AR-12 / Arno Therap - LARVOL DELTA

Antifungal activity of AR-12 and its derivatives against clinically relevant fusarium solani isolates in keratitis. (PubMed, Bioorg Chem) - "AR-12 (OSU-03012) is a celecoxib-derived protein kinase inhibitor with characteristic scaffold of 1,5-diaryl-3-trifluoropyrazole, originally developed as an antitumor agent that reached Phase I clinical trials, but has since shown activity against a broad spectrum of pathogens, including fungi, bacteria, and viruses...The results showed that the minimum inhibitory concentration (MIC) of AR-12 against these isolates ranged from 2 to 8 μg/mL, comparable to that of the control antifungal agent voriconazole...Further investigations with B8 revealed morphological changes and the disruption of the cell membrane. This study underscores the potential of AR-12's chemical scaffold as a valuable foundation for the development of potent antifungal drugs."

Journal • Infectious Disease • Keratitis • Ocular Inflammation • Oncology • Ophthalmology

Identification of Antifungal Agents AR-12 and Fosmanogepix as Anti-Trypanosoma cruzi Drugs through an Enhanced Fluorogenic β-Galactosidase Phenotypic Screening Assay. (PubMed, ACS Infect Dis) - "Finally, the assay was adapted to a semiautomatic methodology and used to explore dual combinations of the active antifungals in the primary screening and with benznidazole. The multitarget compound AR-12 (IC50 = 1.9 μM) and the Gwt1 inhibitor Fosmanogepix (IC50 = 7.2 μM) resulted in bona fide hits, inhibiting parasite replication with only low-to-moderate toxicity on Vero host cells, thus suggesting potential for repurposing to Chagas disease."

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Discovery of Host-Directed Small Molecules with Broad Anti-Leishmanial Efficacy. (PubMed, bioRxiv) - "To address this, we developed 343 analogs of AR-12, a compound that has previously illustrated host-directed anti-leishmanial effects...This work identified 4 hit compounds. We then did proteomic analysis to understand the mechanism of action of the primary lead compound, identifying the protein lysozyme as having a role in host-directed activity against Leishmania infection."

Journal • Infectious Disease

Integrative multi-omics analysis and experimental validation reveal centromere protein W as a potential therapeutic target and predictive biomarker in renal clear cell carcinoma. (PubMed, Int J Biol Macromol) - "Furthermore, predictive modeling and molecular docking revealed that tumors with elevated CENPW levels exhibited enhanced sensitivity to targeted therapies such as OSU-03012 and rapamycin. Collectively, our findings indicate that CENPW acts as a potential oncogenic regulator in KIRC, influencing both immune pathways and therapeutic responsiveness, and may serve as a novel biomarker and treatment target."

Biomarker • IO biomarker • Journal • Clear Cell Carcinoma • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • CDH1 • CENPW • PD-L1

Comparative in vitro efficacy of AR-12 derivatives against Streptococcus pyogenes. (PubMed, J Antimicrob Chemother) - "Among these three AR-12 derivatives, P12-8 had the best potential to be an alternative agent to fight against GAS."

Journal • Preclinical • ANXA5

Sustainable Primary Cell Banking for Topical Compound Cytotoxicity Assays: Protocol Validation on Novel Biocides and Antifungals for Optimized Burn Wound Care. (PubMed, Eur Burn J) - "The obtained cellular materials were then validated for use in cytotoxicity assays through in vitro biosafety testing of topical antiseptics (chlorhexidine, hypochlorous acid) and an antifungal compound (AR-12) of interest for optimized burn wound care...Generally, this study demonstrated that highly sustainable primary cell sources may be established and applied for consistent topical compound biological safety assessments with enhanced translational relevance. Overall, the study underscored the safety-oriented interest of functionally benchmarking the products that are applied on burn patient wounds for the global enhancement of burn care quality."

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Vitamin B5 metabolism is essential for vacuolar and mitochondrial functions and drug detoxification in fungi. (PubMed, Commun Biol) - "The drug potentiation mediated by genetic regulation of genes in the PCA pathway could be recapitulated using the pantazine analog PZ-2891 as well as the celecoxib derivative, AR-12 through inhibition of fungal AcCoA synthase activity. Collectively, the data validate the PCA pathway as a suitable target for enhancing the efficacy and safety of current antifungal therapies."

Journal • Infectious Disease

Electroacupuncture inhibits PDK1/Akt/HCN4 pathway to improve neurogenic urinary retention in rats. (PubMed, Zhen Ci Yan Jiu) - "EA can improve the urinary dysfunction in rats with neurogenic urinary retention, which may be related to its effect in inhibiting the activation of PDK1/Akt pathway, promo-ting HCN4-mediated detrusor excitatory contraction and urinary electrical signal activation."

Journal • Preclinical • CNS Disorders • Orthopedics • Urinary Incontinence • HSPB1 • PDK1 • PDPK1

Molecular docking analysis of MCL-1 inhibitors for breast cancer management. (PubMed, Bioinformation) - "Visual inspection and binding energy analysis revealed that the compounds OSU-03012, Raltitrexed, Ostarine (MK-2866), Dovitinib (TKI-258), and Varespladib (LY315920) had strong binding affinity for the MCL-1 protein. These findings suggest that these compounds may be useful as MCL-1 inhibitors in the treatment of breast cancer. However, additional experimental validation is required to confirm these findings."

IO biomarker • Journal • Breast Cancer • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • BCL2

Identification of a cancer-associated fibroblast classifier for predicting prognosis and therapeutic response in lung squamous cell carcinoma. (PubMed, Medicine (Baltimore)) - "In silico drug screening identified 6 effective compounds for high-risk CAFs-related LUSC: TAK-715, GW 441756, OSU-03012, MP470, FH535, and KIN001-266. Additionally, search tool for interaction of chemicals database highlighted PI3K-Akt signaling as a potential target pathway for high-risk CAFs-related LUSC. Overall, our findings provide a molecular classifier for high-risk CAFs-related LUSC and suggest that treatment with PI3K-Akt signaling inhibitors could benefit these patients."

IO biomarker • Journal • Non Small Cell Lung Cancer • Oncology • Squamous Cell Carcinoma • CAFs • KLF10 • PDGFA • SERPINE1 • SMAD7

A potential combinatorial treatment strategy to overcome olaparib resistance in high-grade ovarian cancer (AACR 2023) - "However, in our study, OSU-03012 did not similarly affect cell viability and phenotype on ovarian cancer cell lines as a DHODH inhibitor BAY2402234. Altogether, we identified a potential non-cancer drug for ovarian cancer treatment and to overcome Olaparib resistance. A multidisciplinary approach highlights the importance of drug target profiling and sensitivity signatures scoring to improve treatment stratification."

Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Solid Tumor • BRCA • BRCA1 • BRCA2 • COL3A1 • PDPK1 • PTPRZ1 • TP53

Construction and Validation of Protein Expression-related Prognostic Models in Clear Cell Renal Cell Carcinoma. (PubMed, J Cancer) - "According to the IC50 values, CGP-60474, vinorelbine, doxorubicin, etoposide, FTI-277, JQ12, OSU-03012, pyrimethamine, and other drugs were more sensitive in the high-risk group. A prognostic model of protein expression in ccRCC was successfully constructed, which had good predictive ability for the prognosis of ccRCC patients. The ccRCC-related proteins in the model can be used as targets for studying the pathogenesis and targeted therapy."

Journal • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor

Salmonella effector SopF regulates PANoptosis of intestinal epithelial cells to aggravate systemic infection. (PubMed, Gut Microbes) - "The administration of both AR-12 (PDK1 inhibitor) and BI-D1870 (RSK inhibitor) potentially overcame Caspase-8 blockade and subverted PANoptosis challenged by SopF. Collectively, these findings demonstrate that this virulence strategy elicited by SopF aggregates systemic infection via modulating IEC PANoptosis through PDK1-RSK signaling, which throws light on novel functions of bacterial effectors, as well as a mechanism employed by pathogens to counteract host immune defense."

Journal • Immunology • Infectious Disease • Inflammation • Inflammatory Bowel Disease • CASP8

Construction and validation of a prognostic model for lung adenocarcinoma based on endoplasmic reticulum stress-related genes. (PubMed, Sci Rep) - "A prognostic prediction model was established based on 7 differentially expressed ERSRGs (PDX1, IGFBP1, DDIT4, PPP1R3G, CFTR, DERL3 and NUPR1), which could effectively predict the prognosis of LUAD patients and give a reference for clinical doctors to help LUAD patients to make better treatment tactics. Based on the 4 small molecule compounds (Phenformin, OSU-03012, GSK-650394 and KIN001-135) we discovered, targeting endoplasmic reticulum stress-related genes may also be a therapeutic approach for LUAD patients."

Journal • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • DDIT4 • IGFBP1 • PDX1

A simple protein histidine kinase activity assay for high-throughput inhibitor screening. (PubMed, Bioorg Chem) - "This kinetic assay was successfully employed for the kinetic characterization of E. coli EnvZ and for high-throughput inhibitor screening of vancomycin-resistant Enterococcus faecium (VRE) VanS, of which histidine kinase activity was hardly detectable with conventional methods. Through the screening, we identified OSU-03012, a potent VanS HK inhibitor, which sensitized VRE toward vancomycin, highlighting the potential of AUDECY in HK inhibitor discovery."

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Development of potent dual PDK1/AurA kinase inhibitors for Ewing sarcoma therapy (AACR 2022) - "OSU-03012 (PDK-1 inhibitor) and MK-5108 (AurA inhibitor) were used as reference compounds.Results. Data Brief 29 (2020) 105206.[2] Sistito S. et al. Eu J Med Chem 226 (2021) 11389."

Colon Cancer • Colorectal Cancer • Ewing Sarcoma • Oncology • Sarcoma • Solid Tumor • AURKA • EGFR • KRAS • PTEN • RB1 • RPS6KA3 • TP53

Canine osteosarcoma cells exhibit basal accumulation of multiple chaperone proteins and are sensitive to small molecule inhibitors of GRP78 and heat shock protein function. (PubMed, Cell Stress Chaperones) - "However, HMPOS cells with acquired resistance to carboplatin were sensitive to inhibition of Grp78 (by HA15; OSU-03012), Hsp70 (by VER-155008), and Hsp90 (by 17-AAG) function. These results suggest that multiple nodes within the osteosarcoma chaperome may be relevant chemotherapeutic targets against platinum resistance."

Journal • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • HSP90AA1 • HSPA5

AR-12 Has a Bactericidal Activity and a Synergistic Effect with Gentamicin against Group A Streptococcus. (PubMed, Int J Mol Sci) - "Moreover, the combination of AR-12 and gentamicin had a synergistic antibacterial activity against GAS replication for both in vitro and in vivo infection. Taken together, these novel findings obtained in this study may provide a new therapeutic strategy for invasive GAS infection."

Journal • Infectious Disease • Septic Shock

Celecoxib Analogues for Cancer Treatment: An Update on OSU-03012 and 2,5-Dimethyl-Celecoxib. (PubMed, Biomolecules) - "These molecules display stronger anti-tumor properties than celecoxib and thus may represent promising anti-cancer molecules. In this review, we discuss the impact of these two analogues on cancerous processes but also their potential for cancer treatment alone or in combination with existing approaches."

Journal • Review • Infectious Disease • Metabolic Disorders • Novel Coronavirus Disease • Oncology • Respiratory Diseases

Studies have shown that the experimental drug AR-12 is a promising treatment for COVID-19 - "Poklepovic said: 'AR-12 is an oral therapy that has been well tolerated in previous clinical trials, so we know it is safe and tolerable.' 'Most drugs for COVID-19 are injected intravenously., So this will be a unique treatment option that may be suitable for outpatient treatment, just like taking antibiotics.'"

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Overcoming reduced antibiotic susceptibility in intracellular Salmonella enterica serovar Typhimurium using AR-12. (PubMed, FEMS Microbiol Lett) - "Additionally, co-treatment of macrophages infected with multi-drug resistant S. Typhimurium with AR-12 and STR or ampicillin showed enhanced clearance of the intracellular bacteria. The drug combination did not elicit this effect on planktonic bacteria. Overall, AR-12 enhanced the clearance of less susceptible S. Typhimurium in an intracellular environment."

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[VIRTUAL] Dual targeting of PDK1 and Aurora A using first-in class OXID-pyridonyl compounds in preclinical models of Ewing sarcoma (AACR 2021) - "OSU-03012 (PDK1 inhibitor) and MK-5108 (AurA inhibitor) were used as reference compounds to investigate the functional crosstalk between the two pathways in sensitive cancer cell lines.Results. Here we report the characterization of two potent first-in-class dual PDK1-AurA inhibitors, SA16 and VI8. Our findings suggest that innovative PDK1/AurA dual-target molecules which could represent an attractive lead scaffold for the design and synthesis of a new multitarget strategy for Ewing sarcoma."

Preclinical • Colon Cancer • Colorectal Cancer • Ewing Sarcoma • Glioblastoma • Oncology • Sarcoma • Solid Tumor • AURKA • CDK1 • CDKN1A • EGFR • KRAS • MYC • PDPK1 • PTEN • RB1 • TP53

OSU-03012 Disrupts Akt Signaling and Prevents Endometrial Carcinoma Progression in vitro and in vivo. (PubMed, Drug Des Devel Ther) - "OSU-03012 is a celecoxib derivative lacking cyclooxygenase-2 inhibitory activity and a potent PDK1 inhibitor which has been shown to inhibit tumor growth in various ways. Our data indicated that OSU-03012 could inhibit the progression of EC in vitro and in vivo. It can potentially be used as the targeted drug for the treatment of EC by inhibiting Akt signaling."

Journal • Preclinical • Endometrial Cancer • Oncology • Solid Tumor • PDPK1

VCU Health team shows experimental cancer drug could be promising COVID-19 treatment (Virginia Commonwealth University) - "Noted Andrew Poklepovic...'Most COVID-19 drugs are given intravenously, so this would be a unique therapeutic option and potentially suitable for outpatient therapy, similar to the way one would take an antibiotic.' Poklepovic hopes to begin enrolling patients in early 2021, but several milestones remain."

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VCU study shows the experimental drug AR-12 could be a promising COVID-19 treatment (Eurekalert) - "Andrew Poklepovic, M.D...is leading efforts to translate these exciting findings into a clinical trial. 'AR-12 is an oral therapy that has been well tolerated in a prior clinical trial, so we know that it is safe and tolerable,' says Poklepovic....Poklepovic hopes to begin enrolling patients in early 2021, but several milestones remain."

Clinical • Media quote