Small Molecule Therapeutic Agents Research Articles

Targeting the Neuropilin-1 receptor with Ovatodiolide and progress in using periodontal ligament organoids for COVID-19 research and therapy

The discovery of SARS-CoV-2 RNA in the periodontal tissues of patients who tested positive for COVID-19, 24 days post the initial symptom onset, indicates the oral cavity could serve as a viral reservoir. This research aims to investigate the antiviral capabilities of Ovatodiolide, introducing a novel periodontal ligament organoid model for the study of SARS-CoV-2. We have successfully established a reliable and expandable organoid culture from the human periodontal ligament, showcasing characteristics typical of epithelial stem cells. This organoid model enables us to delve into the lesser-known aspects of dental epithelial stem cell biology and their interactions with viruses and oral tissues. We conducted a series of in vitro and ex vivo studies to examine the inhibitory impacts of Ova on SARS-CoV-2. Our findings indicate that Ovatodiolide molecules can bind effectively to the NRP1 active domain. Our study identifies potential interaction sites for Ovatodiolide (OVA) within the b1 domain of the NRP1 receptor. We generated point mutations at this site, resulting in three variants: Y25A, T44A, and a double mutation Y25A/T44A. While these mutations did not alter the binding activity of the spike protein, they did impact the concentration of OVA required for inhibition. The inhibitory concentrations for these variants are 15 μM for Y25A, 15.2 μM for T44A, and 25 μM for the double mutant Y25A/T44A. In addition, in vitro inhibition experiments demonstrate that the EC50 of Ova against the main protease (Mpro) of the SARS-CoV-2 virus is 7.316 μM. Our in vitro studies and the use of the periodontal ligament organoid model highlight Ovatodiolide's potential as a small molecule therapeutic agent that impedes the virus's ability to bind to the Neuropilin-1 receptor on host cells. The research uncovers various pathways and biochemical strategies through which Ovatodiolide may function as an effective antiviral small molecule drug.

Abstract 1932: Overcoming acquired resistance to KRAS(G12D) inhibition using a KRAS-HSP90 hetero-bifunctional small molecule therapeutic agent

Abstract KRAS mutations are highly prevalent across many different cancer types. Recent advancements in KRAS-targeted drugs, such as the FDA-approved KRAS(G12C) inhibitors sotorasib and adagrasib for NSCLC patients, have shown great promise in the clinic. Nonetheless, these new agents fail to address other mutations, such as KRAS(G12D), which overall is the most common KRAS mutation in cancers, being found in 37% of pancreatic ductal adenocarcinomas, 12.5% of colorectal cancers and 4.9% of lung adenocarcinomas. Recently, MRTX1133 has been described as a selective, non-covalent inhibitor of KRAS(G12D) that shows promising preclinical efficacy and is undergoing clinical testing. However, based on prior clinical experience with sotorasib and adagrasib, acquired resistance to MRTX1133 may reasonably be anticipated. In fact, we find that KRAS(G12D)-mutated cell lines and a patient-derived organoid model exhibit varying degrees of inherent resistance to MRTX1133. To examine the consequences of blocking KRAS signaling, we employed a KRAS(G12D)-specific PROTAC, which simulated the effects of KRAS deletion. This demonstrated that receptor tyrosine kinase (RTK) activation could compensate for loss of KRAS signaling and was a key de novo resistance mechanism. This suggests that combination therapies may need to be individually tailored to treat patients resistant to KRAS(G12D)-targeted therapies. Additionally, we developed MRTX1133 resistant cells by culturing sensitive AsPC-1 pancreatic cancer cells in gradually increasing concentrations of the inhibitor. The resulting resistant cells displayed a complex RTK activation profile compared to parental cells. To counteract this, we employed KRAS(G12D)-CHAMP RNK08179, a hetero-bifunctional small molecule agent that simultaneously targets both KRAS(G12D) and HSP90, an RTK-regulating chaperone protein. RNK08179 effectively suppressed both KRAS signaling and RTK activation in MRTX1133-resistant cancer models, overcoming the compensatory resistance mechanisms observed with MRTX1133 alone. These findings highlight the potential of KRAS-CHAMPs as a novel, effective treatment strategy for KRAS-driven cancers, particularly those resistant to KRAS(G12D) inhibitors. Citation Format: Ines Pulido Endrino, Laura gunder, Qiyue Luan, Chenghao Ying, Zimo Yang, Jinhua Li, Yaya Wang, Yuetong Sun, Chuhe Liu, Yan Dai, Haoxin Zhou, Malek Massad, Ian Papautsky, Thomas L. Prince, Guoqiang Wang, Kevin P. Foley, Weiwen Ying. Overcoming acquired resistance to KRAS(G12D) inhibition using a KRAS-HSP90 hetero-bifunctional small molecule therapeutic agent [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 1932.

Identification of a Discrete Diglucuronide of GDC-0810 in Human Plasma after Oral Administration.

GDC-0810 is a small molecule therapeutic agent having potential to treat breast cancer. In plasma of the first-in-human study, metabolite M2, accounting for 20.7% of total drug-related materials, was identified as a discrete diglucuronide that was absent in rats. Acyl glucuronide M6 and N-glucuronide M4 were also identified as prominent metabolites in human plasma. Several in vitro studies were conducted in incubations of [14C]GDC-0810, synthetic M6 and M4 with liver microsomes, intestinal microsomes, and hepatocytes of different species as well as recombinant UDP-glucuronosyltransferase (UGT) enzymes to further understand the formation of M2. The results suggested that 1) M2 was more efficiently formed from M6 than from M4, and 2) acyl glucuronidation was mainly catalyzed by UGT1A8/7/1 that is highly expressed in the intestines whereas N-glucuronidation was mainly catalyzed by UGT1A4 that is expressed in the human liver. This complicated mechanism presented challenges in predicting M2 formation using human in vitro systems. The absence of M2 and M4 in rats can be explained by low to no expression of UGT1A4 in rodents. M2 could be the first discrete diglucuronide that was formed from both acyl- and N-glucuronidation on a molecule identified in human plasma. SIGNIFICANCE STATEMENT: A discrete diglucuronidation metabolite of GDC-0810, a breast cancer drug candidate, was characterized as a unique circulating metabolite in humans that was not observed in rats or little formed in human in vitro system.

Deciphering the role of lipoproteins and lipid metabolic alterations in ageing and ageing-associated renal fibrosis.

Fibrosis is the ultimate pathological feature of many chronic diseases, and ageing a major risk factor for fibrotic diseases. Current therapies are limited to those that reduce the rate of functional decline in patients with mild to moderate disease, but few interventions are available to specifically target the pathogenesis of fibrosis. In this context, new treatments that can significantly improve survival time and quality of life for these patients are urgently needed. In this review, we outline both the synthesis and metabolism of lipids and lipoproteins associated with ageing-associated renal fibrosis and the prominent contribution of lipids and lipidomics in the discovery of biomarkers that can be used for the prevention, diagnosis, and treatment of renal ageing and fibrosis. Next, we describe the effect of dyslipidaemia on ageing-related renal fibrosis and the pathophysiological changes in the kidney caused by dyslipidaemia. We then summarize the enzymes, transporters, transcription factors, and RNAs that contribute to dysregulated lipid metabolism in renal fibrosis and discuss their role in renal fibrosis in detail. We conclude by discussing the progress in research on small molecule therapeutic agents that prevent and treat ageing and ageing-associated renal fibrosis by modulating lipid metabolism. A growing number of studies suggest that restoring aberrant lipid metabolism may be a novel and promising therapeutic strategy to combat ageing and ageing-associated renal fibrosis.

Exploring the potential of dried plasma collection cards for liquid chromatography coupled with tandem mass spectrometry quantitation of giredestrant in human plasma.

Microsampling technology for dried blood-derived samples provides an advantageous alternative to conventional venous blood for drug quantitation. Unlike conventional whole blood microsampling techniques, Noviplex is a novel, card-based technology for rapid dried plasma spot collection that retains the benefits of microsampling during collection and transportation, while avoiding the disadvantages of using whole blood samples. Giredestrant is a promising small-molecule therapeutic agent under development by Genentech to treat patients with estrogen receptor-positive breast cancer. In this study, we investigated the feasibility of using Noviplex cards for pharmacokinetic analysis of giredestrant levels in human plasma, including optimizing extraction recovery, evaluating in-card stability, and assessing batch precision and accuracy. We found that while the Noviplex card demonstrated levels of sensitivity, extraction recovery, and stability at ambient temperature that meet the requirements of pharmacokinetic analysis for clinical studies, further optimization of the filtration layers within the Noviplex card is necessary to improve filtration efficiency and consistency. This study reveals the possibilities as well as the limitations of the Noviplex card and provides a better understanding of the capabilities and risks of using the Noviplex card for drug quantitation in plasma.

Novel covalent and non-covalent complex-based pharmacophore models of SARS-CoV-2 main protease (Mpro) elucidated by microsecond MD simulations

As the world enters its second year of the pandemic caused by SARS-CoV-2, intense efforts have been directed to develop an effective diagnosis, prevention, and treatment strategies. One promising drug target to design COVID-19 treatments is the SARS-CoV-2 Mpro. To date, a comparative understanding of Mpro dynamic stereoelectronic interactions with either covalent or non-covalent inhibitors (depending on their interaction with a pocket called S1’ or oxyanion hole) has not been still achieved. In this study, we seek to fill this knowledge gap using a cascade in silico protocol of docking, molecular dynamics simulations, and MM/PBSA in order to elucidate pharmacophore models for both types of inhibitors. After docking and MD analysis, a set of complex-based pharmacophore models was elucidated for covalent and non-covalent categories making use of the residue bonding point feature. The highest ranked models exhibited ROC-AUC values of 0.93 and 0.73, respectively for each category. Interestingly, we observed that the active site region of Mpro protein–ligand complex undergoes large conformational changes, especially within the S2 and S4 subsites. The results reported in this article may be helpful in virtual screening (VS) campaigns to guide the design and discovery of novel small-molecule therapeutic agents against SARS-CoV-2 Mpro protein.

Affinity selection-mass spectrometry in the discovery of anti-SARS-CoV-2 compounds.

Small molecule therapeutic agents are needed to treat or prevent infections by severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2), which is the cause of the COVID‐19 pandemic. To expedite the discovery of lead compounds for development, assays have been developed based on affinity selection‐mass spectrometry (AS‐MS), which enables the rapid screening of mixtures such as combinatorial libraries and extracts of botanicals or other sources of natural products. AS‐MS assays have been used to find ligands to the SARS‐CoV‐2 spike protein for inhibition of cell entry as well as to the 3‐chymotrypsin‐like cysteine protease (3CLpro) and the RNA‐dependent RNA polymerase complex constituent Nsp9, which are targets for inhibition of viral replication. The AS‐MS approach of magnetic microbead affinity selection screening has been used to discover high‐affinity peptide ligands to the spike protein as well as the hemp cannabinoids cannabidiolic acid and cannabigerolic acid, which can prevent cell infection by SARS‐CoV‐2. Another AS‐MS method, native mass spectrometry, has been used to discover that the flavonoids baicalein, scutellarein, and ganhuangenin, can inhibit the SARS‐CoV‐2 protease 3CLpro. Native mass spectrometry has also been used to find an ent‐kaurane natural product, oridonin, that can bind to the viral protein Nsp9 and interfere with RNA replication. These natural lead compounds are under investigation for the development of therapeutic agents to prevent or treat SARS‐CoV‐2 infection.

Cannabinoids Block Cellular Entry of SARS-CoV-2 and the Emerging Variants.

As a complement to vaccines, small-molecule therapeutic agents are needed to treat or prevent infections by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and its variants, which cause COVID-19. Affinity selection–mass spectrometry was used for the discovery of botanical ligands to the SARS-CoV-2 spike protein. Cannabinoid acids from hemp (Cannabis sativa) were found to be allosteric as well as orthosteric ligands with micromolar affinity for the spike protein. In follow-up virus neutralization assays, cannabigerolic acid and cannabidiolic acid prevented infection of human epithelial cells by a pseudovirus expressing the SARS-CoV-2 spike protein and prevented entry of live SARS-CoV-2 into cells. Importantly, cannabigerolic acid and cannabidiolic acid were equally effective against the SARS-CoV-2 alpha variant B.1.1.7 and the beta variant B.1.351. Orally bioavailable and with a long history of safe human use, these cannabinoids, isolated or in hemp extracts, have the potential to prevent as well as treat infection by SARS-CoV-2.

Smart Nanotherapeutics and Lung Cancer.

Lung cancer is a significant health problem worldwide. Unfortunately, current therapeutic strategies lack a sufficient level of specificity and can harm adjacent healthy cells. Consequently, to address the clinical need, novel approaches to improve treatment efficiency with minimal side effects are required. Nanotechnology can substantially contribute to the generation of differentiated products and improve patient outcomes. Evidence from previous research suggests that nanotechnology-based drug delivery systems could provide a promising platform for the targeted delivery of traditional chemotherapeutic drugs and novel small molecule therapeutic agents to treat lung cancer cells more effectively. This has also been found to improve the therapeutic index and reduce the required drug dose. Nanodrug delivery systems also provide precise control over drug release, resulting in reduced toxic side effects, controlled biodistribution, and accelerated effects or responses. This review highlights the most advanced and novel nanotechnology-based strategies, including targeted nanodrug delivery systems, stimuli-responsive nanoparticles, and bio-nanocarriers, which have recently been employed in preclinical and clinical investigations to overcome the current challenges in lung cancer treatments.

Abstract PO-039: Antiproliferative activity of inhibitors of RAD51, singly and in combination with chemotherapy drugs, against pancreatic cancer cell lines

Abstract Despite the innovations in chemotherapeutic treatment of pancreatic cancer, the generally poor outcome of this disease begs the search for novel targets. RAD51 is a critical component of homologous recombination DNA repair, binding with BRCA2 and forming polymeric filaments essential for its function. RAD51 is often elevated in cancer cells compared to normal cells, particularly in pancreatic cancer: RAD51 is a negative prognostic biomarker and promotes tumor cell proliferation in that disease (Cancer Cell Int 19: 356, 2019; doi: 10.1186/s12935-019-1077-6). Therefore, RAD51 is an attractive target for anticancer treatment in that its elevated level and activity in tumor cells provide a potential level of selectivity for such an agent, increasing the therapeutic index. We demonstrated previously that novel inhibitors of RAD51, IBR2 [2-(Benzylsulfonyl)-1-(1H-indol-3-yl)-1,2-dihydroisoquinoline] and IBR120 (an isoindolinyl derivative of IBR2) (Eur J Med Chem. 96:196-208, 2015; doi: 10.1016/j.ejmech.2015.04.021), not only inhibited proliferation of a range of tumor cell lines at micromolar concentrations but also acted in combination with commonly used cytotoxic chemotherapy and molecularly targeted drugs to synergistically inhibit proliferation (J Pharmacol Expt Ther, 364: 46-54, 2018; doi.org/10.1124/jpet.117.241661). To improve ADME properties, enhance activity, and increase potential to selectively target RAD51, advanced computational tools and rational approaches were employed to predict possible modification to the IBR chemical backbone. This effort resulted in discovery of the compound JKYN-1. As a model system in which to test the activity of JKYN-1 in vitro, human pancreatic cancer cell lines PANC-1, Capan-1 and Capan-2 were used. All lines have mutant K-Ras and p53, and Capan-1 has mutant BRCA2 (https://www.cancer.gov/research/key-initiatives/ras; https://web.expasy.org/cellosaurus). JKYN-1 or its water-soluble methylsulfonate salt (JKYN-1-mesylate) inhibit proliferation of PANC-1 cells approximately 5 times more effectively than IBR120 and inhibit Capan-1 and Capan-2 cells even better. Against PANC-1, JKYN-1-mesylate inhibits proliferation synergistically in combination with afatinib (inhibitor of epidermal growth factor receptor) or with IBR120, and is additive with gemcitabine. Biochemical characterization of the interaction between RAD51 and these inhibitors demonstrated the following: (1) IBR2 and IBR120 promote disassembly of RAD51 multimers in an ex vivo native polyacrylamide gel electrophoresis assay using clonal constructs of RAD51, and (2) JKYN-1 binds to RAD51 with higher affinity than IBR120 and B02, a commercially available RAD51 inhibitor, in a surface plasmon resonance spectroscopy assay. Therefore, JKYN-1 is a potential novel small molecule therapeutic agent for treatment of pancreatic cancer, both as a single agent and in combination with standard chemotherapy drugs. Citation Format: Peter Ferguson, Mark D. Vincent, Yousef Najajreh, Brian Shilton, Stephen Ritter, Rima Al-awar, Richard Marcellus, Mohammed Mohammed, Methvin Isaac, James Koropatnnick. Antiproliferative activity of inhibitors of RAD51, singly and in combination with chemotherapy drugs, against pancreatic cancer cell lines [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-039.

Facile preparation of nanomicelles using polymyxin E for enhanced antitumor effects

Chemotherapy is a major cancer treatment that uses antitumor drugs to kill fast-growing cancer cells. Many kinds of drug carriers have been developed to deliver and achieve controlled release of small-molecule therapeutic agents. However, many therapeutic agent carriers need complex preparation process. The natural polypeptides may serve as proper drug carriers. More specifically, polymyxin E (PE) is a kind of natural antibiotic lipopeptides. It is commonly used to treat infections caused by multidrug-resistant Gram-negative bacteria. Herein, we present a facile method to prepare DOX-loaded polymyxin E micelles (PE-DOX micelles) to enhance the therapeutic effect of anticancer drug doxorubicin (DOX). The hydrodynamic sizes and zeta potential of the prepared nanomedicine (PE-DOX micelles) were 142.0 nm and 6.47 mV, respectively. The release of DOX from PE-DOX micelles was faster at pH 5.5 than that at pH 7.4. Furthermore, PE exhibited negligible cytotoxicity to A549 cells and HeLa cells within 50 μg/mL, while PE-DOX micelles caused higher cytotoxicity than that of free DOX. Moreover, the intravenously injected PE-DOX micelles showed good biocompatibility and obvious antitumor effect after 14 days’ treatment in vivo. The PE-DOX micelles have great potential to be used as anticancer agent in the future.

TREM2 is thyroid hormone regulated making the TREM2 pathway druggable with ligands for thyroid hormone receptor

Triggering receptor expressed on myeloid cells-2 (TREM2) is a cell surface receptor on macrophages and microglia that senses and responds to disease-associated signals to regulate the phenotype of these innate immune cells. The TREM2 signaling pathway has been implicated in a variety of diseases ranging from neurodegeneration in the central nervous system to metabolic disease in the periphery. Here, we report that TREM2 is a thyroid hormone-regulated gene and its expression in macrophages and microglia is stimulated by thyroid hormone and synthetic thyroid hormone agonists (thyromimetics). Our findings report the endocrine regulation of TREM2 by thyroid hormone, and provide a unique opportunity to drug the TREM2 signaling pathway with orally active small-molecule therapeutic agents.

Polymeric Nanoparticle Delivery of Combination Therapy with Synergistic Effects in Ovarian Cancer.

Treatment of ovarian cancer is challenging due to late stage diagnosis, acquired drug resistance mechanisms, and systemic toxicity of chemotherapeutic agents. Combination chemotherapy has the potential to enhance treatment efficacy by activation of multiple downstream pathways to overcome drug resistance and reducing required dosages. Sequence of delivery and the dosing schedule can further enhance treatment efficacy. Formulation of drug combinations into nanoparticles can further enhance treatment efficacy. Due to their versatility, polymer-based nanoparticles are an especially promising tool for clinical translation of combination therapies with tunable dosing schedules. We review polymer nanoparticle (e.g., micelles, dendrimers, and lipid nanoparticles) carriers of drug combinations formulated to treat ovarian cancer. In particular, the focus on this review is combinations of platinum and taxane agents (commonly used first line treatments for ovarian cancer) combined with other small molecule therapeutic agents. In vitro and in vivo drug potency are discussed with a focus on quantifiable synergistic effects. The effect of drug sequence and dosing schedule is examined. Computational approaches as a tool to predict synergistic drug combinations and dosing schedules as a tool for future nanoparticle design are also briefly discussed.

PEGylated AdipoRon derivatives improve glucose and lipid metabolism under insulinopenic and high-fat diet conditions

The pleiotropic actions of adiponectin in improving cell survival and metabolism have motivated the development of small-molecule therapeutic agents for treating diabetes and lipotoxicity. AdipoRon is a synthetic agonist of the adiponectin receptors, yet is limited by its poor solubility and bioavailability. In this work, we expand on the protective effects of AdipoRon in pancreatic β-cells and examine how structural modifications could affect the activity, pharmacokinetics, and bioavailability of this small molecule. We describe a series of AdipoRon analogs containing amphiphilic ethylene glycol (PEG) chains. Among these, AdipoRonPEG5 induced pleiotropic effects in mice under insulinopenic and high-fat diet (HFD) conditions. While both AdipoRon and AdipoRonPEG5 substantially attenuate palmitate-induced lipotoxicity in INS-1 cells, only AdipoRonPEG5 treatment is accompanied by a significant reduction in cytotoxic ceramides. In vivo, AdipoRonPEG5 can substantially reduce pancreatic, hepatic, and serum ceramide species, with a concomitant increase in the corresponding sphingoid bases and improves insulin sensitivity of mice under HFD feeding conditions. Furthermore, hyperglycemia in streptozotocin (STZ)-induced insulinopenic adiponectin-null mice is also attenuated upon AdipoRonPEG5 treatment. Our results suggest that AdipoRonPEG5 is more effective in reducing ceramides and dihydroceramides in the liver of HFD-fed mice than AdipoRon, consistent with its potent activity in activating ceramidase in vitro in INS-1 cells. Additionally, these results indicate that the beneficial effects of AdipoRonPEG5 can be partially attributed to improved pharmacokinetics as compared with AdipoRon, thus suggesting that further derivatization may improve affinity and tissue-specific targeting.

Exosomes: Their Role in Pathogenesis, Diagnosis and Treatment of Diseases.

Simple SummaryThe aim of this review is to provide an overview of the current scientific evidence concerning the role played by exosomes in the pathogenesis, diagnosis and treatment of diseases. The potential use of exosomes as delivery vectors for small-molecule therapeutic agents will be discussed. In addition, a special emphasis will be placed on the involvement of exosomes in oncological diseases, as well as to their potential therapeutic application as liquid biopsy tools mainly in cancer diagnosis. A better understanding of exosome biology could improve the results of clinical interventions using exosomes as therapeutic agents.Exosomes are lipid bilayer particles released from cells into their surrounding environment. These vesicles are mediators of near and long-distance intercellular communication and affect various aspects of cell biology. In addition to their biological function, they play an increasingly important role both in diagnosis and as therapeutic agents. In this paper, we review recent literature related to the molecular composition of exosomes, paying special attention to their role in pathogenesis, along with their application as biomarkers and as therapeutic tools. In this context, we analyze the potential use of exosomes in biomedicine, as well as the limitations that preclude their wider application.

Macrophage migration inhibitory factor-2 of Wuchereria bancrofti suppressed the DSS-induced colitis in a mouse model by promoting alternative activation of peritoneal macrophages and increasing the number of Treg cells in the colon

Abstract In this study, we cloned the homologue of macrophage migration inhibitory factor (MIF) secreted by the human filarial parasite Wuchereria bancrofti (rWbaMIF-2) and evaluated its potential in ameliorating inflammation in a dextran sulfate sodium salt (DSS)-induced colitis model. DSS administration resulted in substantial loss of body weight along with bloody diarrhea, severe inflammation in the colon and reduced length of the colon in just under 7 days. Treatment with rWbaMIF-2 reversed the clinical symptoms in DSS administered mice, characterized by no blood in the stools, minimal inflammation on the colon wall and the mice maintained normal colon length. rWbaMIF-2 treatment downregulated TNF-α, IL-6, IFN-γ, IL-1β, IL-17A, and NOS2 genes in the colon tissue and upregulated the percentage of IL-10 producing Treg and B1 cells in the colon and peritoneal cavity. Thus, one of the mechanisms by which rWbaMIF-2 induce its anti-inflammatory effect appeared to be by promoting the infiltration of IL-10 producing Treg cells into the colon. Further analysis showed alternative activation of F4/80+ large peritoneal macrophages (LPMs) with increased expression of arginase (p≤0.05) and reduced expression of iNOS, MPO activity, TNF-α, IL-6 and TLR4 in LPMs following rWbaMIF-2 treatment. Thus, for the first time, we demonstrate here that rWbaMIF-2 treatment can activate LMP macrophages alternatively and promote infiltration of Treg cells into the colon to suppress inflammation in a colitis model. These studies also demonstrate the potential of developing rWbaMIF-2 as a small molecule therapeutic agent for colitis and other inflammatory conditions. Studies funded by NIH RO1 AI116441.

Novel small molecule therapeutic agents for Alzheimer disease: Focusing on BACE1 and multi-target directed ligands.

Alzheimer's Disease (AD) is a progressive neurodegenerative disorder that effects 50 million people worldwide. In this review, AD pathology and the development of novel therapeutic agents targeting AD were fully discussed. In particular, common approaches to prevent Aβ production and/or accumulation in the brain including α-secretase activators, specific γ-secretase modulators and small molecules BACE1 inhibitors were reviewed. Additionally, natural-origin bioactive compounds that provide AD therapeutic advances have been introduced. Considering AD is a multifactorial disease, the therapeutic potential of diverse multi target-directed ligands (MTDLs) that combine the efficacy of cholinesterase (ChE) inhibitors, MAO (monoamine oxidase) inhibitors, BACE1 inhibitors, phosphodiesterase 4D (PDE4D) inhibitors, for the treatment of AD are also reviewed. This article also highlights descriptions on the regulator of serotonin receptor (5-HT), metal chelators, anti-aggregants, antioxidants and neuroprotective agents targeting AD. Finally, current computational methods for evaluating the structure-activity relationships (SAR) and virtual screening (VS) of AD drugs are discussed and evaluated.

Small Molecular Theranostic Assemblies Functionalized by Doxorubicin-Hyaluronic Acid-Methotrexate Prodrug for Multiple Tumor Targeting and Imaging-Guided Combined Chemo-Photothermal Therapy.

Because of high drug payload and minimized burden of foreign materials in the course of metabolism and excretion, carrier-free nanomedicine based on self-assembly of small-molecule therapeutic agents has attracted considerable attention in cancer therapy. However, obstacles still remained, such as lack of targeting efficiency, poor physiological stability, and serious drug burst release. Herein, we developed a self-dual-targeting prodrug conjugate by coupling methotrexate (MTX) and doxorubicin (DOX) to a hyaluronic acid (HA) backbone which enveloped the small molecular drug coassemblies of DOX and indocyanine green for specific targeting and imaging-guided chemo-photothermal therapy (PTT). The constructed nanosystems exhibited a diameter of ∼200 nm, superior physiological stability, and improved photothermal effect. Taking advantage of functionality of MTX-HA-DOX conjugate, the nanosystems remarkably enhanced the accumulation in the tumor regions by enhanced penetration and retention effect and CD44/folate receptor-mediated endocytosis. Upon the stimuli of acid, the nanosystems showed the rapid disassembly followed by the accelerated drug release. Consequently, the nanosystems demonstrated highly efficient apoptosis in cancer cells and remarkable tumor ablation by synergy between chemotherapy and PTT upon the irradiation of near-infrared laser. The multifunctional nanosystems based on small molecular theranostic assemblies could provide a promising potential in developing dual-targeting drug delivery and imaging-guided combinational therapy.

A First-in-Human Study of Novel Cereblon Modulator Avadomide (CC-122) in Advanced Malignancies

Avadomide is a novel, small-molecule therapeutic agent that modulates cereblon E3 ligase activity and exhibits potent antitumor and immunomodulatory activities. This first-in-human phase I study (NCT01421524) evaluated the safety and clinical activity of avadomide in patients with advanced solid tumors, non-Hodgkin lymphoma (NHL), and multiple myeloma. Thirty-four patients were treated with avadomide in 7 dose-escalation cohorts using a 3 + 3 design (0.5-3.5 mg, 28-day continuous dosing cycles). The primary objectives were to determine the dose-limiting toxicity (DLT), nontolerated dose (NTD), maximum tolerated dose (MTD), recommended phase II dose, and pharmacokinetics of avadomide. The secondary objective was to determine preliminary avadomide efficacy. Exploratory objectives included evaluation of pharmacodynamic effects of avadomide. DLTs were reported in 2 patients, and grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 14 patients (41%). The most common TEAEs (≥15%) were fatigue, neutropenia, and diarrhea. The NTD and MTD were 3.5 and 3.0 mg, respectively. Of 5 patients with NHL, 1 achieved a complete response, and 2 had partial responses. Although no objective responses were observed in patients with solid tumors, 5 of 6 patients with brain cancer experienced nonprogression of ≥6 months. A dose-dependent relationship between Aiolos degradation in peripheral B and T cells occurred within 5 hours of the first dose of avadomide administered, starting at 0.5 mg. Avadomide monotherapy demonstrated acceptable safety and favorable pharmacokinetics in patients with solid tumors, NHL, and multiple myeloma. In addition, 3 objective responses were observed in NHL.

Small molecules inhibit ex vivo tumor growth in bone.

Bone is a common site of metastasis for breast, prostate, lung, kidney and other cancers. Bone metastases are incurable, and substantially reduce patient quality of life. To date, there exists no small-molecule therapeutic agent that can reduce tumor burden in bone. This is partly attributed to the lack of suitable in vitro assays that are good models of tumor growth in bone. Here, we take advantage of a novel ex vivo model of bone colonization to report a series of pyrrolopyrazolone small molecules that inhibit cancer cell invasion and ex vivo tumor growth in bone at single-digit micromolar concentration. We find that the compounds modulated the expression levels of genes associated with bone-forming osteoblasts, bone-destroying osteoclasts, cancer cell viability and metastasis. Our compounds provide chemical tools to uncover novel targets and pathways associated with bone metastasis, as well as for the development of compounds to prevent and reverse bone tumor growth in vivo.