Energy-Based Pharmacophore and Three-Dimensional Quantitative Structure–Activity Relationship (3D-QSAR) Modeling Combined with Virtual Screening To Identify Novel Small-Molecule Inhibitors of Silent Mating-Type Information Regulation 2 Homologue 1 (SIRT1)

Silent mating-type information regulation 2 homologue 1 (SIRT1), being the homologous enzyme of silent information regulator-2 gene in yeast, has multifaceted functions. It deacetylates a wide range of histone and nonhistone proteins; hence, it has good therapeutic importance. SIRT1 was believed to be overexpressed in many cancers (prostate, colon) and inflammatory disorders (rheumatoid arthritis). Hence, designing inhibitors against SIRT1 could be considered valuable. Both structure-based and ligand-based drug design strategies were employed to design novel inhibitors utilizing high-throughput virtual screening of chemical databases. An energy-based pharmacophore was generated using the crystal structure of SIRT1 bound with a small molecule inhibitor and compared with a ligand-based pharmacophore model that showed four similar features. A three-dimensional quantitative structure–activity relationship (3D-QSAR) model was developed and validated to be employed in the virtual screening protocol. Among the designed compounds, <b>Lead 17</b> emerged as a promising SIRT1 inhibitor with IC₅₀ of 4.34 μM and, at nanomolar concentration (360 nM), attenuated the proliferation of prostate cancer cells (LnCAP). In addition, <b>Lead 17</b> significantly reduced production of reactive oxygen species, thereby reducing pro inflammatory cytokines such as IL6 and TNF-α. Furthermore, the anti-inflammatory potential of the compound was ascertained using an animal paw inflammation model induced by carrageenan. Thus, the identified SIRT1 inhibitors could be considered as potent leads to treat both cancer and inflammation

Design, Synthesis, and Identification of Silicon Incorporated Oxazolidinone Antibiotics with Improved Brain Exposure

Therapeutic options for brain infections caused by pathogens with a reduced sensitivity to drugs are limited. Recent reports on the potential use of linezolid in treating brain infections prompted us to design novel compounds around this scaffold. Herein, we describe the design and synthesis of various oxazolidinone antibiotics with the incorporation of silicon. Our findings in preclinical species suggest that silicon incorporation is highly useful in improving brain exposures. Interestingly, three compounds from this series demonstrated up to a 30-fold higher brain/plasma ratio when compared to linezolid thereby indicating their therapeutic potential in brain associated disorders

Phase I/II evaluation of RV1001, a novel PI3Kδ inhibitor, in spontaneous canine lymphoma

<div><p>Background</p><p>RV1001 is a novel, potent, and selective PI3Kδ inhibitor. The purpose of this study was to evaluate the safety and efficacy of RV1001 in canine Non-Hodgkin lymphoma (NHL).</p><p>Methods and results</p><p>Inhibition of endogenous pAKT by RV1001 in primary canine NHL cells was determined by Western blotting. A phase I study of RV1001 was performed in 21 dogs with naïve and drug resistant T and B-cell NHL to assess safety, pharmacokinetic profile, and response to therapy. The objective response rate was 62% (complete response (CR) n = 3; partial response (PR) n = 10), and responses were observed in both naïve and chemotherapy-resistant B and T cell NHL. This study provided the recommended starting dose for a phase II, non-pivotal, exploratory, open label multi-centered clinical trial in 35 dogs with naïve and drug resistant T and B-cell NHL, to further define the efficacy and safety profile of RV1001. The objective response rate in the phase II study was 77% (CR n = 1; PR n = 26). Clinical toxicities were primarily hepatobiliary and gastrointestinal, and were responsive to dose modifications and/or temporary drug discontinuation. Hepatotoxicity was the primary dose limiting toxicity.</p><p>Conclusions</p><p>RV1001 exhibits good oral bioavailability, an acceptable safety profile, and biologic activity with associated inhibition of pAKT in dogs with B and T cell NHL. Data from these studies can be leveraged to help inform the design of future studies involving isoform-selective PI3K inhibitors in humans.</p></div

Response to RV1001 administration in dogs with NHL.

<p><b>(A)</b> Blood samples were collected to assess plasma concentrations of RV1001 over an 8 hour period after RV1001 administration. <b>(B)</b> Dogs were evaluated once weekly for response assessments. Objective responses were noted in all dosing cohorts. <b>(C)</b> Lymph node samples were collected from dogs before and after RV1001 administration. Inhibition of pAKT was observed within 2 hours of drug administration. Dosing groups: Dog 1 (10 mg/kg); Dog 4 (15 mg/kg); Dogs 18, 19, 20, 21 (25 mg/kg M-F).</p

Biochemical adverse events.

<p>Biochemical adverse events.</p

Median time to progression.

<p>Median time to progression.</p

Demographics.

<p>Demographics.</p

Adverse events.

<p>Adverse events.</p

Biologic activity of RV1001 against canine primary NHL cells treated <i>ex vivo</i>.

<p>Inhibition of pAKT in primary canine NHL cells treated <i>ex vivo</i> with RV1001 is demonstrated by western blotting.</p