Article
Microbiology
Isabell Berneburg, Satyamaheshwar Peddibhotla, Kim C. Heimsch, Kristina Haeussler, Patrick Maloney, Palak Gosalia, Janina Preuss, Mahsa Rahbari, Oleksii Skorokhod, Elena Valente, Daniela Ulliers, Luigi Felice Simula, Kathrin Buchholz, Michael P. Hedrick, Paul Hershberger, Thomas D. Y. Chung, Michael R. Jackson, Evelin Schwarzer, Stefan Rahlfs, Lars Bode, Katja Becker, Anthony B. Pinkerton
Summary: This study reports on a highly selective PfGluPho inhibitor, SBI-0797750, which shows potent activity against Plasmodium parasites. The compound disturbs the redox potential and H2O2 homeostasis of the parasites, without harming red blood cell integrity and phagocytosis.
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
(2022)
Article
Infectious Diseases
Sangdao Somsri, Mathirut Mungthin, Natthaporn Klubthawee, Poom Adisakwattana, Warunee Hanpithakpong, Ratchaneewan Aunpad
Summary: Mitochondria are considered a novel drug target due to their key role in energy production and programmed cell death. A mitochondria-penetrating peptide, (F(x)r)(3), showed potent and selective antimalarial activity by entering malaria-infected red cells and targeting the parasite mitochondria without significant toxicity to mammalian cells. This study provides a first report on the antimalarial activity of (F(x)r)(3) and its rapid killing activity compared to the known drug atovaquone.
Article
Biochemistry & Molecular Biology
Leticia Tiburcio Ferreira, Joyce V. B. Borba, Jose Teofilo Moreira-Filho, Aline Rimoldi, Carolina Horta Andrade, Fabio Trindade Maranhao Costa
Summary: Malaria remains a public health burden in tropical and subtropical areas, with drug-resistant Plasmodium strains driving the exploration of novel antimalarial compounds. Through virtual screening, promising natural compound-based antimalarial molecules can be identified for further development.
Article
Chemistry, Medicinal
Vigyasa Singh, Rahul Singh Hada, Ravi Jain, Manu Vashistha, Geeta Kumari, Snigdha Singh, Neha Sharma, Meenakshi Bansal, Poonam, Martin Zoltner, Conor R. Caffrey, Brijesh Rathi, Shailja Singh
Summary: This study found that phthalimide analogs with benzimidazole and 1,2,3-triazole structures have anti-malarial activity, effectively inhibiting the growth of drug-resistant Plasmodium falciparum without apparent toxicity to cells. These analogs interact with tubulin protein of the parasite, leading to mitochondrial membrane depolarization and cell death. Combination with artemisinin enhances their efficacy. In a mouse model, these analogs also reduce parasitemia and prolong host survival. These findings suggest that phthalimide analogs could be a promising avenue for the development of anti-malarial drugs.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biology
Ines Bouzon-Arnaiz, Yunuen Avalos-Padilla, Arnau Biosca, Omar Cano-Prades, Lucia Roman-Alamo, Javier Valle, David Andreu, Diana Moita, Miguel Prudencio, Elsa M. Arce, Diego Munoz-Torrero, Xavier Fernandez-Busquets
Summary: This study found that inhibiting protein aggregation significantly reduces the viability of the malaria parasite in vitro. A compound called YAT2150 demonstrated powerful anti-malarial activity, inhibiting the growth of the parasite in different developmental stages by affecting its protein composition. Due to its novel structure and potential targeting of multiple gene products, the evolution of resistance to YAT2150 is unlikely, making it a promising compound for the post-artemisinin era.
Article
Chemistry, Medicinal
Wei Liu, Chuyi Yu, Miaomiao Wang, Youyou He, Zhongjie Guo, Jin He, Ru Jiang, Qin Xu, Jianming Liang, Shengzheng Wang
Summary: Recently, the antitumor activity of artemisinin and its derivatives has been discovered. This study constructed novel Pt-IV-artesunate complexes to combine the antitumor advantages of artesunate and platinum drugs. The derivatives, especially 10f, exhibited potent in vitro antitumor activities against various cancer cell lines. Compound 10f demonstrated remarkable in vivo antitumor efficacy in a xenograft model, and also showed potent in vivo antimalarial activity. This study highlights the therapeutic potential of Pt(IV)-artesunate complexes as antitumor and antimalarial agents.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Review
Chemistry, Medicinal
Preeti Kushwaha, Vipin Kumar, Biswajit Saha
Summary: beta-Carboline alkaloids are important nitrogen-based natural alkaloids and therapeutic molecules that exhibit various pharmacological activities through diverse mechanisms. There has been increasing attention towards developing effective antimalarial drugs based on this compound. This article comprehensively reviews the clinical and preclinical antimalarial scaffolds containing beta-carboline structure. The study focuses on the natural and semi-synthetic analogues of beta-carbolines reported in the last decade (2011-2021), providing insights into their mechanisms of action and potential for future therapeutic development.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Benjamin R. Taft, Fumiaki Yokokawa, Tom Kirrane, Anne-Catherine Mata, Richard Huang, Nicole Blaquiere, Grace Waldron, Bin Zou, Oliver Simon, Subramanyam Vankadara, Wai Ling Chan, Mei Ding, Sandra Sim, Judith Straimer, Armand Guiguemde, Suresh B. Lakshminarayana, Jay Prakash Jain, Christophe Bodenreider, Christopher Thompson, Christian Lanshoeft, Wei Shu, Eric Fang, Jafri Qumber, Katherine Chan, Luying Pei, Yen-Liang Chen, Hanna Schulz, Jessie Lim, Siti Nurdiana Abas, Xiaoman Ang, Yugang Liu, Inigo Angulo-Barturen, Maria Belen Jimenez-Diaz, Francisco Javier Gamo, Benigno Crespo-Fernandez, Philip J. Rosenthal, Roland A. Cooper, Patrick Tumwebaze, Anna Caroline Campos Aguiar, Brice Campo, Simon Campbell, Jurgen Wagner, Thierry T. Diagana, Christopher Sarko
Summary: A highly potent antimalarial compound, INE963 (1), with favorable pharmacological properties, has been identified through high-throughput screening and shows potential for curing uncomplicated malaria.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Multidisciplinary Sciences
Celia Miguel-Blanco, James M. Murithi, Ernest Diez Benavente, Fiona Angrisano, Katarzyna A. Sala, Donelly A. van Schalkwyk, Manu Vanaerschot, Frank Schwach, Matthew J. Fuchter, Oliver Billker, Colin J. Sutherland, Susana G. Campino, Taane G. Clark, Andrew M. Blagborough, David A. Fidock, Esperanza Herreros, Francisco Javier Gamo, Jake Baum, Michael J. Delves
Summary: New antimalarial therapeutics are urgently needed to combat emerging parasite and mosquito resistance. Intense drug screening efforts have identified promising new antimalarial molecules with novel modes of action to combat existing drug resistance.
SCIENTIFIC REPORTS
(2021)
Article
Pharmacology & Pharmacy
Nanang Rudianto Ariefta, Baldorj Pagmadulam, Coh-ichi Nihei, Yoshifumi Nishikawa
Summary: This study evaluated the growth-inhibitory effects of the antimalarial agent sparsomycin against drug-resistant malaria parasites. The results showed that sparsomycin had inhibitory effects on both sensitive and resistant strains of the parasites. This study suggests that sparsomycin has potential as an alternative treatment for malaria.
Article
Chemistry, Medicinal
Christopher M. Woodley, Gemma L. Nixon, Nicoletta Basilico, Silvia Parapini, Weiqian David Hong, Stephen A. Ward, Giancarlo A. Biagini, Suet C. Leung, Donatella Taramelli, Keiko Onuma, Takashi Hasebe, Paul M. O'Neill
Summary: Research has developed a method for synthesizing nonlinear analogues of second-generation antimalarials, showing up to 10-fold improvement in solubility compared to linear counterparts. Pharmacokinetic studies in rats revealed that a selected nonlinear analogue demonstrated significantly improved oral absorption and exposure in vivo, with more than double the AUC and increased oral bioavailability.
ACS MEDICINAL CHEMISTRY LETTERS
(2021)
Article
Multidisciplinary Sciences
Arne Alder, Cecilia P. Sanchez, Matthew R. G. Russell, Lucy M. Collinson, Michael Lanzer, Michael J. Blackman, Tim-Wolf Gilberger, Joachim M. Matz
Summary: Malaria parasites use a complex to acidify the digestive vacuole and degrade host erythrocyte hemoglobin, which is essential for their survival in the human bloodstream.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Chemistry, Medicinal
Wanthani Paengsri, Napapha Promsawan, Apiwat Baramee
Summary: A series of 3-substituted-2-hydroxy-1,4-naphthoquinone derivatives were successfully synthesized by Mannich reaction and evaluated for their in-vitro antimalarial activity. Ten derivatives showed good activity, with compound 1 exhibiting the best biological profile. These active Mannich components could potentially be used as promising antimalarial agents against malaria infections and multidrug resistance.
CHEMICAL & PHARMACEUTICAL BULLETIN
(2021)
Article
Microbiology
Heather J. Painter, Joanne M. Morrisey, Michael W. Mather, Lindsey M. Orchard, Cuyler Luck, Martin J. Smilkstein, Michael K. Riscoe, Akhil B. Vaidya, Manuel Llinas
Summary: The emergence of drug-resistant Plasmodium falciparum parasites poses a challenge to global malaria eradication efforts, highlighting the importance of identifying new antimalarial drugs. Studying the molecular mechanism of drug resistance has revealed a novel resistance mechanism that could potentially guide the development of future antimalarial combination therapies.
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
(2021)
Article
Chemistry, Medicinal
Chhuttan L. Meena, Tejashri Hingamire, Tanya Gupta, Bhagyashree Deshmukh, Krishanpal Karmodiya, Rakesh Joshi, Dhanasekaran Shanmugam, Gangadhar J. Sanjayan
Summary: We synthesized peptide-histidinal conjugated drug scaffolds that can target falcipain-2/3 hemoglobin-degrading proteases from the malaria parasite. Various substitutions were tested and compounds 8g, 8h, and 15 showed strong antimalarial activity. Docking studies revealed that these compounds interacted strongly with the binding sites of falcipain-2/3. ADME studies showed that the molecules of interest had good drug-likeness properties. These findings provide a starting point for the development of potential antimalarial drug candidates.
Article
Biochemical Research Methods
Wenwei Lin, Yongtao Li, Jaeki Min, Jiuyu Liu, Lei Yang, Richard E. Lee, Taosheng Chen
BIOCONJUGATE CHEMISTRY
(2020)
Article
Medicine, General & Internal
Rafi Kabarriti, N. Patrik Brodin, Maxim Maron, Chandan Guha, Shalom Kalnicki, Madhur K. Garg, Andrew D. Racine
Article
Multidisciplinary Sciences
Michael A. Willcockson, Sean E. Healton, Cary N. Weiss, Boris A. Bartholdy, Yair Botbol, Laxmi N. Mishra, Dhruv S. Sidhwani, Tommy J. Wilson, Hugo B. Pinto, Maxim I. Maron, Karin A. Skalina, Laura Norwood Toro, Jie Zhao, Chul-Hwan Lee, Harry Hou, Nevin Yusufova, Cem Meydan, Adewola Osunsade, Yael David, Ethel Cesarman, Ari M. Melnick, Simone Sidoli, Benjamin A. Garcia, Winfried Edelmann, Fernando Macian, Arthur I. Skoultchi
Summary: Histone H1 functions as a critical regulator of gene silencing by controlling chromatin compaction, genome organization, and histone methylation. Experimental evidence using a conditional triple-knockout mouse strain demonstrates that H1 plays a key role in regulating the activity of chromatin domains.
Article
Chemistry, Medicinal
Ho Shin Kim, Jared T. Hammill, Daniel C. Scott, Yizhe Chen, Amy L. Rice, William Pistel, Bhuvanesh Singh, Brenda A. Schulman, R. Kiplin Guy
Summary: This study has improved the pharmacokinetic performance of inhibitors targeting cullin-RING ubiquitin ligases and established the impact of the inhibitor on tumor cell growth.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Hematology
Yunchao Chang, Jaeki Min, Jamie A. Jarusiewicz, Marisa Actis, Shanshan Yu-Chen Bradford, Anand Mayasundari, Lei Yang, Divyabharathi Chepyala, Lisa J. Alcock, Kathryn G. Roberts, Stanley Nithianantham, Dylan Maxwell, Lauren Rowland, Randolph Larsen, Aman Seth, Hiroaki Goto, Toshihiko Imamura, Koshi Akahane, Baranda S. Hansen, Shondra M. Pruett-Miller, Elisabeth M. Paietta, Mark R. Litzow, Chunxu Qu, Jun J. Yang, Marcus Fischer, Zoran Rankovic, Charles G. Mullighan
Summary: The study evaluated the efficacy of proteolysis-targeting chimeras (PROTACs) against JAKs, and developed multiple PROTACs that could degrade JAKs and effectively inhibit CRLF2r cell lines, with one compound showing the potential to suppress the proliferation of CRLF2r ALL in vivo. This highlights the potential of JAK-directed protein degradation as a therapeutic approach in JAK-STAT-driven ALL.
Article
Chemistry, Medicinal
Gisele Nishiguchi, Fatemeh Keramatnia, Jaeki Min, Yunchao Chang, Barbara Jonchere, Sourav Das, Marisa Actis, Jeanine Price, Divyabharathi Chepyala, Brandon Young, Kevin McGowan, P. Jake Slavish, Anand Mayasundari, Jamie A. Jarusiewicz, Lei Yang, Yong Li, Xiang Fu, Shalandus H. Garrett, James B. Papizan, Kiran Kodali, Junmin Peng, Shondra M. Pruett Miller, Martine F. Roussel, Charles Mullighan, Marcus Fischer, Zoran Rankovic
Summary: This study describes the design, synthesis, and screening of a large diverse library of thalidomide analogues against leukemia and medulloblastoma cell lines, leading to the discovery of potent GSPT1/2 degraders with selectivity over IMiD neosubstrates and high oral bioavailability in mice. Compound 6 (SJ6986) is proposed as a valuable tool for studying the role of GSPT1/2 and supports the utility of a diverse library of CRBN binders in targeting undruggable oncoproteins.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Multidisciplinary Sciences
Maxim Maron, Stephanie M. Lehman, Sitaram Gayatri, Joseph D. DeAngelo, Subray Hegde, Benjamin M. Lorton, Yan Sun, Dina L. Bai, Simone Sidoli, Varun Gupta, Matthew R. Marunde, James R. Bone, Zu-Wen Sun, Mark T. Bedford, Jeffrey Shabanowitz, Hongshan Chen, Donald F. Hunt, David Shechter
Summary: This study explores the cellular consequences of type I and II PRMTs through a variety of approaches, revealing their impact on cellular dimethylarginine levels, substrate recognition motifs, and phenotypic consequences. The research expands our understanding of PRMT substrate diversity, the arginine methylome, and the complex interplay between type I and II PRMTs.
Article
Chemistry, Multidisciplinary
Jaeki Min, Anand Mayasundari, Fatemeh Keramatnia, Barbara Jonchere, Seung Wook Yang, Jamie Jarusiewicz, Marisa Actis, Sourav Das, Brandon Young, Jake Slavish, Lei Yang, Yong Li, Xiang Fu, Shalandus H. Garrett, Mi-Kyung Yun, Zhenmei Li, Stanley Nithianantham, Sergio Chai, Taosheng Chen, Anang Shelat, Richard E. Lee, Gisele Nishiguchi, Stephen W. White, Martine F. Roussel, Patrick Ryan Potts, Marcus Fischer, Zoran Rankovic
Summary: IMiDs and IMiD-based PROTACs rapidly hydrolyze in commonly utilized cell media, affecting their efficacy; Novel CRBN binders, phenyl glutarimide (PG) analogues, were designed with high affinity and improved stability; Discovery of PG PROTAC 4c as a potent degrader of BET proteins, supporting the utility of PG derivatives in CRBN-directed PROTACs design.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2021)
Article
Chemistry, Medicinal
Santanu Hati, Marisa Zallocchi, Robert Hazlitt, Yuju Li, Sarath Vijayakumar, Jaeki Min, Zoran Rankovic, Sandor Lovas, Jian Zuo
Summary: This study introduced a new class of small molecules called PROTACs that can effectively degrade the CDK2 protein, with PROTAC-8 showing potential therapeutic activities. Experimental results demonstrated that PROTAC-8 can protect zebrafish from drug-induced auditory and neurotoxicity, indicating its promising role in treating hearing loss and cancer.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Lisa J. Alcock, Yunchao Chang, Jamie A. Jarusiewicz, Marisa Actis, Stanley Nithianantham, Anand Mayasundari, Jaeki Min, Dylan Maxwell, Jeremy Hunt, Brandon Smart, Jun J. Yang, Gisele Nishiguchi, Marcus Fischer, Charles G. Mullighan, Zoran Rankovic
Summary: The study describes the design and synthesis of JAK2/3 PROTACs and their potency in patient-derived ALL cells. SJ10542 showed high selectivity and potency, making it a promising candidate for the treatment of hematological malignancies.
ACS MEDICINAL CHEMISTRY LETTERS
(2022)
Article
Biochemistry & Molecular Biology
Giovanni Quarato, Fabien Llambi, Cliff S. Guy, Jaeki Min, Marisa Actis, Huan Sun, Shilpa Narina, Shondra M. Pruett-Miller, Junmin Peng, Zoran Rankovic, Douglas R. Green
Summary: The imbalance of intracellular Ca2+ and mitochondrial Ca2+ overload can lead to mitochondrial inner membrane permeabilization and cell death, which is distinct from Bcl-2 family-regulated mitochondrial outer membrane permeabilization. Cyclosporin A can prevent cell death by inhibiting Ca2+ release from endoplasmic reticulum stores.
CELL DEATH AND DIFFERENTIATION
(2022)
Article
Cell Biology
Jianzhong Hu, Jamie Jarusiewicz, Guoqing Du, Gisele Nishiguchi, Satoshi Yoshimura, John C. Panetta, Zhenhua Li, Jaeki Min, Lei Yang, Divyabharathi Chepyala, Marisa Actis, Noemi Reyes, Brandon Smart, Ching-Hon Pui, David T. Teachey, Zoran Rankovic, Jun J. Yang
Summary: T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy. The LCK inhibitor dasatinib has shown efficacy against T-ALL, but its effect is temporary. Using the PROTAC approach, researchers developed a series of LCK degraders based on dasatinib, with lead compound SJ11646 exhibiting significant efficiency in cereblon-mediated LCK degradation. SJ11646 showed higher cytotoxicity and prolonged suppression of LCK signaling compared to dasatinib, both in vitro and in vivo. SJ11646 also showed binding affinity to several human kinases, making it a potential therapeutic agent for other cancers.
SCIENCE TRANSLATIONAL MEDICINE
(2022)
Review
Chemistry, Multidisciplinary
Robert G. Guenette, Seung Wook Yang, Jaeki Min, Baikang Pei, Patrick Ryan Potts
Summary: Targeted protein degradation strategies, such as PROTAC and molecular glue technology, have provided highly selective control of target inhibition, revolutionizing the approach to challenging protein targets. These advancements have broad implications in treating diseases by expanding the range of possible targets that can be addressed by small molecules.
CHEMICAL SOCIETY REVIEWS
(2022)
Article
Medicine, General & Internal
Ankur Srivastava, Delia Shen, Maxim Maron, Howard S. Herman, Brandon S. Cohen, Avigdor Nosrati, Amarilys R. Cortijo, Sarah Nosal, Ellie Schoenbaum
CUREUS JOURNAL OF MEDICAL SCIENCE
(2020)
Article
Oncology
Rafi Kabarriti, N. Patrik Brodin, Maxim I. Maron, Wolfgang A. Tome, Balazs Halmos, Chandan Guha, Shalom Kalnicki, Madhur K. Garg, Nitin Ohri
ADVANCES IN RADIATION ONCOLOGY
(2020)