Topoisomerase (Top) inhibitors used in clinical cancer treatments are limited because of their toxicity and severe side effects. Noteworthily, Top1/2 dual inhibitors overcome the compensatory effect between Top1 and 2 inhibitors to exhibit stronger antitumor efficacies. In this study, a series of indolo[3,2-c]isoquinoline derivatives were designed as Top1/2 dual inhibitors possessing apparent antiproliferative activities. Mechanistic studies indicated that the optimal compounds 23 and 31 with increasing reactive oxygen species levels damage DNA, inducing both cancer cell apoptosis and cycle arrest. Importantly, the results of the toxicity studies showed that compounds 23 and 31 possessed good oral safety profiles. In xenograft models, compound 23 exhibited remarkable antitumor potency, which was superior to the clinical Top inhibitors irinotecan and etoposide. Overall, this work highlights the therapeutic potential and safety profile of compound 23 as a Top1/2 dual inhibitor in tumor therapy and provides valuable lead compounds for further development of Top inhibitors.

2024-05-01·Nihon yakurigaku zasshi. Folia pharmacologica Japonica

低酸素応答を標的とした新規薬剤の開発史

Review

作者: Yoshikawa, Kiyotsugu ; Nakamura, Eijiro ; Hagimoto, Hiroki

The 2019 Nobel Prize in Physiology or Medicine was awarded to Dr. William G. Kaelin Jr, Dr. Peter J. Ratcliffe, and Dr. Gregg L. Semenza for their elucidation of new physiological mechanisms "How cells sense and adapt to oxygen availability". Moreover, two different drugs, HIF-PH inhibitors and HIF-2 inhibitors were also developed based on the discovery. Interestingly, those three doctors have different backgrounds as a medical oncologist, a nephrologist, and a pediatrician, respectively. They have started the research based on their own unique perspectives and eventually merged as "the elucidation of the response mechanism of living organisms to hypoxic environments". In this review, we will explain how the translational research that has begun to solve unmet clinical needs successfully contributed to the development of innovative therapeutic drugs.

Cancers2区 · 医学

2区 · 医学

ArticleOA

作者: Lahrmann, Bernd ; Adlesic, Mojca ; Zodel, Kyra ; Seidel, Philipp ; Grabe, Niels ; Heide, Danijela ; Göcmen, Burulca ; Boerries, Melanie ; Köttgen, Anna ; Haug, Stefan ; Heikenwalder, Mathias ; Hoefflin, Rouven ; Frew, Ian J ; Peighambari, Asin ; Abhari, Behnaz A ; Li, Yong ; Harlander, Sabine

Specific inhibitors of HIF-2α have recently been approved for the treatment of ccRCC in VHL disease patients and have shown encouraging results in clinical trials for metastatic sporadic ccRCC. However, not all patients respond to therapy and pre-clinical and clinical studies indicate that intrinsic as well as acquired resistance mechanisms to HIF-2α inhibitors are likely to represent upcoming clinical challenges. It would be desirable to have additional therapeutic options for the treatment of HIF-2α inhibitor resistant ccRCCs. Here we investigated the effects on tumor growth and on the tumor microenvironment of three different direct and indirect HIF-α inhibitors, namely the HIF-2α-specific inhibitor PT2399, the dual HIF-1α/HIF-2α inhibitor Acriflavine, and the S1P signaling pathway inhibitor FTY720, in the autochthonous Vhl/Trp53/Rb1 mutant ccRCC mouse model and validated these findings in human ccRCC cell culture models. We show that FTY720 and Acriflavine exhibit therapeutic activity in several different settings of HIF-2α inhibitor resistance. We also identify that HIF-2α inhibition strongly suppresses T cell activation in ccRCC. These findings suggest prioritization of sphingosine pathway inhibitors for clinical testing in ccRCC patients and also suggest that HIF-2α inhibitors may inhibit anti-tumor immunity and might therefore be contraindicated for combination therapies with immune checkpoint inhibitors.

项与 Dual HIF-1/HIF-2 inhibitor (Curve Therapeutics) 相关的新闻（医药）

2024-03-26

·PRNewswire

Research published in Journal of the American Chemical Society highlights potential of HIF Inhibition as a therapeutic approach for cancers

Research led by Curve CSO Professor Ali Tavassoli's laboratory at University of Southampton Landmark paper on dual HIF-1 and HIF-2 inhibitor that works by inhibiting the interaction of both HIF-1α and HIF-2α with HIF-1β SOUTHAMPTON, England, March 26, 2024 /PRNewswire/ -- Curve Therapeutics ("Curve" or the "Company"), a private biotechnology company pioneering a revolutionary intracellular screening platform addressing complex and challenging disease targets, today announces the publication of an article in the Journal of the American Chemical Society (JACS). The paper entitled 'Identification and Development of Cyclic Peptide Inhibitors of Hypoxia Inducible Factors (HIF) 1 and 2 That Disrupt Hypoxia-Related Signalling in Cancer Cells' can be viewed here.1 Curve's Chief Scientific Officer, Professor Ali Tavassoli, co-authored the article and leads the academic group at the University of Southampton where the work was undertaken. Professor Ali Tavassoli, Chief Scientific Officer of Curve Therapeutics, said: "It is well recognised that HIF plays a key role in the survival and growth of solid tumours. The compounds we report in this paper inhibit the protein-protein interaction of the two subunits that form the HIF transcription factor. We show that these compounds prevent the hypoxia-induced activity of this transcription factor, stopping hypoxia-response in cell-based assays. This paper underlines the promising therapeutic potential of dual HIF inhibition as an approach for the treatment of a variety of cancers." Curve Therapeutics is a leader in the discovery of innovative therapeutics to address disease targets which are difficult to target using conventional drug discovery methods. Through the utilisation of its world leading Microcyle® discovery platform, Curve can screen directly inside mammalian cells, allowing for the identification of biologically active library members within an intracellular environment where both the library and the target are present in their native conformations. Curve is developing a non-peptidic, small-molecule dual inhibitor of HIF-1 and HIF-2 with first-in-class potential. This is the first report of a dual HIF-1 and HIF-2 inhibitor which functions by inhibiting the interaction of both HIF-1α and HIF-2α with HIF-1β. The Microcycles discovered by Prof. Tavassoli were identified using his SICLOPPS screening platform and show good cellular activity. Patents and patent applications describing these HIF inhibitory Microcycles are exclusively licensed to Curve. About Curve Therapeutics Curve Therapeutics is a private biotechnology company pioneering a revolutionary intracellular screening platform to enable the discovery of innovative therapeutics that address complex and challenging disease targets with the potential to transform the lives of patients. Curve originated from world-leading Microcycle® research conducted by Professor Tavassoli's group in the Department of Chemistry at the University of Southampton, UK. Curve is backed by blue chip investors including Advent Life Sciences, Epidarex Capital, Pfizer Ventures, Columbus Venture Partners and British Patient Capital. Curve has a US$1.7bn global research collaboration with MSD the trade name of Merck & Co., Inc., Kenilworth, NJ USA, to discover and validate modulators of up to five therapeutic targets using its Microcycle® technology, initially for oncology and neurology indications. For more information visit: . About Curve's Microcycle® platform Curve has developed an IP-protected, mammalian cell platform technology for functional screening and enrichment of diverse hexameric cyclic peptide Microcycle® libraries to identify those library members that have the desired biological activity against a therapeutic target. Curve's platform allows direct screening for biologically active library members inside mammalian cells and facilitates small molecule hit-to-lead programmes. A key advantage of the technology is that both the library and the target are present in all of their native conformations within a cell. Uniquely, the compact size and rigid structure of Microcycles® enables the design of non-peptide small molecule leads. The platform can be used for a wide range of therapeutically relevant targets, including protein-protein and protein-DNA interactions and has been used by Curve to develop a pipeline of cancer programmes against targets including a dual HIF-1/HIF-2 inhibitor and an inhibitor of ATIC homodimerization. [1] Andrew T. Ball, Soran Mohammed, Cyrielle Doigneaux, Reece M. Gardner, James W. Easton, Steven Turner, Jonathan W. Essex, Garry Pairaudeau, Ali Tavassoli, Identification and Development of Cyclic Peptide Inhibitors of Hypoxia Inducible Factors 1 and 2 That Disrupt Hypoxia-Response Signaling in Cancer Cells, Journal of the American Chemical Society (19 March 2024) DOI: 10.1021/jacs.3c10508 SOURCE Curve Therapeutics

100 项与 Dual HIF-1/HIF-2 inhibitor (Curve Therapeutics) 相关的药物交易

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