◽

Antitumor Activity ◽

Small Molecule ◽

Plasma Concentrations ◽

Specific Antigen ◽

Maximum Tolerated Dose ◽

Small Molecule Inhibitor ◽

Pharmacokinetic Parameters ◽

Minor Response ◽

Molecule Inhibitor

Purpose To determine the maximum-tolerated dose (MTD) and assess the safety, pharmacokinetics, and preliminary evidence of antitumor activity of YM155, a small-molecule inhibitor of survivin. Patients and Methods Patients with advanced solid malignancies or lymphoma were treated with escalating doses of YM155 administered by 168-hour continuous intravenous infusion (CIVI). Plasma and urine samples were assayed to determine pharmacokinetic parameters and excretion. Results Forty-one patients received 127 cycles of YM155 at doses ranging from 1.8 to 6.0 mg/m2/d by 168-hour CIVI every 3 weeks. Overall, the most common grade 1 to 2 toxicities were stomatitis, pyrexia, and nausea, whereas grade 3 and 4 toxicities were rare. Reversible elevation in serum creatinine in two patients, with one developing acute tubular necrosis, was dose-limiting at 6.0 mg/m2. The MTD was 4.8 mg/m2. At the MTD, the mean steady-state concentration, clearance, volume of distribution at steady-state, and terminal elimination half-life were 7.7 ng/mL, 47.7 L/h, 1,763 L, and 26 hours, respectively. One complete and two partial responses lasting 8, 24+ and 48+ months occurred in three patients with non-Hodgkin's lymphoma, two patients with hormone- and docetaxel-refractory prostate cancer had prostate-specific antigen responses, and one patient with non–small-cell lung cancer had a minor response. Conclusion YM155 can be administered safely at 4.8 mg/m2/d 168 hours CIVI every 3 weeks. The absence of severe toxicities, attainment of plasma concentrations active in preclinical models, and compelling antitumor activity warrant further disease-directed studies of this agent alone and in combination with chemotherapy in a broad array of tumors.

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Mechanism-based enzyme activating compounds

10.1101/2020.04.08.032235 ◽

2020 ◽

Cited By ~ 1

Author(s):

Xiangying Guan ◽

Alok Upadhyay ◽

Raj Chakrabarti

Keyword(s):

Steady State ◽

Small Molecule ◽

Active Sites ◽

Degrees Of Freedom ◽

Enzymatic Catalysis ◽

Enzyme Activation ◽

Allosteric Site ◽

Age Related ◽

Small Molecule Modulators ◽

Enzyme Activators

Compared to inhibitors, which constitute the vast majority of today’s drugs, enzyme activators have considerable advantages, especially in the context of enzymes that regulate reactive flux through metabolic pathways associated with chronic, age-related diseases and lifespan. Across all families of enzymes, only a dozen or so distinct classes of small molecule activators have been characterized. Enzyme activators that are not based on naturally evolved allosteric mechanisms are much more difficult to design than inhibitors, because enzymatic catalysis has been optimized over billions of years of evolution. Here, we introduce modes of enzyme activation based on the catalytic reaction mechanisms of enzymes for which naturally evolved activators may not exist. We establish biophysical properties of small molecule modulators that are necessary to achieve desired changes in the steady state and non-steady state parameters of these enzymes, including changes in local conformational degrees of freedom conducive to the enhancement of catalytic activity that can be identified through computational modeling of their active sites. We illustrate how the modes of action of several compounds reported to activate enzymes without known allosteric sites may be understood using the framework presented. We also present simulations and new experimental results in support of this framework, including identification of the mechanism of a compound that activates the human SIRT3 enzyme, which does not contain a known allosteric site, under physiologically relevant conditions.

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