Article
Chemistry, Medicinal
Shawn J. Stachel, Deping Wang, Anthony T. Ginnetti, Shahriar Niroomand, Lei Ma, Yinghui Hu, John F. Fay, Wei Lemaire, Daniel J. Krosky, Andres D. Ramirez, Hatim A. Zariwala, Paul J. Coleman
Summary: Virtual screening was used to identify four novel, potent, and highly selective HDAC6 inhibitor series with favorable ligand binding efficiencies and good potential for further optimization.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2023)
Review
Cell Biology
Bingyi Zhou, Deliang Liu, Yuyong Tan
Summary: Cancer is the second leading cause of death worldwide, with digestive system cancers being a primary contributor. Acetylation and deacetylation play crucial roles in cancer development, with HDAC6 being a widely studied enzyme that is upregulated in various tumors and associated with clinicopathological characteristics. There is ongoing research on HDAC6 inhibitors and their potential in inhibiting tumor growth.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2021)
Review
Pharmacology & Pharmacy
Marcin Cieslak, Marta Slowianek
Summary: The traditional low-molecular-weight drugs target specific biological targets with receptor or enzymatic activity to inhibit their function. However, there are disease proteins that cannot be targeted using this approach. PROTACs, on the other hand, can bind both the protein of interest and the E3 ubiquitin ligase complex, leading to degradation. This review focuses on PROTACs recruiting CRBN E3 ubiquitin ligase and targeting various proteins involved in tumorigenesis.
Article
Chemistry, Medicinal
Marine C. Aublette, Tom A. Harrison, Elizabeth J. Thorpe, Morgan S. Gadd
Summary: The Ser/Thr protein kinase Wee1 plays a regulatory role in DNA damage by phosphorylating CDK1. The selective inhibitor AZD1775 has off target effects on other protein kinases. This study describes the synthesis and evaluation of Wee1-degrading PROTACs with different linkers.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2022)
Article
Chemistry, Medicinal
Kairui Yue, Simin Sun, Geng Jia, Mengting Qin, Xiaohan Hou, C. James Chou, Chao Huang, Xiaoyang Li
Summary: This study reports the development of a highly selective HDAC6 inhibitor with hydrazide as the zinc-binding group (ZBG), which exhibits superior pharmacokinetic properties compared to current hydroxamic acid inhibitors. Structure-activity relationship analysis reveals that the presence of an ethyl group substituent in the hydrazide-based ZBG and a cap group with increased rigidity and volume enhance the HDAC6 selectivity of the designed compounds. The representative inhibitor 35m demonstrates potent HDAC6 inhibitory activity and improved pharmacokinetic properties compared to hydroxamic acid-based HDAC6 inhibitors Tubastatin A and ACY1215. Furthermore, low-dose 35m effectively decreases LPS-induced IL-1 beta release by blocking the activation of NLRP3, indicating its potential as an orally active therapeutic agent for NLRP3-related diseases.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Multidisciplinary
Davide Moi, Andrea Citarella, Davide Bonanni, Luca Pinzi, Daniele Passarella, Alessandra Silvani, Clelia Giannini, Giulio Rastelli
Summary: In this study, two potent and selective HDAC6 inhibitors were obtained through chemoinformatic analysis. The newly discovered aminotriazole-based compounds showed higher inhibitory activity and have the potential to be optimized as anticancer compounds.
Article
Chemistry, Medicinal
Ning Yang, Zhiya Fan, Shiyang Sun, Xiaotong Hu, Yaqiu Mao, Changkai Jia, Xu Cai, Tingting Xu, Bingkun Li, Yi Li, Luobing Han, Ting Wei, Xiaohong Qian, Weijie Qin, Pengyun Li, Zhibing Zheng, Song Li
Summary: A series of highly potent and selective KRAS(G12C) Proteolysis Targeting Chimeras (PROTACs) were developed, among which YN14 showed significant inhibition of KRAS(G12C)-dependent cancer cells growth and tumor regression in mice models. KRAS(G12C) degradation exhibited advantages in overcoming resistance and combination with other inhibitors showed synergistic efficacy.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Neurosciences
Cuiying Peng, Yilin Wang, Zhiping Hu, Chunli Chen
Summary: The inhibition of HDAC6 has a protective effect on BBB disruption after intracerebral hemorrhage (ICH) by upregulating acetylated a-tubulin and reducing stress fiber formation, which suggests that HDAC6 could be a potential target for ICH treatment.
CNS NEUROSCIENCE & THERAPEUTICS
(2023)
Article
Biochemistry & Molecular Biology
Habib Bouguenina, Andrea Scarpino, Jack A. O'Hanlon, Justin Warne, Hannah Z. Wang, Laura Chan Wah Hak, Amine Sadok, P. Craig McAndrew, Mark Stubbs, Olivier A. Pierrat, Tamas Hahner, Marc P. Cabry, Yann-Vai Le Bihan, Costas Mitsopoulos, Fernando J. Sialana, Theodoros I. Roumeliotis, Rosemary Burke, Rob L. M. van Montfort, Jyoti Choudhari, Rajesh Chopra, John J. Caldwell, Ian Collins
Summary: This study addresses the challenge of selectivity in PROTACs by leveraging structural insights from known CRL4(CRBN) molecular glue degraders, and demonstrates improved selectivity by using computational modeling. The tools and principles presented in this work are valuable for the development of targeted protein degradation.
Article
Biochemistry & Molecular Biology
Meran Keshawa Ediriweera, Ngoc Bao To, Yoongho Lim, Somi Kim Cho
Summary: The dysregulation of histone deacetylases is closely related to tumorigenesis and has potential in anti-cancer drug development. Odd-chain fatty acids have shown nutritional benefits and can act as novel HDAC6 inhibitors, with pentadecanoic and undecanoic acid exhibiting strong anti-proliferative effects on cancer cells. The length of the aliphatic carbon chain of these fatty acids may play a role in their inhibitory potential against HDAC6.
Review
Pharmacology & Pharmacy
Jianglei Li, Meihong Yu, Shifeng Fu, Deliang Liu, Yuyong Tan
Summary: This review summarizes the research progress and underlying mechanism of ACY-1215 in cancer and other human diseases.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Shunda Li, Chunlong Zhao, Guozhen Zhang, Qifu Xu, Qian Liu, Wei Zhao, C. James Chou, Yingjie Zhang
Summary: The novel pyrrolo[2,3-d]pyrimidine-based HDAC inhibitors demonstrated potent inhibitory activities and selectivities against HDAC6, showing superior antiproliferative activity against human multiple myeloma cell lines while maintaining low cytotoxicity. In addition, one representative compound showed good metabolic stability and in vivo anti-multiple myeloma potency in a xenograft model.
BIOORGANIC CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Jan Legaardandersson, Jesper Christensen, Daniela Kleine-Kohlbrecher, Itys Vacher Comet, Jonatan Fullerton Stoier, Yasuko Antoku, Visnja Poljak, Loris Moretti, Johannes Dolberg, Tomas Jacso, Soren Jensby Nielsen, Mads Norregaard-Madsen, Thomas Franch, Kristian Helin, Paul A. C. Cloos
Summary: This study identified small molecule ligands that can selectively and effectively bind to NSD2, and demonstrated that their conversion into degraders can degrade NSD2 and inhibit cell proliferation. These findings are important for understanding the role of NSD2 in cancer and developing novel therapeutic approaches.
Article
Chemistry, Medicinal
Nabanita Nawar, Shazreh Bukhari, Ashley A. Adile, Yujin Suk, Pimyupa Manaswiyoungkul, Krimo Toutah, Olasunkanmi O. Olaoye, Yasir S. Raouf, Abootaleb Sedighi, Harsimran Kaur Garcha, Muhammad Murtaza Hassan, William Gwynne, Johan Israelian, Tudor B. Radu, Mulu Geletu, Ayah Abdeldayem, Justyna M. Gawel, Aaron D. Cabral, Chitra Venugopal, Elvin D. de Araujo, Sheila K. Singh, Patrick T. Gunning
Summary: Through a second-generation structure-activity relationship study, the selective HDAC6 inhibitor NN-390 was designed and evaluated, showing therapeutic potential in the treatment of metastatic Group 3 MB and demonstrating high selectivity and potency in targeting cells in vitro.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Lena Ripa, Jenny Sandmark, Glyn Hughes, Igor Shamovsky, Anders Gunnarsson, Julia Johansson, Antonio Llinas, Mia Collins, Bomi Jung, Anna Noven, Nils Pemberton, Mickael Mogemark, Yao Xiong, Qing Li, Stefan Tangefjord, Margareta Ek, Annika Astrand
Summary: The study identifies and characterizes 2-(difluoromethyl)-1,3,4-oxadiazoles (DFMOs) as selective nonhydroxamic acid HDAC6 inhibitors. These inhibitors show potential for inhibiting HDAC6 and have promise for in vitro and in vivo studies.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Anne Schedel, Ulrike Anne Friedrich, Mina N. F. Morcos, Rabea Wagener, Juha Mehtonen, Titus Watrin, Claudia Saitta, Triantafyllia Brozou, Pia Michler, Carolin Walter, Asta Foersti, Arka Baksi, Maria Menzel, Peter Horak, Nagarajan Paramasivam, Grazia Fazio, Robert J. Autry, Stefan Froehling, Meinolf Suttorp, Christoph Gertzen, Holger Gohlke, Sanil Bhatia, Karin Wadt, Kjeld Schmiegelow, Martin Dugas, Daniela Richter, Hanno Glimm, Merja Heinaniemi, Rolf Jessberger, Gianni Cazzaniga, Arndt Borkhardt, Julia Hauer, Franziska Auer
Summary: Mutations in RAD21 gene in germline are associated with childhood lymphoblastic leukemia or lymphoma without CdLS phenotype.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Sergi Herve Akone, Hao Wang, Eitel Ngoh Misse Mouelle, Attila Mandi, Tibor Kurtan, Pierre Roger Koliye, Rudolf Hartmann, Sanil Bhatia, Jing Yang, Werner E. G. Muller, Daowan Lai, Zhen Liu, Rainer Kalscheuer, Peter Proksch
Summary: Chemical investigation of a fungal endophyte Pseudopestalotiopsis theae isolated from leaves of Caloncoba welwitschii collected in Cameroon has led to the discovery of two previously undescribed sulfur-containing xanthone derivatives sydoxanthones D and E, as well as three previously undescribed monomeric diisoprenyl-cyclohexene-type meroterpenoids biscognienynes D-F and five known natural products.
Article
Chemistry, Medicinal
Lukas von Bredow, Thomas Martin Schafer, Julian Hogenkamp, Maik Tretbar, Daniel Stopper, Fabian B. Kraft, Julian Schliehe-Diecks, Andrea Scholer, Arndt Borkhardt, Sanil Bhatia, Jana Held, Finn K. Hansen
Summary: This study presents the design, synthesis, and biological evaluation of a mini library of dihydroartemisinin-HDACi hybrid molecules. The hybrid molecules showed potent activity against P. falciparum parasites and leukemia cell lines, indicating their potential as antimalarial and antileukemia drug leads.
Article
Medicine, General & Internal
Grazia Fazio, Silvia Bresolin, Daniela Silvestri, Manuel Quadri, Claudia Saitta, Elena Vendramini, Barbara Buldini, Chiara Palmi, Michela Bardini, Andrea Grioni, Silvia Rigamonti, Marta Galbiati, Stefano Mecca, Angela Maria Savino, Alberto Peloso, Jia-Wey Tu, Sanil Bhatia, Arndt Borkhardt, Concetta Micalizzi, Luca Lo Nigro, Franco Locatelli, Valentino Conter, Carmelo Rizzari, Maria Grazia Valsecchi, Geertruij te Kronnie, Andrea Biondi, Giovanni Cazzaniga
Summary: This study provides new insights into high-risk Ph-like leukemia and identifies a potential therapy for targeting the PAX5-fusion poor-risk group.
Article
Chemistry, Medicinal
Nina Ressing, Julian Schliehe-Diecks, Paris R. Watson, Melf Soennichsen, Abigail D. Cragin, Andrea Schoeler, Jing Yang, Linda Schaeker-Huebner, Arndt Borkhardt, David W. Christianson, Sanil Bhatia, Finn K. Hansen
Summary: By using a microwave-assisted protocol, 16 peptoid-capped HDAC inhibitors were synthesized with fluorinated linkers, resulting in the identification of two active compounds. Compound 10h displayed potent and unselective HDAC inhibition in biochemical and cellular assays, showing remarkable cytotoxic potential against various therapy-resistant leukemia cell lines. Moreover, compound 10h showed synergistic interactions with the DNA methyltransferase inhibitor decitabine in AML cell lines.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Luisa M. Bachmann, Maria Hanl, Felix Feller, Laura Sinatra, Andrea Schoeler, Jens Pietzsch, Markus Laube, Finn K. Hansen
Summary: Multi-target drugs (MTDs) offer a new approach for combination therapies. In this study, a library of dual HDAC-COX inhibitors was designed, synthesized, and evaluated. The synthesized compounds showed significant inhibitory activities against HDAC and COX isoforms. Selected compounds were confirmed to have membrane permeability and inhibition of cellular HDAC activity. The most promising dual inhibitors, C3 and C4, demonstrated antiproliferative effects and increased apoptotic cells. However, simultaneous inhibition of HDAC and COX by these inhibitors or combination treatments did not result in additive or synergistic anticancer activities.
Article
Cell Biology
Fabian Stuhldreier, Laura Schmitt, Thomas Lenz, Ilka Hinxlage, Marcel Zimmermann, Philipp Wollnitzke, Julian Schliehe-Diecks, Yang Liu, Paul Jaeger, Stefanie Geyh, Nicole Teusch, Christoph Peter, Sanil Bhatia, Rainer Haas, Bodo Levkau, Andreas S. Reichert, Kai Stuehler, Peter Proksch, Bjoern Stork, Sebastian Wesselborg
Summary: Viriditoxin (VDT), derived from Cladosporium cladosporioides, shows promising potential as a candidate for leukemia and lymphoma treatment. It exhibits high cytotoxicity in leukemia and lymphoma cells, while having minimal impact on solid tumor cells. Furthermore, VDT does not affect hematopoietic stem and progenitor cells, making it a potentially effective and safe therapeutic approach.
CELL DEATH & DISEASE
(2022)
Article
Chemistry, Multidisciplinary
Luisa Maria Gatzemeier, Franc Meyer, Ulf Diederichsen, Tiago Fleming Outeiro
Summary: Alpha-Synuclein is a protein involved in neurodegenerative disorders that accumulate in brain protein inclusions. We have developed a chemical synthesis method for Alpha-Synuclein, allowing the synthesis of protein variants for further investigation of its structure and aggregation behavior.
CHEMISTRY-A EUROPEAN JOURNAL
(2023)
Article
Hematology
Chiara Palmi, Silvia Bresolin, Stefanie Junk, Grazia Fazio, Daniela Silvestri, Marketa Zaliova, Athanasios Oikonomou, Katerina Scharov, Martin Stanulla, Anja Moericke, Martin Zimmermann, Martin Schrappe, Barbara Buldini, Sanil Bhatia, Arndt Borkhardt, Claudia Saitta, Marta Galbiati, Michela Bardini, Luca Lo Nigro, Valentino Conter, Maria Grazia Valsecchi, Andrea Biondi, Geertruy Te Kronnie, Gunnar Cario, Giovanni Cazzaniga
Summary: Children with Down syndrome have an increased risk for B-cell acute lymphoblastic leukemia (DS-ALL) with poor prognosis. This study evaluated the incidence and prognostic value of the Philadelphia-like (Ph-like) profile and IKZF1plus pattern in DS-ALL. The presence of Ph-like signature and IKZF1 deletion were associated with worse outcomes, and ex vivo drug screening showed sensitivity of IKZF1plus blasts to drugs active against Ph-like ALL. Tailored therapeutic strategies are needed for DS-ALL patients with these high-risk features.
Article
Pharmacology & Pharmacy
Athanasios Oikonomou, Luigia Valsecchi, Manuel Quadri, Titus Watrin, Katerina Scharov, Simona Procopio, Jia-Wey Tu, Melina Vogt, Angela Maria Savino, Daniela Silvestri, Maria Grazia Valsecchi, Andrea Biondi, Arndt Borkhardt, Sanil Bhatia, Giovanni Cazzaniga, Grazia Fazio, Michela Bardini, Chiara Palmi
Summary: This study utilized high-throughput drug screening to identify 9 compounds that are active against BCP-ALL but spare normal cells. It also confirmed the anti-leukemic effect of the BCL2 inhibitor venetoclax. This research provides potential therapeutic options for difficult-to-treat childhood BCP-ALL subgroups.
BIOCHEMICAL PHARMACOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Pawel Stachura, Wei Liu, Haifeng C. Xu, Agnes Wlodarczyk, Olivia Stencel, Piyush Pandey, Melina Vogt, Sanil Bhatia, Daniel Picard, Marc Remke, Karl S. Lang, Dieter Haeussinger, Bernhard Homey, Philipp A. Lang, Arndt Borkhardt, Aleksandra A. Pandyra
Summary: This study identifies a drug called 5-NL that can enhance the ability of T cells to target tumor cells, and it shows improved efficacy when used in combination with PD-1 antibody treatment.
Article
Chemistry, Multidisciplinary
Silas Wurnig, Melina Vogt, Julian Hogenkamp, Niklas Dienstbier, Arndt Borkhardt, Sanil Bhatia, Finn K. Hansen
Summary: Despite limitations with HSP90 inhibitors as anticancer drugs, a new approach using PROTACs to degrade the protein shows promise. This study focuses on designing and evaluating geldanamycin-based HSP90 degraders based on the PROTAC technology. The best degrader, 3a, effectively reduced HSP90 alpha and HSP90 beta levels in cells using the ubiquitin-proteasome pathway.
FRONTIERS IN CHEMISTRY
(2023)
Article
Cell Biology
Melina Vogt, Niklas Dienstbier, Julian Schliehe-Diecks, Katerina Scharov, Jia-Wey Tu, Philip Gebing, Julian Hogenkamp, Berna-Selin Bilen, Silke Furlan, Daniel Picard, Marc Remke, Layal Yasin, David Bickel, Munishikha Kalia, Alfredo Iacoangeli, Thomas Lenz, Kai Stuehler, Aleksandra A. Pandyra, Julia Hauer, Ute Fischer, Rabea Wagener, Arndt Borkhardt, Sanil Bhatia
Summary: HSP90 has emerged as an appealing anti-cancer target, but its inhibitors are limited by the development of resistance. This study identified that the loss of HSP90 beta isoform leads to overexpression of HSP90 alpha and extracellular-secreted HSP90 alpha. Additionally, the absence of HSP90 alpha restricts the growth of leukemia cells.
CELL DEATH & DISEASE
(2023)