Poor Pharmacokinetic Properties Research Articles

A Review on the Mechanism and Structure-activity Relationship of Resveratrol Heteroaryl Analogues.

Resveratrol is one of the most interesting naturally-occurring nonflavonoid phenolic compounds with various biological activities, such as anticancer, neuroprotection, antibacterial, and anti-inflammatory. However, there is no clinical usage of resveratrol due to either its poor activity or poor pharmacokinetic properties. Heteroarenes-modified resveratrol is one pathway to improve its biological activities and bioavailability, and form more modification sites. In this review, we present the progress of heteroaryl analogues of resveratrol with promising biological activities in the latest five years, ranging from the synthesis to the structure-activity relationship and mechanism of actions. Finally, introducing heteroarenes into resveratrol is an effective strategy, which focuses on the selectivity of structure-activity relationship in vivo.

Design, Synthesis, and Biological Evaluation of Novel Arylomycins against Multidrug-Resistant Gram-Negative Bacteria.

G0775, an arylomycin-type SPase I inhibitor that is being evaluated in a preclinical study, exhibited potent antibacterial activities against some Gram-negative bacteria but meanwhile suffered defects such as a narrow antibacterial spectrum and poor pharmacokinetic properties. Herein, systematic structural modifications were carried out, including optimization of the macrocyclic skeleton, warheads, and lipophilic regions. The optimization culminated in the discovery of 138f, which showed more potent activity and a broader spectrum against clinically isolated carbapenem-resistant Gram-negative bacteria, especially against Acinetobacter baumannii and Pseudomonas aeruginosa. 162, the free amine of 138f, exhibited an excellent pharmacokinetic profile in rats. In a neutropenic mouse thigh model of infection with multidrug-resistant P. aeruginosa, the potent in vivo antibacterial efficacy of 162 was confirmed and superior to that of G0775 (3.5-log decrease vs 1.1-log decrease in colony-forming unit (CFU)). These results support 162 as a potential antimicrobial agent for further research.

Abstract 4479: Design, synthesis, and evaluation of amino acid conjugated niclosamide prodrugs as a PepT1 substrate

Abstract The anthelmintic drug, Niclosamide, has a multitude of promising anticancer properties including inhibition of key signaling pathways involved in tumorigenesis, disruption of mitochondrial function, degradation of the overexpressed androgen receptor, and more. However, a key limitation of the clinical use of Niclosamide in cancer treatment is its low solubility and cellular uptake, which result in poor pharmacokinetic properties and dose-limiting GI toxicities at concentrations lower than the therapeutic threshold of the drug. To overcome this, we hypothesized that we could use amino acid conjugated niclosamide prodrugs to improve cellular uptake by creating a substrate of the PepT1 transport protein. The overexpression of the PepT1 transport protein that is involved in many hormonal cancers is being used to our advantage. Our study involved first synthesizing a group of niclosamide and niclosamide analogs conjugated with polar or nonpolar amino acids. Next, we conducted a Glycine-Sarcosine assay measuring changes in the uptake of the dipeptide glycyl-sarcosine (Gly-Sar). Our initial step was to examine if our conjugates could disrupt the absorption of Gly-Sar. The active conjugate will be tested whether they are substrates or inhibitors of the transporter. For the future, we have plans to determine the half-maximal inhibitory concentration (IC50) of niclosamide conjugates in various cancer cell lines and to quantify cleavage of the prodrugs intracellularly. Citation Format: Alaina C. McDonough, Jeffery Y. Cheng, Shabber Mohammed, Pui-Kai Li, Yangzom Bhutia. Design, synthesis, and evaluation of amino acid conjugated niclosamide prodrugs as a PepT1 substrate [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4479.

Abstract 5817: pH responsive delivery of gemcitabine/pirarubicin co-loaded biodegradable polymeric nanoparticles for synergistic anti-cancer therapy

Abstract Gemcitabine, a nucleoside antimetabolite, is a widely known chemotherapeutic agent being used as a first line treatment alone or in combination with other chemo drugs for different types of cancer. However, due to its extremely short half-life in the body caused by enzymatic degradation and poor pharmacokinetics, the I.V. dosage of administration is quite high i.e., >1000 mg/m2 for metastatic breast cancer treatment. Moreover, gemcitabine in combination with anthracyclines imparts synergy but free anthracyclines are reported to be associated with long term cardiac toxicity. Nanoparticle-based drug delivery systems have provided a befitted solution for improving the poor pharmacokinetic properties and systemic toxicity caused by the chemo drugs because of their ability to improve bioavailability of the drugs at the desired site as well as overcoming multi-drug resistance (MDR).In the present work, PLA-based biodegradable block copolymeric nanoparticles have been employed to co-load Gemcitabine and Pirarubicin for improved anti-cancer activity. Gemcitabine and Pirarubicin have been chemically conjugated to the amphiphilic block copolymer mPEG PLA via a pH responsive Schiff’s Base linkage using a linker molecule Levulinic acid. The prepared PIRA/GEM co-loaded nanoparticles exhibited an optimum size, zeta potential and polydispersity index i.e., 187 ± 3.5 nm, -10 ± 2.0 and < 0.1 PDI respectively. Further, in the drug release experiments, these Nps displayed sustained and higher drug release in lysosomal pH (pH 5.0) than in the physiological buffer environment (pH 7.4) attributed to the pH sensitive bonding. The co-loaded Nps were prepared in multiple ratios (Pira: Gem - 1:1, 1:3, and 3:1) and investigated for in-vitro cellular inhibition studies in comparison to singly loaded drug Nps and corresponding free drug formulations in various breast cancer cell lines. Additionally, apoptotic studies revealed significant enhancement in synergistic activity in the case of PIRA/GEM co-loaded Nps in comparison to conventional free drug formulations. In conclusion, this nano-formulation demonstrated excellent anti-cancer activity against breast cancer cells therefore it may be used as a potential candidate for therapeutic use. Citation Format: Priya Gupta, Surender M. Kharbanda, Harpal Singh. pH responsive delivery of gemcitabine/pirarubicin co-loaded biodegradable polymeric nanoparticles for synergistic anti-cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5817.

Unleashing the Potential of Camptothecin: Exploring Innovative Strategies for Structural Modification and Therapeutic Advancements.

Camptothecin (CPT) is a potent anti-cancer agent targeting topoisomerase I (TOP1). However, CPT has poor pharmacokinetic properties, causes toxicities, and leads to drug resistance, which limit its clinical use. In this paper, to review the current state of CPT research. We first briefly explain CPT's TOP1 inhibition mechanism and the key hurdles in CPT drug development. Then we examine strategies to overcome CPT's limitations through structural modifications and advanced delivery systems. Though modifications alone seem insufficient to fully enhance CPT's therapeutic potential, structure-activity relationship analysis provides insights to guide optimization of CPT analogs. In comparison, advanced delivery systems integrating controlled release, imaging capabilities, and combination therapies via stimulus-responsive linkers and targeting moieties show great promise for improving CPT's pharmacological profile. Looking forward, multifaceted approaches combining selective CPT derivatives with advanced delivery systems, informed by emerging biological insights, hold promise for fully unleashing CPT's anti-cancer potential.

In silico Toxicity and Pharmaceutical Properties to Get Candidates for Antitumor Drug

Background: Drug metabolism is a crucial aspect of medical practice and pharmacology, involving the transformation of drugs by various bodily systems to create compounds that are more easily eliminated from the body. Sorafenib was reported as a useful adjuvant treatment in patients with hepatocellular carcinoma who underwent surgical resection. However, poor pharmacokinetic properties such as limited water solubility, rapid elimination and metabolism lead to low bioavailability, restricting its further clinical application. Rosmarinic acid, soluble in ethanol and found in Rosemary leaves, has demonstrated therapeutic benefits in conditions such as cancer, diabetes, inflammatory disorders, neurodegenerative disorders, and liver disease. 
 Method: In silico is a term for experiments or tests carried out using computer simulation methods. In silico testing has emerged as a valuable approach for initiating the exploration of novel drug compounds or enhancing the efficacy of existing ones. This method involves predicting, generating hypotheses, and uncovering potential breakthroughs in medicine and therapy through virtual simulations.
 Results: Caco2 value of Sorafenib ligand as a comparison, namely 0.762. The highest Caco2 value is owned by Betulinic Acid and the value The lowest Caco2 is owned by Rosmarinic Acid. The highest sample HIA value was owned by Ursolic Acid and the lowest was owned by Rosmarinic Acid. Meanwhile, Sorafenib's HIA value is 85,494. ligands such as Carnosol and rosmanol have a high distribution volume, while the Sama carnosic league, ursolic acid and betulinic acid have a low distribution volume. The Rosmarinic acid ligand has a good distribution volume of 0.393, while the distribution volume value of Sorafenib is -0.009. The highest BBB sample value was owned by Carnosol and the lowest was owned by Rosmarinic acid. Meanwhile, the comparison ligand has a value of -1.473 and is considered less distributed in the brain. all ligands such as Carnosic Acid, Carnosol, Rosmanol, Ursolic Acid, Betulinic Acid, Rosmarinic acid do not have mutagenicity and Cytotoxic effects, but have an effect on immunity. The comparison ligand Sorafenib turned out to have effects on hepatotoxicity, immunity and cytotoxicity.
 Conclusion: In pharmacokinetic research, the six phenolic acid compounds in Rosemary exhibited superior properties compared to the reference ligand Sorafenib.

Palazestrant (OP-1250), A Complete Estrogen Receptor Antagonist, Inhibits Wild-type and Mutant ER-positive Breast Cancer Models as Monotherapy and in Combination.

The estrogen receptor (ER) is a well-established target for the treatment of breast cancer, with the majority of patients presenting as ER-positive (ER+). Endocrine therapy is a mainstay of breast cancer treatment but the development of resistance mutations in response to aromatase inhibitors, poor pharmacokinetic properties of fulvestrant, agonist activity of tamoxifen, and limited benefit for elacestrant leave unmet needs for patients with or without resistance mutations in ESR1, the gene that encodes the ER protein. Here we describe palazestrant (OP-1250), a novel, orally bioavailable complete ER antagonist and selective ER degrader. OP-1250, like fulvestrant, has no agonist activity on the ER and completely blocks estrogen-induced transcriptional activity. In addition, OP-1250 demonstrates favorable biochemical binding affinity, ER degradation, and antiproliferative activity in ER+ breast cancer models that is comparable or superior to other agents of interest. OP-1250 has superior pharmacokinetic properties relative to fulvestrant, including oral bioavailability and brain penetrance, as well as superior performance in wild-type and ESR1-mutant breast cancer xenograft studies. OP-1250 combines well with cyclin-dependent kinase 4 and 6 inhibitors in xenograft studies of ER+ breast cancer models and effectively shrinks intracranially implanted tumors, resulting in prolonged animal survival. With demonstrated preclinical efficacy exceeding fulvestrant in wild-type models, elacestrant in ESR1-mutant models, and tamoxifen in intracranial xenografts, OP-1250 has the potential to benefit patients with ER+ breast cancer.

Synergism of non-thermal plasma and low concentration RSL3 triggers ferroptosis via promoting xCT lysosomal degradation through ROS/AMPK/mTOR axis in lung cancer cells

BackgroundThough (1S, 3R)-RSL3 has been used widely in basic research as a small molecular inducer of ferroptosis, the toxicity on normal cells and poor pharmacokinetic properties of RSL3 limited its clinical application. Here, we investigated the synergism of non-thermal plasma (NTP) and low-concentration RSL3 and attempted to rise the sensitivity of NSCLC cells on RSL3.MethodsCCK-8 assay was employed to detect the change of cell viability. Microscopy and flowcytometry were applied to identify lipid peroxidation, cell death and reactive oxygen species (ROS) level respectively. The molecular mechanism was inspected with western blot and RT-qPCR. A xenograft mice model was adopted to investigate the effect of NTP and RSL3.ResultsWe found the synergism of NTP and low-concentration RSL3 triggered severe mitochondria damage, more cell death and rapid ferroptosis occurrence in vitro and in vivo. NTP and RSL3 synergistically induced xCT lysosomal degradation through ROS/AMPK/mTOR signaling. Furthermore, we revealed mitochondrial ROS was the main executor for ferroptosis induced by the combined treatment.ConclusionOur research shows NTP treatment promoted the toxic effect of RSL3 by inducing more ferroptosis rapidly and provided possibility of RSL3 clinical application.Graphical DeK3en8zu4Ed_UHNNMi2cXVideo

Inhibition of protein-protein interactions using biodegradable depsipeptide nanoassemblies

Although peptides notoriously have poor intrinsic pharmacokinetic properties, it is well-known that nanostructures with excellent pharmacokinetic properties can be designed. Noticing that peptide inhibitors are generally nonpolar, here, we consolidate the peptide inhibitor targeting intracellular protein–protein interactions (PPIs) as an integral part of biodegradable self-assembled depsipeptide nanostructures (SdPNs). Because the peptide inhibitor has the dual role of PPI inhibition and self-assembly in this design, problems associated with the poor pharmacokinetics of peptides and encapsulation/entrapment processes can be overcome. Optimized SdPNs displayed better tumor targeting and PPI inhibition properties than the comparable small molecule inhibitor in vivo. Kinetics of PPI inhibition for SdPNs were gradual and controllable in contrast to the rapid inhibition kinetics of the small molecule. Because SdPN is modular, any appropriate peptide inhibitor can be incorporated into the platform without concern for the poor pharmacokinetic properties of the peptide.

Recombinant human endostatin as a potential anti-angiogenic agent: therapeutic perspective and current status.

Angiogenesis is the physiological process that results in the formation of new blood vessels develop from pre-existing vasculature and plays a significant role in several physiological and pathological processes. Inhibiting angiogenesis, a crucial mechanism in the growth and metastasis of cancer, has been proposed as a potential anticancer therapy. Different studies showed the beneficial effects of angiogenesis inhibitors either in patients suffering from different cancers, alone or in combination with conventional therapies. Even though there are currently a number of efficient anti-angiogenic drugs, including monoclonal antibodies and kinase inhibitors, the associated toxicity profile and theiraffordability constraints are prompting researchers to search for a safe and affordable angiostatic agent for cancer treatment. Endostatin is one of the endogenous anti-angiogenic candidates that have been extensively pursued for the treatment of cancer, but even over three decades after its discovery, we have not made much advancement in employing it as an anticancer therapeutic despite of its remarkable anti-angiogenic effect with low toxicity profile. A recombinant human endostatin (rh-Es) variant for non-small cell lung cancer was approved by China in 2006 and has since been used effectively. Several other successful clinical trials related to endostatin for various malignancies are either ongoing or have already been completed with promising results. Thus, in this review, we have provided an overview of existing anti-angiogenic drugs developed for cancer therapy, with a summary of tumour angiogenesis in the context of Endostatin, and clinical status of rh-Es in cancer treatment. Furthermore, we briefly discuss the various strategies to improve endostatin features (poor pharmacokinetic properties) for developing rh-Es as a safe and effective agent for cancer treatment.

Discovery of GPX4 inhibitors through FP-based high-throughput screening

Ferroptosis is a form of non-apoptotic cell death, regulated by phospholipid hydroperoxide glutathione peroxidase 4 (GPX4), a selenoprotein with a selenocysteine residue (sec) in the active site. GPX4 is a promising target for cancer cells in therapy-resistant conditions via ferroptosis, which can reduce the level of lipid reactive oxygen species (ROS). So far, all existing GPX4 inhibitors covalently bind to GPX4 via a reactive alkyl chloride moiety or masked nitrile-oxide electrophiles with poor selectivity and pharmacokinetic properties and most were obtained by cell phenotype-based screening. Lacking of effective high-throughput screening methods for GPX4 protein limits the discovery of GPX4 inhibitors. Here, we report a fluorescence polarization (FP)-based high throughput screening (HTS) assay for GPX4-U46C-C10A-C66A in vitro, and found Metamizole sodium from our in-house compound library inhibits GPX4-U46C-C10A-C66A enzyme activity. Structure-activity relationships (SAR) demonstrated the importance of sulfonyl group on interaction between Metamizole sodium and GPX4-U46C-C10A-C66A. Our FP assay could be an effective tool for discovery of GPX4 inhibitors and Metamizole sodium was a potential inhibitor for GPX4 in vitro.

Abstract B049: Phase II study of NUC-3373, leucovorin, irinotecan (NUFIRI) + bevacizumab vs FOLFIRI + bevacizumab for the second-line treatment of patients with advanced/metastatic colorectal cancer (NuTide:323)

Abstract Background: NUC-3373 is a phosphoramidate transformation of fluorodeoxyuridine monophosphate (FUDR-MP) designed to replace fluoropyrimidines, such as 5-FU. Fluoropyrimidines predominantly exert their activity via FUDR-MP, which inhibits thymidylate synthase (TS). NUC-3373 has been designed to overcome the shortcomings that limit the clinical utility of 5-FU, such as inefficient conversion to FUDR-MP, generation of toxic metabolites, and a lengthy administration schedule due to poor pharmacokinetic (PK) properties. Promising data have been observed in the NuTide:302 study where heavily pre-treated patients (pts) received NUC-3373 (± leucovorin, LV) or NUC-3373 + LV + irinotecan (NUFIRI), and second-line pts received NUFIRI + bevacizumab (NUFIRI-bev). NUC-3373 was well-tolerated in all combinations. Prolonged stable disease was observed in heavily pre-treated pts, with tumour shrinkages as well as periods of progression-free survival (PFS) longer than those achieved on prior lines. Methods: NuTide:323 is a Phase II, open-label, randomised study of NUFIRI-bev vs FOLFIRI-bev in pts with advanced/metastatic CRC who have previously received ≥2 months of a first-line fluoropyrimidine and oxaliplatin-containing regimen or have relapsed within 6 months of completing adjuvant fluoropyrimidine and oxaliplatin. Pts with measurable disease, ECOG 0-1 and wildtype BRAF are eligible. Pts with MSI-H or dMMR are ineligible. 171 pts will be randomised (1:1:1) to either 1500 mg/m2 NUC-3373 + LV Q1W or 1500 mg/m2 NUC-3373 + LV Q2W, both with 180 mg/m2 irinotecan and 5 mg/kg bevacizumab Q2W or FOLFIRI-bev Q2W. NUC-3373 will be administered over 2 h (vs 46 h for 5-FU). Randomisation is stratified by RAS status, prior bevacizumab and duration of prior line of therapy. Primary objectives are to compare the PFS of NUFIRI-bev to FOLFIRI-bev and determine the optimal NUFIRI-bev dosing schedule. Secondary objectives are to compare the efficacy and safety of NUFIRI-bev to FOLFIRI-bev, and assess the PK of NUFIRI-bev. NuTide:323 is being conducted at 65 sites in Europe and the USA. Clinical trial information: NCT05678257 Citation Format: Richard H Wilson, Kristen K Ciombor, Andrew L Coveler, Janet S Graham, Benjamin L Schlechter, Thomas J George, Elena Élez, TR Jeffry Evans, Jordan Berlin, Aimery de Gramont, Fiona G McKissock, Elisabeth Oelmann, Jeffrey D Bloss, Giulia Martini, Jaafar Bennouna, Dominik P Modest, Julien Taieb, Josep Tabernero. Phase II study of NUC-3373, leucovorin, irinotecan (NUFIRI) + bevacizumab vs FOLFIRI + bevacizumab for the second-line treatment of patients with advanced/metastatic colorectal cancer (NuTide:323) [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B049.

Abstract A031: Development of poly lactic acid based biodegradable nanoparticles for co-delivery of pirarubicin and gemcitabine for synergistic anti-tumor efficacy

Abstract Nanoparticles based drug delivery systems have provided a befitted solution for the poor pharmacokinetic properties and systemic toxicity caused by the chemo drugs because of their ability to improve bioavailability of the drugs at the desired site and thereby decreasing extracellular toxicity. The present work investigates the single or dual chemo drugs loaded PLA-based biodegradable polymeric nanoparticles for improved anti-tumor efficacy as compared to free drug formulations. For the study, an amphiphilic block copolymer; mPEG PLA has been synthesized and characterized using Gel permeation chromatography (GPC) for its molecular weight and poly dispersity index as well as with Nuclear magnetic resonance (NMR) and Fourier-transform Infrared (FT-IR) spectroscopies. Thereafter, two different chemo drugs Pirarubicin (PIRA, THP analogue of Doxorubicin) and Gemcitabine (GEM) have been chemically conjugated individually to mPEG PLA block copolymer via a linker molecule, Levulinic acid to give an acid labile polymer-drug conjugate and the % drug conjugation efficiency has been calculated using High performance liquid chromatography (HPLC). The synthesized polymer-drug conjugates have been employed to prepare PIRA/GEM single or dual-loaded nanoparticles via nanoprecipitation technique and the physiochemical properties including size, zeta potential, and stability were analyzed using Dynamic Light Scattering (DLS) and High-resolution transmission electron microscopy (HR-TEM). To carry out toxicity assessment of the mPEG PLA nanoparticles, both cytocompatibility and hemocompatibility were checked using MTT assay and Hemolysis assay respectively. Moreover, the cellular internalization studies of dye-loaded mPEG PLA nanoparticles were done using Confocal microscopy on SUM-149, breast cancer cells. Besides, the drug release kinetic studies of the free PIRA/GEM from the PIRA/GEM single or dual-loaded nanoparticles were carried out in different pH environments; pH 7.4 and pH 5.0. The in-vitro cell proliferation inhibition studies of PIRA/GEM or dual-loaded nanoparticles were carried out on different human and murine breast cancer cell lines including MCF-7, MDA-MB-468, SUM 149, MDA-MB-231 and 4T1 and half-maximal inhibitory concentrations (IC50 values) were compared to that of respective free drug formulations. The overall results suggested that the prepared sub-nano sized PIRA/GEM single or dual-loaded particles are highly stable, uniformly spherical in size and biocompatible in nature. They were found to possess high cellular uptake, sustained drug release rate and synergistic efficacy and potential against both human and murine breast cancer cells in-vitro conditions. Citation Format: Priya Gupta. Development of poly lactic acid based biodegradable nanoparticles for co-delivery of pirarubicin and gemcitabine for synergistic anti-tumor efficacy [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A031.

Novel Small Molecule VLA-4 Inhibitors Optimized for Extended Hematopoietic and Progenitor Cell Mobilization

Background: Hematopoietic stem and progenitor cell (HSPC) transplant is an essential treatment for a variety of blood disorders and malignancies, and more recently, for gene editing therapies such as sickle cell anemia. A key step in this procedure is the effective mobilization of a large quantity of primitive donor HSPCs to ensure a durable and long lasting engraftment capable of developing into all blood cell lineages. The most commonly used regimen for donor mobilization is a 5-day course of Granulocyte Colony Stimulating Factor (G-CSF). However, G-CSF does not effectively mobilize a sufficient number or quality of stem cells in all donors, can have unwanted side effects, and is contraindicated in sickle cell disease. Therefore, it is desirable to identify an alternative treatment that is safe, rapid and cost effective. The cell surface integrin receptor VLA-4 (a4b1) and the chemokine receptor CXCR4 are essential for HSPC homing and retention in the bone marrow. Inhibition of these receptors rapidly mobilizes HSPCs within an hour, as opposed to the multi-day process using G-CSF. Small molecule inhibitors of VLA-4 have been reported previously, but most have poor pharmacokinetic properties and/or weak inhibition of VLA4. These inhibitors rapidly mobilize HSPCs into the peripheral blood of mice after a single s.c. injection, but their effect is short lived, yielding an inadequate number of HSPCs necessary for stem cell transplantation or for gene therapy. Therefore, VLA4 inhibitors with improved pharmacokinetic properties imparting extended and greater HSPC mobilization after a single dose is desirable. Methods: We designed and synthesized multiple novel VLA-4 inhibitor molecules and tested their potency using soluble VCAM-1 binding assays. Inhibitors determined to be most potent with improved aqueous solubility were then tested in vivo in DBA mice for extended HSPC mobilization beyond 4 hours after a single SC injection, alone and in combination with the CXCR4 inhibitors. Results: We developed two main core molecules that each incorporate key VLA4 receptor binding motifs critical for potent inhibition of VLA4 binding to VCAM-1. Our first generation of inhibitors were quite potent and rapidly mobilized HSPCs, but their effect was short lived and yielded insufficient numbers of HSPCs for gene editing and engraftment studies. Most had poor solubility and very short plasma half-lives after s.c. injection in mice. We designed later generation analogues that strategically exploited a region of each optimized core, allowing for covalent addition of polyethylene glycol (PEG) chains of increasing length without decreasing potency. We determined that a minimum PEG length of 24 PEG units was required for extended HSPC mobilization in mice. WU-106, one of our VLA-4 inhibitors containing 24 PEG units, exhibited excellent aqueous solubility, longer plasma half-life after s.c. dosing, and mobilized 2-fold more murine HSPCs for a longer time than previously published best-in-class VLA-4 inhibitors or our first generation VLA4 inhibitor leads. Importantly, a synergistic effect on HSPC mobilization was achieved when WU-106 was co-administered with CXCR4 inhibitors (Plerixafor or BL-8040). Further optimization by the addition of longer PEG chains, even up to 40KD, retained sub nM potency and extended mobilization beyond 24 hours after a single injection. Our 20kD PEG analogues attached to our two different core molecules (WU-125 and WU-133) allowed for dosing of the drug in the evening, with maximum mobilization still present the next morning, thereby enabling HSPC collection to initiate soon (2-4 hours) after CXCR4 inhibitor dosing in the morning. The quantity of HSPCs obtained using this staggered dosing regimen was greater than simultaneous administration of the VLA-4 and CXCR4 inhibitors ( Fig. 1). Furthermore, our novel, long-acting PEG analogues demonstrated superior HSPC mobilization compared to an alpha 4-targeted antibody (anti-CD49d) in mice ( Fig.2). Conclusion: We have developed novel, potent PEGylated small molecule VLA-4 inhibitors that have excellent aqueous solubility and pharmacokinetics. The kinetics and magnitude of HSPC mobilization by our PEGylated inhibitors are superior to other previously described VLA-4 inhibitors and an antibody to alpha-4(anti-CD49d).

Applications and advancements of nanoparticle-based drug delivery in alleviating lung cancer and chronic obstructive pulmonary disease.

Lung cancer (LC) and chronic obstructive pulmonary disease (COPD) are among the leading causes of mortality worldwide. Cigarette smoking is among the main aetiologic factors for both ailments. These diseases share common pathogenetic mechanisms including inflammation, oxidative stress, and tissue remodelling. Current therapeutic approaches are limited by low efficacy and adverse effects. Consequentially, LC has a 5-year survival of < 20%, while COPD is incurable, underlining the necessity for innovative treatment strategies. Two promising emerging classes of therapy against these diseases include plant-derived molecules (phytoceuticals) and nucleic acid-based therapies. The clinical application of both is limited by issues including poor solubility, poor permeability, and, in the case of nucleic acids, susceptibility to enzymatic degradation, large size, and electrostatic charge density. Nanoparticle-based advanced drug delivery systems are currently being explored as flexible systems allowing to overcome these limitations. In this review, an updated summary of the most recent studies using nanoparticle-based advanced drug delivery systems to improve the delivery of nucleic acids and phytoceuticals for the treatment of LC and COPD is provided. This review highlights the enormous relevance of these delivery systems as tools that are set to facilitate the clinical application of novel categories of therapeutics with poor pharmacokinetic properties.

Molecular Docking, ADMET Study, Synthesis, Characterization and Preliminary Antiproliferative Activity of Potential Histone Deacetylase Inhibitors with Isoxazole as New Zinc Binding Group

Histone acetylation is a highly interesting epigenetic target for drug therapy. Histone deacetylase enzymes (HDACs) are overexpressed in several diseases, including cancers. Most of the clinically used HDAC inhibitors involve hydroxamate group as a zinc-binding group (ZBG). Hydroxamates have a poor pharmacokinetic properties and high toxicity profile. Therefore, developing non-hydroximate HDAC inhibitors is a promising strategy for potency and selectivity enhancement. In this work, we designed new HDAC inhibitors with isoxazole moiety as ZBG using Ligand Designer from Glide (Schrodinger LLC). The cap group and the linker were optimized through trying various aliphatic and aromatic residues. The potential inhibition over HDAC8 for the optimally designed products was virtually evaluated using licensed Schrodinger modelling software. The results showed that the isoxazole has a potential bidentate interaction with HDAC8 active site zinc ion with acceptable fitness. ADMET/tox study performed to predict the pharmacokinetic properties for the final compounds. The final compounds showed a decent estimated drug-like properties. The intermediates and final compounds were successfully synthesized and purified using column chromatography. The chemical structure for intermediates and final compounds were characterized by IR and NMR spectroscopy.

Microglia Depletion Attenuates the Pro-Resolving Activity of the Formyl Peptide Receptor 2 Agonist AMS21 Related to Inhibition of Inflammasome NLRP3 Signalling Pathway: A Study of Organotypic Hippocampal Cultures.

Microglial cells have been demonstrated to be significant resident immune cells that maintain homeostasis under physiological conditions. However, prolonged or excessive microglial activation leads to disturbances in the resolution of inflammation (RoI). Formyl peptide receptor 2 (FPR2) is a crucial player in the RoI, interacting with various ligands to induce distinct conformational changes and, consequently, diverse biological effects. Due to the poor pharmacokinetic properties of endogenous FPR2 ligands, the aim of our study was to evaluate the pro-resolving effects of a new ureidopropanamide agonist, compound AMS21, in hippocampal organotypic cultures (OHCs) stimulated with lipopolysaccharide (LPS). Moreover, to assess whether AMS21 exerts its action via FPR2 specifically located on microglial cells, we conducted a set of experiments in OHCs depleted of microglial cells using clodronate. We demonstrated that the protective and anti-inflammatory activity of AMS21 manifested as decreased levels of lactate dehydrogenase (LDH), nitric oxide (NO), and proinflammatory cytokines IL-1β and IL-6 release evoked by LPS in OHCs. Moreover, in LPS-stimulated OHCs, AMS21 treatment downregulated NLRP3 inflammasome-related factors (CASP1, NLRP3, PYCARD) and this effect was mediated through FPR2 because it was blocked by the FPR2 antagonist WRW4 pre-treatment. Importantly this beneficial effect of AMS21 was only observed in the presence of microglial FPR2, and absent in OHCs depleted with microglial cells using clodronate. Our results strongly suggest that the compound AMS21 exerts, at nanomolar doses, protective and anti-inflammatory properties and an FPR2 receptor located specifically on microglial cells mediates the anti-inflammatory response of AMS21. Therefore, microglial FPR2 represents a promising target for the enhancement of RoI.

Amygdalin/chitosan-polyvinyl alcohol/cerium-tannic acid hydrogel as biodegradable long-time implant for cancer recurrence care applications: An in vitro study

Cancer recurrence following surgery is a serious and worrying problem for the patient. Common treatment strategies, such as chemotherapy, radiotherapy, and surgery, are restricted because of low uptake of the drugs, poor pharmacokinetic properties, and toxicity issues for healthy tissues. The development of engineering platforms for improving the postoperative treatment of cancer can help solve this problem. In this study, the ceria-tannic acid nanoparticles (CeTA-NPs) were successfully synthesized and characterized. Chitosan-polyvinyl/alcohol (CS-PVA) hydrogels containing CeTA NPs (CS-PVA/CeTA) and amygdalin as an anticancer substance were fabricated using freeze-thaw and immersion-drying techniques. The swelling and degradation behaviors, antibacterial activity, and biocompatibility of as-prepared hydrogel were done. The apoptotic effects of amygdalin/CS-PVA/CeTA hydrogel were evaluated by flow cytometry technique on a human colorectal cancer (SW-480) cell line. The CeTA-NPs were investigated as antibacterial and cross-linker agents for greater stability of the hydrogel network. The CS-PVA/CeTA hydrogel demonstrated good safety and antibacterial activity. The results of swelling and biodegradation suggest that CS-PVA/CeTA hydrogels can inspire long-time application. The anticancer effects of the amygdalin/CS-PVA/CeTA hydrogel were confirmed by apoptosis results. Hence, amygdalin/CS-PVA/CeTA hydrogel can be a promising candidate for long-time biomedical application.

Therapeutic considerations of bioactive compounds in Alzheimer's disease and Parkinson's disease: Dissecting the molecular pathways.

Leading neurodegenerative diseases Alzheimer's disease (AD) and Parkinson's disease (PD) are characterized by the impairment of memory and motor functions, respectively. Despite several breakthroughs, there exists a lack of disease-modifying treatment strategies for these diseases, as the available drugs provide symptomatic relief and bring along side effects. Bioactive compounds are reported to bear neuroprotective properties with minimal toxicity, however, a detailed elucidation of their modes of neuroprotection is lacking. The review elucidates the neuroprotective mechanism(s) of some of the major phyto-compounds in pre-clinical and clinical studies of AD and PD to understand their potential in combating these diseases. Curcumin, eugenol, resveratrol, baicalein, sesamol and so on have proved efficient in countering the pathological hallmarks of AD and PD. Curcumin, resveratrol, caffeine and so on have reached the clinical phases of these diseases, while aromadendrin, delphinidin, cyanidin and xanthohumol are yet to be extensively explored in pre-clinical phases. The review highlights the need for extensive investigation of these compounds in the clinical stages of these diseases so as to utilize their disease-modifying abilities in the real field of treatment. Moreover, poor pharmacokinetic properties of natural compounds are constraints to their therapeutic yields and this review suggests a plausible contribution of nanotechnology in overcoming these limitations.

Optimization of 3-Cyano-7-cyclopropylamino-pyrazolo[1,5-a]pyrimidines toward the Development of an In Vivo Chemical Probe for CSNK2A.

3-Cyano-7-cyclopropylamino-pyrazolo[1,5-a]pyrimidines, including the chemical probe SGC-CK2-1, are potent and selective inhibitors of CSNK2A in cells but have limited utility in animal models due to their poor pharmacokinetic properties. While developing analogues with reduced intrinsic clearance and the potential for sustained exposure in mice, we discovered that phase II conjugation by GST enzymes was a major metabolic transformation in hepatocytes. A protocol for codosing with ethacrynic acid, a covalent reversible GST inhibitor, was developed to improve the exposure of analogue 2h in mice. A double codosing protocol, using a combination of ethacrynic acid and irreversible P450 inhibitor 1-aminobenzotriazole, increased the blood level of 2h by 40-fold at a 5 h time point.