作者: Wegner, Sven ; Tabori, Sarah ; Gomez, Mario ; Krüger, Nenja ; Eyerich, Kilian ; Lauffer, Felix ; Pinter, Andreas ; Sendecki, Jocelyn ; Personke, Yvonne ; Sabat, Robert ; Schäkel, Knut ; Wolk, Kerstin ; Reich, Kristian ; Leung, Monica W. L. ; Asadullah, Khusru ; Chen, Yanqing ; Eyerich, Stefanie ; Angsana, Julianty ; Taut, Friedemann J. H. ; Weisenseel, Peter ; Paul, Carle ; Kohler, Kristen

ImportancePsoriasis is a chronic inflammatory skin disease with unmet needs for tailored treatment and therapy de-escalation strategies.ObjectiveTo evaluate early intervention with and prolonging the dosing interval for guselkumab, a p19 subunit-targeted interleukin (IL)-23 inhibitor, in patients with moderate to severe psoriasis.Design, Setting, and ParticipantsThe GUIDE clinical trial is an ongoing phase 3b, randomized, double-blinded trial conducted across 80 centers in Germany and France comprising 3 parts evaluating the impact of early disease intervention, prolonged dosing interval, and maintenance of response following treatment withdrawal among adults with moderate to severe plaque psoriasis. In study part 2, reported herein, first and last patient visits were September 2019 and March 2022, respectively.InterventionsIn GUIDE part 1 (week [W]0-W28), patients received guselkumab, 100 mg, at W0, W4, W12, and W20. Those achieving a Psoriasis Area and Severity Index (PASI) of 0 at both W20 and W28 were termed super responders (SRes). In part 2 (W28-W68), SRes were randomized to guselkumab, 100 mg, every 8 weeks or every 16 weeks; non-SRes continued open-label guselkumab every 8 weeks.Main Outcomes and MeasuresPrimary objective was to demonstrate noninferiority (with a 10% margin) of guselkumab every 16 weeks vs every 8 weeks dosing among SRes for maintenance of disease control (PASI &lt;3 at W68). Biomarker substudies assessed immunologic effects in skin and blood.ResultsOverall, 822 patients received guselkumab in part 2 (297 [36.1%] SRes [every 8 weeks/every 16 weeks; n = 148/n = 149] and 525 [63.9%] non-SRes). Among SRes, mean (SD) age was 39.4 (14.1) years, 95 (32.0%) were female, and 202 (68.0%) were male. The primary end point of noninferiority for guselkumab every 16 weeks vs every 8 weeks in SRes was met (P = .001), with 91.9% (137/149; 90% CI, 87.3%-95.3%) of SRes receiving every 16 weeks and 92.6% (137/148; 90% CI, 88.0%-95.8%) of SRes receiving dosing every 8 weeks having PASI lower than 3 at W68. Clinical effects corresponded with immunologic changes; skin CD8-positive tissue-resident memory T (TRM)–cell count decreased quickly from baseline, remaining low in both dosing groups. Similarly, serum IL-17A, IL-17F, IL-22, and β defensin (BD)–2 levels decreased significantly from baseline, remaining low in both dosing groups to W68. Guselkumab was well-tolerated; no new safety signals were identified.Conclusions and RelevancePsoriasis treatment guidelines lack or provide inconsistent advice on patient stratification and treatment de-escalation. We present the first randomized trial providing evidence that, in patients with early complete skin clearance at 2 consecutive visits (W20 and W28), extending the guselkumab dosing interval may control disease activity.Trial RegistrationClinicalTrials.gov Identifier: NCT03818035

2018-12-01·Cell Communication and Signaling2区 · 生物学

DNA damage and apoptosis induced by a potent orally podophyllotoxin derivative in breast cancer

2区 · 生物学

ArticleOA

作者: Li, Fangfang ; Wang, Yajie ; Zhang, Dan ; Gao, Yuanchao ; Wei, Ning ; Xiao, Zhiyan ; Sun, Hua ; Bao, Xiuqi ; Wu, Shaoyu ; Zhang, Gang

BACKGROUNDTargeting TopoisomeraseII (TopoII) and generate enzyme mediated DNA damage is an effective strategy for treatment of breast cancer. TopoII is known as a validated target for drug discovery and cancer chemotherapy.METHODSXWL-1-48, a new orally podophyllotoxin derivative, was designed and synthesized. The effect of XWL-1-48 on TopoII binding and activity was determined by molecular docking software and kDNA-decatenation assay, respectively. In vitro and in vivo breast cancer models were used to document the antitumor activity of XWL-1-48. Cellular apoptosis, cell cycle and ROS were analyzed by flow cytometry. Alteration of XWL-1-48-mediated downstream pathways was determined by western blot analysis.RESULTSThe cytotoxicity of XWL-1-48 is more potent than that of its congener GL331. Molecular docking demonstrated that XWL-1-48 could bind to TopoII through forming two strong hydrogen bonds and potential pi-pi interactions. Noticeably, XWL-1-48 exerts potent antitumor activity in in vitro and in vivo breast cancer model. Treatment with XWL-1-48 caused ROS generation and triggered DNA damage through induction of γ-H2AX and activation of ATM/p53/p21 pathway. Further studies showed that XWL-1-48 led to S-phase arrest and mitochondrial apoptosis. Meanwhile, XWL-1-48 significantly blocked PI3K/Akt/Mdm2 pathway and enhanced Mdm2 degradation.CONCLUSIONXWL-1-48 may be a promising orally topoII inhibitor, its mechanisms are associated with suppression of TopoII, induction of DNA damage and apoptosis, blockage of PI3K/AKT/Mdm2 pathway.

2015-09-02·Expert Opinion on Therapeutic Patents2区 · 医学

Podophyllotoxin derivatives: a patent review (2012 – 2014)

2区 · 医学

Review

作者: Riyaz, Syed ; Rahim, Abdul ; Kamal, Ahmed ; Ali Hussaini, Syed Mohammed

INTRODUCTIONPodophyllotoxin (PPT) is a naturally occurring antimitotic agent and an interesting lead in the development of anticancer agents. Its optimization led to the development of etoposide and teniposide used in combination chemotherapy with other anticancer drugs; unlike PPT these drugs act by inhibiting topoisomerases. Clinical success and toxicity issues at later stages of etoposide usage inclined researchers to develop structurally modified PPT derivatives. Some of the compounds obtained are under clinical investigations and are anticipated to reach the market.AREAS COVEREDThe present review summarizes the attempts made by researchers across the globe to find out newer anticancer agents based on the PPT structure. It brings out the outline of the inventions filed in the form of patents during the years 2012 - 2014.EXPERT OPINIONAfter the successful development of etoposide and teniposide there has been considerable interest in the PPT skeleton to develop newer chemotherapeutic agents. In this regard, several PPT derivatives such as TOP53, GL331, NK611, F11782, and so on, have been developed and are undergoing clinical trials. However, its low natural abundance is a major problem in carrying out research on PPT skeleton. This issue is expected to be addressed with the development of newer synthetic strategies to access structurally modified PPTs.

100 项与 GL-331 相关的药物交易

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适应症	最高研发状态	国家/地区	公司	日期
小细胞肺癌	临床2期	-	Genelabs Technologies, Inc.	-
小细胞肺癌	临床2期	-	德全药品（江苏）股份有限公司	-
胃癌	临床2期	中国台湾	台湾中央研究院	-
胃癌	临床2期	-	Genelabs Technologies, Inc.	-
胃癌	临床2期	-	德全药品（江苏）股份有限公司	-