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Objective: A3 adenosine receptor (A3AR) is overexpressed in the skin and peripheral blood mononuclear cells of psoriasis patients. We investigated the efficacy/safety of piclidenoson (CF101), an orally bioavailable A3AR agonist that inhibits IL‐17 and IL‐23 production in keratinocytes, in moderate‐to‐severe plaque psoriasis. Methods: The randomized, placebo‐ and active‐controlled, double‐blind phase 3 COMFORT‐1 trial randomized patients (3:3:3:2) to piclidenoson 2 mg BID, piclidenoson 3 mg BID, apremilast 30 mg BID or placebo. At Week 16, patients in the placebo arm were re‐randomized (1:1:1) to piclidenoson 2 mg BID, piclidenoson 3 mg BID or apremilast 30 mg BID. The primary end point was the proportion of patients achieving ≥75% improvement in Psoriasis Area and Severity Index (PASI) from baseline (PASI‐75) at Week 16 versus placebo. Results: A total of 529 patients were randomized and received ≥1 dose of study medication (safety population). The efficacy analysis population for the primary end point included 426 patients (piclidenoson 2 mg BID, 127; piclidenoson 3 mg BID, 103; apremilast, 118; placebo, 78). Piclidenoson at 2 and 3 mg BID exhibited similar efficacy. The primary end point was met with the 3 mg BID dose: PASI 75 rate of 9.7% versus 2.6% for piclidenoson versus placebo, p = 0.037. The PASI responses with piclidenoson continued to increase throughout the study period in a linear manner. At week 32, analysis in the per‐protocol population showed that a greater proportion of patients in the piclidenoson 3 mg BID arm (51/88, 58.0%) achieved improvement from baseline in Psoriasis Disability Index (PDI) compared to apremilast (59/108, 55.1%), and the test for noninferiority trended towards significance (p = 0.072). The safety/tolerability profile of piclidenoson was excellent and superior to apremilast. Conclusions: Piclidenoson demonstrated efficacy responses that increased over time alongside a favourable safety profile. These findings support its continued clinical development as a psoriasis treatment (ClinicalTrials.gov identifier: NCT03168256). [ABSTRACT FROM AUTHOR]

Established treatments for advanced hepatocellular carcinoma (HCC) with Child-Pugh cirrhosis B (CPB, moderate hepatic dysfunction) are lacking. A recently published randomized phase 2 study in CPB HCC investigating the safety and efficacy of namodenoson (25 mg BID), an A3 adenosine-receptor agonist vs. placebo, suggested a favorable safety profile and a positive efficacy signal in patients with HCC with a CPB score of 7 (CPB7). The present study reports a 61-year-old woman with CPB7 HCC who received namodenoson for over 6 years through this study and its open-label extension. Computed tomography scans demonstrated partial and complete responses after 7 weeks and 4 years of treatment, respectively. Low albumin levels (31 g/l) and elevated baseline levels of alanine transaminase and aspartate aminotransferase (68 U/l and 44 U/l, respectively) were reported. After 4 weeks of treatment, these levels normalized and were stable for over 6 years. No treatment-emergent adverse events were noted. At the time of reporting, the response is ongoing as manifested by imaging studies and liver function evaluation., Competing Interests: MF, ZH, MHS, and PF are Can-Fite BioPharma, Ltd employees. SMS received research grant and stock options from Can-Fite BioPharma Ltd. AB-S is a consultant for Can-Fite BioPharma Ltd. The remaining authors declare no competing interests. Can-Fite BioPharma sponsored the phase 2 study; however, this sponsorship had no bearing on the results of the study or their scientific interpretation., (Copyright: © 2024 Ciurescu et al.)

Glioblastoma Multiforme (GBM) is the most aggressive and most common primary malignant brain tumor. The age of GBM patients is considered as one of the disease's negative prognostic factors and the mean age of diagnosis is 62 years. A promising approach to preventing both GBM and aging is to identify new potential therapeutic targets that are associated with both conditions as concurrent drivers. In this work, we present a multi-angled approach of identifying targets, which takes into account not only the disease-related genes but also the ones important in aging. For this purpose, we developed three strategies of target identification using the results of correlation analysis augmented with survival data, differences in expression levels and previously published information of aging-related genes. Several studies have recently validated the robustness and applicability of AI-driven computational methods for target identification in both cancer and aging-related diseases. Therefore, we leveraged the AI predictive power of the PandaOmics TargetID engine in order to rank the resulting target hypotheses and prioritize the most promising therapeutic gene targets. We propose cyclic nucleotide gated channel subunit alpha 3 ( CNGA3 ), glutamate dehydrogenase 1 ( GLUD1 ) and sirtuin 1 ( SIRT1 ) as potential novel dual-purpose therapeutic targets to treat aging and GBM.

Background: Namodenoson, an A3 adenosine receptor (A3AR) agonist, improved liver function/pathology in non-alcoholic steatohepatitis (NASH) preclinical models., Aim: To evaluate the efficacy and safety of namodenoson for the treatment of non-alcoholic fatty liver disease (NAFLD) with or without NASH METHODS: This phase 2 study included 60 patients with NAFLD (ALT ≥60 IU/L) who were randomised (1:1:1) to oral namodenoson 12.5 mg b.d. (n = 21), 25 mg b.d. (n = 19), or placebo (n = 20) for 12 weeks (total follow-up: 16 weeks). The main efficacy endpoint involved serum ALT after 12 weeks of treatment., Results: Serum ALT decreased over time with namodenoson in a dose-dependent manner. The difference between change from baseline (CFB) for ALT in the namodenoson 25 mg b.d. arm vs placebo trended towards significance at 12 weeks (P = 0.066). Serum AST levels also decreased with namodenoson in a dose-dependent manner; at 12 weeks, the CFB for 25 mg b.d. vs placebo was significant (P = 0.03). At Week 12, 31.6% in the namodenoson 25 mg b.d. arm and 20.0% in the placebo arm achieved ALT normalisation (P = 0.405). At week 16, the respective rates were 36.8% and 10.0% (P = 0.038). A3AR expression levels were stable over time across study arms. Both doses of namodenoson were well tolerated with no drug-emergent severe adverse events, drug-drug interactions, hepatotoxicity, or deaths. Three adverse events were considered possibly related to study treatment: myalgia (12.5 mg b.d. arm), muscular weakness (25 mg b.d. arm), and headache (25 mg b.d. arm)., Conclusion: A3AR is a valid target; namodenoson 25 mg b.d. was safe and demonstrated efficacy signals (ClinicalTrials.gov #NCT02927314)., (© 2021 Can-Fite BioPharma Ltd. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Namodenoson, an A3 adenosine-receptor agonist, showed promising results in advanced hepatocellular carcinoma (HCC) and moderate hepatic dysfunction (Child-Pugh B; CPB) in a phase I/II clinical study. This phase II study investigated namodenoson as second-line therapy in such patients. Patients were randomized 2:1 to twice a day (BID) namodenoson (25 mg; n = 50) or placebo ( n = 28). The primary endpoint (overall survival [OS]) was not met. Median OS was 4.1/4.3 months for namodenoson/placebo (hazard ratio [HR], 0.82; 95% confidence interval [CI] 0.49-1.38; p = 0.46). Pre-planned subgroup analysis of CPB7 patients (34 namodenoson-treated, 22 placebo-treated) showed a nonsignificant improvement in OS/progression-free survival (PFS). OS: 6.9 versus 4.3 months; HR, 0.81; 95% CI: 0.45-1.43, p = 0.46. PFS: 3.5 versus 1.9 months; HR, 0.89; 95% CI: 0.51-1.55, p = 0.67 (log-rank test). The difference in 12-month OS was significant (44% versus 18%, p = 0.028). Response rates were determined in patients for whom ≥ 1 assessment post-baseline was available (34 namodenoson-treated, 21 placebo-treated). Partial response was achieved by 3/34 (8.8%) and 0/21 (0%) patients, respectively. Namodenoson was well-tolerated, with a safety profile comparable to that of the placebo group. No treatment-related deaths were reported; no patients withdrew due to toxicity. In conclusion, namodenoson demonstrated a favorable safety profile and a preliminary efficacy signal in HCC CPB.

Background: CF101, an adenosine A3 receptor agonist, is an orally bioavailable small molecule drug presenting an anti-psoriatic effect demonstrated in a Phase 2 clinical trial in psoriasis patients.
, Objective: To evaluate the safety and efficacy of CF101 treatment in a Phase 2/3 study in patients with moderate to severe plaque-type psoriasis.
, Methods: This multicenter, double-blind, 2-segment, placebo-controlled study randomized subjects with moderate to severe plaque psoriasis to CF101 1 or 2 mg, or placebo twice daily. At either week 12 (Segment 1) or 16 (Segment 2), the placebo group crossed over to CF101 BID through week 32 in an open-label fashion. At week 12, following an interim analysis, the CF101 1mg group was discontinued due to futility. The primary endpoint was proportion of patients achieving ≥75% improvement in Psoriasis Area Severity Index (PASI 75). Efficacy testing was performed using the Cochran-Mantel Haenszel test, the primary analysis of PASI 75 was performed at the 0.035 significance level.
, Results: CF101 had an excellent safety profile at all tested dosages with a profile similar to the placebo group. The most common adverse events were infections and gastrointestinal events, and there was no cumulative intolerance over the 32-week dosing period. The study did not meet the primary endpoint of PASI 75 at week 12 (2 mg: 8.5% vs. placebo: 6.9%, P=0.621). However, at week 32, PASI mean percent improvement with CF101 2 mg was 57% (P<0.001) compared to baseline, with linear improvement in PASI 50 (63.5%), 75 (35.5%), 90 (24.7%), and 100 (10.6%).
, Conclusions: Oral CF101 was found to be safe and very well tolerated, demonstrating evidence of efficacy in patients with moderate to severe plaque psoriasis through 32 weeks of treatment.

J Drugs Dermatol. 2016;15(8):931-938.

Native chemical ligation (NCL) proceeds via a S-N acyl shift and, therefore, requires N-terminal cysteine. N(α)-auxiliaries have long been used to enable NCL beyond cysteine. However, the reversibility of the S-N acyl shift under the acidic conditions used to remove the commonly applied N-benzyl auxiliaries limits the scope of this reaction. Herein, we introduce a new class of N(α)-auxiliary which is designed for removal under mild basic conditions. The 3-N-linked 4-mercaptobutyrate auxiliary is readily synthesized in a single step and enables introduction on solid phase by means of reductive amination. The usefulness of the new auxiliary was demonstrated in the synthesis of the anti-microbial C-terminal domain of Dermicidine-1L., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Native chemical ligation enables the chemical synthesis of proteins. Previously, thiol-containing auxiliary groups have been used to extend the reaction scope beyond N-terminal cysteine residues. However, the N-benzyl-type auxiliaries used so far result in rather low reaction rates. Herein, a new N(α) -auxiliary is presented. Consideration of a radical fragmentation for cleavage led to the design of a new auxiliary group which is selectively removed under mildly basic conditions (pH 8.5) in the presence of TCEP and morpholine. Most importantly and in contrast to previously described auxiliaries, the 2-mercapto-2-phenethyl auxiliary is not limited to Gly-containing sites and ligations succeed at sterically demanding junctions. The auxiliary is introduced in high yield by on-resin reductive amination with commercially available amino acid building blocks. The synthetic utility of the method is demonstrated by the synthesis of two antimicrobial proteins, DCD-1L and opistoporin-2., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: The A(3) adenosine receptor (A(3)AR) is overexpressed in the tumor and in the peripheral blood mononuclear cells of patients with hepatocellular carcinoma (HCC). The orally active drug candidate CF102, an A(3)AR agonist, induces apoptosis of HCC cells via deregulation of the Wnt signaling pathway. In this open label phase I/II trial, the safety and clinical effects of CF102 were assessed in patients with advanced unresectable HCC., Methods: The primary objectives of this trial were to examine the safety and pharmacokinetic (PK) behavior of CF102 given orally (1, 5, and 25 mg BID) in 28-day cycles. Evaluation of anti-tumor effects and the utilization of A(3)AR as a biological predictive marker of response to CF102 were the secondary objectives., Results: Eighteen patients received CF102-six at each dose level. No serious drug-related adverse events or dose-limiting toxicities were observed. CF102 demonstrated good oral bioavailability and linear PK behavior. Median overall survival in the study population, 67% of whom had received prior sorafenib, was 7.8 months, and for Child Pugh B patients (28%) it was 8.1 months. Stable disease by RECIST was observed in four patients for at least 4 months. CF102 maintained liver function over a 6-month period. A correlation between receptor overexpression levels at baseline and patients' overall survival was found. One of the patients who presented with skin nodules that were biopsy-proven to be HCC metastases prior to the trial showed complete metastasis regression during three months of treatment with CF102., Conclusions: CF102 is safe and well-tolerated, showing favorable PK characteristics in Child Pugh A and B HCC patients, justifying further clinical development.

Objective: To explore the safety and efficacy of CF101, an A(3) adenosine receptor agonist, in patients with moderate to severe dry eye syndrome., Design: Phase 2, multicenter, randomized, double-masked, placebo-controlled, parallel-group study., Participants: Sixty-eight patients completed the study, 35 patients in the placebo group and 33 patients in the CF101 group., Intervention: Patients were treated orally with either 1 mg CF101 pills or matching vehicle-filled placebo pills, given twice daily for 12 weeks, followed by a 2-week posttreatment observation., Main Outcome Measures: An improvement of more than 25% over baseline at week 12 in one of the following parameters: (1) tear break-up time (BUT); (2) superficial punctate keratitis assessed by fluorescein staining results; and (3) Schirmer tear test 1 results. Clinical laboratory safety tests, ophthalmic examinations, intraocular pressure (IOP) measurements, electrocardiographic evaluations, vital sign measurements, and monitoring of adverse events., Results: A statistically significant increase in the proportion of patients who achieved more than 25% improvement in the corneal staining and in the clearance of corneal staining was noted between the CF101-treated group and the placebo group. Treatment with CF101 resulted in a statistically significant improvement in the mean change from baseline at week 12 of the corneal staining, BUT, and tear meniscus (TM) height in the CF101-treated group. CF101 was well tolerated and exhibited an excellent safety profile with no serious adverse events. A statistically significant decrease from baseline was observed in the IOP of the CF101-treated group in comparison with the placebo group., Conclusions: CF101, given orally, induced a statistically significant improvement in the corneal staining and an improvement in the BUT and TM in patients with moderate to severe dry eye syndrome. The drug was very well tolerated. These data and the anti-inflammatory characteristic of CF101 support further study of the drug as a potential treatment for the signs and symptoms of dry eye syndrome., Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references., (Copyright 2010 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Chemical ligation methods for the assembly of functional proteins continue to advance our basic understanding of protein structure and function. In this work, we report on our progress towards the full synthesis of HIV-1 Tat utilizing our newly developed ligation method; side-chain assisted ligation. The HIV-1 Tat was assembled from three fragments wherein the two thioester peptides were synthesized efficiently using the side-chain anchoring strategy following Fmoc-SPPS. The side-chain assisted ligation step was efficient and provided the ligation product in good yield. Following this step, native chemical ligation was used to fully assemble the HIV-1 Tat protein. Although the removal of the auxiliary in small peptides was straightforward, in the case of HIV-1 Tat this step was inefficient thus hampering the completion of the synthesis.