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PK/PD data, Journal: Bridging population pharmacokinetic and semimechanistic absorption modeling of APX3330. (Pubmed Central) - Jan 15, 2024 Delayed APX3330 absorption with food may be related to higher conversion to the more soluble but less permeable hydroquinone form in the gastrointestinal tract. Future work should address pharmacokinetic differences between APX3330 quinone and hydroquinone forms.
- |||||||||| MitoQ (mitoquinone) / Antipodean, Vincerinone (vatiquinone) / Sumitomo Pharma, PTC Therap, APX3330 / Apexian, Ocuphire Pharma
Review, Journal: Quinones as Neuroprotective Agents. (Pubmed Central) - Jul 29, 2023 Additional neuroprotective quinones that can be regarded as coenzyme Q analogues are idobenone, mitoquinone and plastoquinone. Other endogenous quinones with neuroprotective activities include tocopherol-derived quinones, most notably vatiquinone, and vitamin K. A final group of non-endogenous quinones with neuroprotective activity is discussed, comprising embelin, APX-3330, cannabinoid-derived quinones, asterriquinones and other indolylquinones, pyrroloquinolinequinone and its analogues, geldanamycin and its analogues, rifampicin quinone, memoquin and a number of hybrid structures combining quinones with amino acids, cholinesterase inhibitors and non-steroidal anti-inflammatory drugs.
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REFLUX CONDITIONS-INDUCED E-CADHERIN CLEAVAGE AND EPITHELIAL-TO-MESENCHYMAL TRANSITION IS MEDIATED BY APE1 REDOX FUNCTION IN ESOPHAGEAL ADENOCARCINOMA (South Hall A, Poster Hall - McCormick Place) - Mar 23, 2023 - Abstract #DDW2023DDW_6540; Other endogenous quinones with neuroprotective activities include tocopherol-derived quinones, most notably vatiquinone, and vitamin K. A final group of non-endogenous quinones with neuroprotective activity is discussed, comprising embelin, APX-3330, cannabinoid-derived quinones, asterriquinones and other indolylquinones, pyrroloquinolinequinone and its analogues, geldanamycin and its analogues, rifampicin quinone, memoquin and a number of hybrid structures combining quinones with amino acids, cholinesterase inhibitors and non-steroidal anti-inflammatory drugs. APE1 silencing, or APE1-redox-specific inhibitor (E3330), abrogated the ABS-induced EMT process and signaling by downregulating MMP14...Conclusion This study demonstrates the role of ABS in promoting EMT via the redox-sensitive signaling axis of APE1/MMP14/E-cadherin/
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APE1/REF-1 AS A NOVEL MOLECULAR TARGET FOR IBD TREATMENT (South Hall A, Poster Hall - McCormick Place) - Mar 23, 2023 - Abstract #DDW2023DDW_699; Importantly, APX3330 can be administered orally providing a significant reduction in health care costs and the burden of disease. Hence, this work is likely to result in fundamental outcomes leading to improvement of IBD treatment and change the clinical practice and policy.
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Gastroesophageal reflux disease promotes E-cadherin cleavage and activates EMT via APE1-redox function in esophageal adenocarcinoma (Section 2; Poster Board #9) - Mar 14, 2023 - Abstract #AACR2023AACR_4270; Hence, this work is likely to result in fundamental outcomes leading to improvement of IBD treatment and change the clinical practice and policy. APE1 silencing, or APE1-redox-specific inhibitor (E3330), abrogated the ABS-induced EMT process and signaling by downregulating MMP14...In a summary, this study demonstrates the role of ABS in promoting EMT via the redox-sensitive signaling axis of APE1/MMP14/E-cadherin/
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Trial completion date, Trial primary completion date: ZETA-1: Study of the Safety and Efficacy of APX3330 in Diabetic Retinopathy (clinicaltrials.gov) - Jan 18, 2023 P2, N=103, Active, not recruiting, APE1 silencing, or APE1-redox-specific inhibitor (E3330), abrogated the ABS-induced EMT process and signaling by downregulating MMP14...In a summary, this study demonstrates the role of ABS in promoting EMT via the redox-sensitive signaling axis of APE1/MMP14/E-cadherin/ Trial completion date: Dec 2022 --> Mar 2023 | Trial primary completion date: Dec 2022 --> Mar 2023
- |||||||||| resatorvid (TAK-242) / Takeda, Akaza Bioscience, APX3330 / Apexian, Ocuphire Pharma
ABCA1 Deficiency Primes Inflammasome via APE1/IRF1 Axis in Podocytes (Exhibit Hall, Orange County Convention Center, West Building) - Oct 13, 2022 - Abstract #KIDNEYWEEK2022KIDNEY_WEEK_3602; APE1 protein expression was also increased in the nuclear fraction of siABCA1 podocytes compared to siCO. Conclusion These data indicate that ABCA1 deficiency in podocytes caused nuclear APE1 accumulation, which reduces transcription factors to increase the expression of IRF1 and IRF1 target inflammasome-related genes, leading to proptosis priming.
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APE1/Ref-1 is overexpressed and colocalizes with neovascular tufts and hypoxic regions in the oxygen-induced retinopathy mouse model (F0314) - Apr 29, 2022 - Abstract #ARVO2022ARVO_231; Here, we revealed that Ref-1 is highly expressed in pathological angiogenic tufts in the murine OIR retina, suggesting that Ref-1 is likewise important for retinal neovascularization, thus providing context for new potential therapeutic use in PDR and/or ROP. Layman Abstract: Retinopathy of prematurity (ROP) is a blinding disease that affects premature babies by causing abnormal blood vessel growth in the neural layer of the eye called the retina.
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APE1 REDOX-DEPENDENT ACTIVATION OF YAP IN RESPONSE TO REFLUX CONDITIONS IN ESOPHAGEAL CARCINOGENESIS (Poster Hall - San Diego Convention Center) - Apr 25, 2022 - Abstract #DDW2022DDW_1048; Moreover, silencing APE1 induced YAP K48-linked poly-ubiquitination thus promoting YAP degradation. Conclusion : Our findings establish a role for YAP in EAC progression and provide a possible druggable opportunity for future therapies combining E3330 and YAP inhibitors for the treatment of EAC.
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Enrollment closed: ZETA-1: Study of the Safety and Efficacy of APX3330 in Diabetic Retinopathy (clinicaltrials.gov) - Mar 22, 2022 P2, N=103, Active, not recruiting, Our data further support a pivotal role of RelA in mediating Ref-1 redox signaling in PDAC cells with the Kras genotype and provide novel therapeutic strategies to combat PDAC drug resistance. Recruiting --> Active, not recruiting
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Inhibition of Ref-1/APE1 redox activity with APX3330 enhances Ref-1/APE1 protein unfolded conformation in human PDAC cells (Section 7) - Mar 9, 2022 - Abstract #AACR2022AACR_4861; In vivo studies demonstrated significant reduction in tumor size, weight, and growth in C65A PDAC cells compared to the Cas9 control lines, further demonstrating the critical role of C65 in the Ref-1 redox signaling and downstream pathways including metabolism and proliferation. In conclusion, we demonstrate direct interactions between Ref-1 and APX3330 in PDAC cells and subsequent biological results confirm a critical involvement of Ref-1-C65 in the redox signaling and tumor phenotype.
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Elucidating the mechanistic effect of targeting Ref-1 redox function on MPNST survival signaling using patient-derived xenolines (Section 33) - Mar 9, 2022 - Abstract #AACR2022AACR_3842; P1 Ref-1 redox inhibitor, APX3330 that completed Phase I clinical trial (NCT03375086), potently inhibited in vitro growth of a panel of MPNST cells...Two new xenolines were established from patient PDXs and are being validated for growth inhibition and downregulation of MPNST survival genes with Ref-1 knockdown and redox inhibition using APX analogs both in vitro and in vivo. Successful derailing of MPNST survival pathways by targeting Ref-1 redox function is our aim to treat this rare but deadly cancer.
- |||||||||| resatorvid (TAK-242) / Takeda, Akaza Bioscience, APX3330 / Apexian, Ocuphire Pharma
PK/PD data, Review, Journal: Advanced Bioinformatics Tools in the Pharmacokinetic Profiles of Natural and Synthetic Compounds with Anti-Diabetic Activity. (Pubmed Central) - Jan 13, 2022 Here, we presented the efficacy of natural (gymnemic acids, quercetin, resveratrol) and synthetic (TAK-242, propofol, or APX3330) compounds in reducing diabetes symptoms and improving BBB dysfunctions. Bioinformatics tools can be helpful in the quest for chemical compounds with effective anti-diabetic activity that can enhance the druggability of molecular targets and provide a deeper understanding of diabetes mechanisms.
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Trial completion date, Trial primary completion date: ZETA-1: Study of the Safety and Efficacy of APX3330 in Diabetic Retinopathy (clinicaltrials.gov) - Nov 15, 2021 P2, N=100, Recruiting, Our findings help to elucidate the role played by APE1 in cervical cancer metastasis and targeting APE1 redox function may be a novel strategy for inhibiting cervical cancer metastasis. Trial completion date: Jun 2022 --> Dec 2022 | Trial primary completion date: Mar 2022 --> Dec 2022
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Review, Journal: New Horizons for the Roles and Association of APE1/Ref-1 and ABCA1 in Atherosclerosis. (Pubmed Central) - Oct 29, 2021 The LXR agonist LXR-623 (WAY-252623) is an agonist of ABCA1 and the first LXR-targeting compound to be evaluated in clinical trials. In this article, we review the roles of ABCA1 and APE1/Ref-1 in atherosclerosis and focus on new insights into the ABCA1-APE1/Ref-1 axis and its potential as a novel therapeutic target in atherosclerosis.
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Preclinical, Journal: Inhibitors of APE1 Redox Function Effectively inhibit γ-herpesvirus Replication In Vitro and In Vivo. (Pubmed Central) - Aug 8, 2021 C10 and E3330 were able to significantly reduce the pulmonary alveolar loss and pulmonary septal enlargement in mice caused by MHV-68 infection. Altogether, (i) APE1 redox function is validated as a new antiviral target; (ii) APE1 redox inhibitors, especially C10, have potentials to be used for the treatment of γ-herpesvirus infection and associated diseases; (iii) MHV-68 is validated to be a surrogate for the study of the pathogenesis and therapy of EBV and KSHV infection in vivo.
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Journal: The redox function of apurinic/apyrimidinic endonuclease 1 as key modulator in photodynamic therapy. (Pubmed Central) - May 1, 2021 The APE1's downregulation correlated to an increase of DNA fragmentation (17% and 66% in A549 and HeLa cells, respectively) and cell death rate (total: 24% and 74% in A549 and HeLa cells, respectively) characterized by annexin V and 7-AAD markers as well as a considerable difference in superoxide detected in mitochondria (29% and 78% in A549 and HeLa cells, respectively). This study definitively detected an increase in PDT efficacy when APE1's redox function is dysregulated by E3330.
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Trial completion date, Trial primary completion date: ZETA-1: Study of the Safety and Efficacy of APX3330 in Diabetic Retinopathy (clinicaltrials.gov) - Mar 18, 2021 P2, N=100, Not yet recruiting, Not yet recruiting --> Recruiting Trial completion date: Mar 2022 --> Jun 2022 | Trial primary completion date: Dec 2021 --> Mar 2022
- |||||||||| APX3330 / Apexian, Ocuphire Pharma
[VIRTUAL] Deciphering mechanisms of Ref-1 signaling and its inhibition in aggressive tumor-stroma PDAC models () - Mar 11, 2021 - Abstract #AACR2021AACR_3462; P1 Our group was able to generate a Ref-1 redox inhibitor, APX3330, that completed Phase I clinical trial (NCT03375086) with a good safety profile, verified target engagement and a recommended phase II dose...As confirmation of significantly reduced Ref-1 redox activity, PDAC cells expressing Ref-1C65A did not induce hypoxia marker (CA9) under hypoxia, similar to when Ref-1 was knocked down or blocked via small molecule inhibitor. Ref-1 redox signaling and validation for selective killing of PDAC cells leaving the stomal cells undisturbed paves the way to improved PDAC treatment.
- |||||||||| APX3330 / Apexian, Ocuphire Pharma
Trial completion, Enrollment change, Metastases: A Study of APX3330 in Patients With Advanced Solid Tumors (clinicaltrials.gov) - Sep 8, 2020 P1, N=19, Completed, The findings of the present study provide theoretical and experimental bases for the design of tumor-associated macrophage (TAM)-targeted therapy, with APE1 as the target molecule. Recruiting --> Completed | N=30 --> 19
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