Article
Chemistry, Medicinal
Robin A. Fairhurst, Pascal Furet, Patricia Imbach-Weese, Frederic Stauffer, Heinrich Rueeger, Clive McCarthy, Sebastien Ripoche, Susanne Oswald, Bertrand Arnaud, Aline Jary, Michel Maira, Christian Schnell, Daniel A. Guthy, Markus Wartmann, Michael Kiffe, Sandrine Desrayaud, Francesca Blasco, Toni Widmer, Frank Seiler, Sascha Gutmann, Mark Knapp, Giorgio Caravatti
Summary: Balanced pan-class I phosphoinositide 3-kinase inhibition is a promising approach for cancer treatment, offering the potential to treat various tumor types and enhance efficacy with a single inhibitor. This study identified a best-in-class phosphoinositide 3-kinase inhibitor, 40 (NVP-CLR457), by optimizing its properties, including eliminating off-target activity and balancing the inhibition profile.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Cell Biology
Yao Wang, Xiaolong Miao, Yuancong Jiang, Zelai Wu, Xuhang Zhu, Han Liu, Xiaoying Wu, Jinzhen Cai, Xianfeng Ding, Weihua Gong
Summary: In this study, the combination of anti-IL-6 antibody and NVP-BEZ235 showed enhanced antitumor effects in hepatocellular carcinoma (HCC) by synergistically inhibiting the PI3K/AKT/mTOR signaling pathway. These findings provide guidance for the analysis and clinical treatment of HCC.
CELL DEATH & DISEASE
(2022)
Article
Chemistry, Medicinal
Janek Szychowski, Robert Papp, Evelyne Dietrich, Bingcan Liu, Frederic Vallee, Marie-Eve Leclaire, Jimmy Fourtounis, Giovanni Martino, Alexander L. Perryman, Victor Pau, Shou Yun Yin, Pavel Mader, Anne Roulston, Jean-Francois Truchon, C. Gary Marshall, Mohamed Diallo, Nicole M. Duffy, Rino Stocco, Claude Godbout, Alexanne Bonneau-Fortin, Rosie Kryczka, Vivek Bhaskaran, Daniel Mao, Stephen Orlicky, Patrick Beaulieu, Pascal Turcotte, Igor Kurinov, Frank Sicheri, Yael Mamane, Michel Gallant, W. Cameron Black
Summary: PKMYT1 acts as a regulator of CDK1 phosphorylation and has been identified as a potential therapeutic target for certain types of DNA damage response cancers. In this study, a weak inhibitor of PKMYT1 was identified and further optimized using structure-based drug design to improve its potency. The resulting potent and selective inhibitors, such as RP 6306, showed inhibitory effects on CCNE1-amplified tumor cell growth in preclinical xenograft models. RP 6306 is currently being evaluated in Phase 1 clinical trials for the treatment of various solid tumors.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Review
Immunology
Jun Zeng, Qiang Zhong, Xiaobing Feng, Linde Li, Shijian Feng, Yu Fan, Turun Song, Zhongli Huang, Xianding Wang, Tao Lin
Summary: Conversion from CNIs to mTORi therapy in kidney transplant recipients can improve renal function and reduce the incidence of malignancy, but is associated with a higher risk of adverse events such as acute rejection, infection, proteinuria, leukopenia, acne, and mouth ulcer, leading to increased drug discontinuation rates. The conversion strategy may be suitable for selected patients.
FRONTIERS IN IMMUNOLOGY
(2021)
Article
Pharmacology & Pharmacy
Jean B. Regard, Tyler J. Harrison, Jake Axford, Laura Axford, Lac Lee, Xianglin Ren, Lin Deng, Aimee Reynolds, Justin Mao, Qian Liu, Anup Patnaik, Evan Cohick, Micah Hollis-Symynkywicz, Sally Loi, Simone Riek, Una McKeever, David Dunstan, MooJe Sung, Nathaniel F. Ware, Alan P. Brown, Lawrence G. Hamann, Jovita Marcinkeviciene, Andrew W. Patterson, Martin L. Marro
Summary: MPO is an important enzyme involved in the innate immune response. A novel MPO inhibitor, IN-4, has been discovered with high potency, selectivity, and oral bioavailability. This inhibitor shows promise as a therapeutic agent for various inflammatory conditions, including cardiovascular disease.
BIOCHEMICAL PHARMACOLOGY
(2023)
Article
Hematology
Stefan Heitmeier, Mayken Visser, Adrian Tersteegen, Julia Dietze-Torres, Julia Glunz, Christoph Gerdes, Volker Laux, Jan Stampfuss, Susanne Roehrig
Summary: Asundexian is an oral inhibitor targeting FXIa, which has antithrombotic effects on arterial and venous thrombosis without increasing the risk of bleeding.
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
(2022)
Article
Chemistry, Medicinal
Monica Bubenik, Pavel Mader, Philippe Mochirian, Frederic Vallee, Jillian Clark, Jean-Francois Truchon, Alexander L. Perryman, Victor Pau, Igor Kurinov, Karl E. Zahn, Marie-Eve Leclaire, Robert Papp, Marie-Claude Mathieu, Martine Hamel, Nicole M. Duffy, Claude Godbout, Matias Casas-Selves, Jean-Pierre Falgueyret, Prasamit S. Baruah, Olivier Nicolas, Rino Stocco, Hugo Poirier, Giovanni Martino, Alexanne Bonneau Fortin, Anne Roulston, Amandine Chefson, Stephane Dorich, Miguel St-Onge, Purvish Patel, Charles Pellerin, Stephane Ciblat, Thomas Pinter, Francis Barabe, Majida El Bakkouri, Paranjay Parikh, Christian Gervais, Agnel Sfeir, Yael Mamane, Stephen J. Morris, W. Cameron Black, Frank Sicheri, Michel Gallant
Summary: This study describes the search for a selective inhibitor of DNA polymerase theta and the successful identification of RP-6685 as a potent, selective, and orally bioavailable inhibitor with potential efficacy in breast and ovarian cancer treatment.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Weihe Zhang, Satish Vadlakonda, Minwan Wu, Venkat Chintareddy, L. N. Vogeti, Luis Juarez, Saritha Muppa, Cynthia Parker, Debra Kellogg-Yelder, Jason Williams, Kevin Polach, Xilin Chen, Krishnan Raman, Y. S. Babu, Pravin Kotian
Summary: HAE is a rare and potentially life-threatening disease. BCX7353 is the only small molecule approved by the FDA for prophylactic treatment of HAE attacks in patients 12 years and older. During the discovery of BCX7353, a novel series of small molecules containing a quaternary carbon as potent PKal inhibitors were also identified.
BIOORGANIC & MEDICINAL CHEMISTRY
(2022)
Review
Neurosciences
Henry Querfurth, Han-Kyu Lee
Summary: mTOR is involved in regulating energy metabolism, neuronal growth, insulin signaling, and autophagy, playing both beneficial and pathogenic roles in neurodegenerative diseases. Balanced actions of mTOR complexes may have implications for Alzheimer's disease, Parkinson's disease, Huntington's disease, Frontotemporal dementia, and Amyotrophic Lateral Sclerosis. Beyond rapamycin, rapalogs with improved tolerability and delivery modes hold promise in treating age-related conditions.
MOLECULAR NEURODEGENERATION
(2021)
Article
Oncology
Raisa Krutilina, Kelli L. Hartman, Damilola Oluwalana, Hilaire C. Playa, Deanna N. Parke, Hao Chen, Duane D. Miller, Wei Li, Tiffany N. Seagroves
Summary: The study demonstrates the effectiveness of sabizabulin in inhibiting the growth and migration of HER2+ breast cancer cells, and inducing cell death. Sabizabulin is a promising alternative to taxanes for the treatment of HER2+ breast cancer, with similar anti-metastatic efficacy but better oral bioavailability and lower toxicity.
Article
Chemistry, Medicinal
Mingfeng Yu, Theodosia Teo, Yuchao Yang, Manjun Li, Yi Long, Stephen Philip, Benjamin Noll, Gary K. Heinemann, Sarah Diab, Preethi Eldi, Laychiluh Mekonnen, Abel T. Anshabo, Muhammed H. Rahaman, Robert Milne, John D. Hayball, Shudong Wang
Summary: CDK8 plays a crucial role in transcriptional regulation and its dysregulation is associated with various types of cancer. Inhibition of CDK8 with compound 38 showed potent anti-proliferative effects on acute myeloid leukaemia cells without systemic toxicity in preclinical studies. Further research on compound 38 as an anticancer agent is warranted.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Medicine, Research & Experimental
Mohamed El-Tanani, Hamdi Nsairat, Alaa A. Aljabali, Angel Serrano-Aroca, Vijay Mishra, Yachana Mishra, Gowhar A. Naikoo, Walhan Alshaer, Murtaza M. Tambuwala
Summary: The mammalian target of rapamycin (mTOR), a signalling system, is necessary for various cell proliferation activities. It recognizes PI3KAKT stress signals as a serine-threonine kinase. The abnormal regulation of mTOR pathway has been proven to be crucial in cancer growth and advancement. This review primarily discusses the normal functions of mTOR as well as its abnormal roles in cancer development.
Article
Multidisciplinary Sciences
Jia Feng, Luchang Wang, Kaijiong Zhang, Sujiao Ni, Baolin Li, Jinbo Liu, Dongsheng Wang
Summary: Taking NVP-BEZ235 as an example, this study screened drug response-related genes (DRRGs) and explored their potential value in triple-negative breast cancer (TNBC). Through high-throughput technique, transcriptome data of BEZ235-treated and untreated MDA-MB-468 cell lines were obtained. Analyses were performed to identify DRRGs associated with tumor trait and to construct a ceRNA network, demonstrating the successful construction of a BEZ235-treated cell line model and explaining the antitumor mechanism of BEZ235.
SCIENTIFIC REPORTS
(2023)
Article
Chemistry, Medicinal
Xiaojing Chen, Lu Liu, Peng Liu, Yingying Chen, Dan Lin, Hao Yan, Qi Yan, Yi Wang, Yinda Qiu, Bo Fang, Huijing Huang, Jianchang Qian, Yunjie Zhao, Zhou Du, Qianwen Zhang, Xiaokun Li, Xiaohui Zheng, Zhiguo Liu
Summary: This study investigated the design, synthesis, and structure-activity relationships of novel pyrimidine-2,4-diamine derivatives that selectively inhibit PDGFR alpha/beta kinases. Compound 7m showed the most promising activity against PDGFR alpha and beta, with low IC50 values. It also exhibited significant cytotoxic effects against osteosarcoma cancer cell lines, as well as robust antitumor effects and low toxicity in a xenograft model. The compound demonstrated favorable pharmacokinetic properties and showed potential as a drug candidate for PDGFR-driven osteosarcoma.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Franck Brebion, Romain Gosmini, Pierre Deprez, Marie Varin, Christophe Peixoto, Luke Alvey, Helene Jary, Natacha Bienvenu, Nicolas Triballeau, Roland Blanque, Celine Cottereaux, Thierry Christophe, Nele Vandervoort, Patrick Mollat, Robert Touitou, Philip Leonard, Frederic De Ceuninck, Iuliana Botez, Alain Monjardet, Ellen van der Aar, David Amantini
Summary: GLPG1972/S201086 is a potent and selective ADAMTS-5 inhibitor obtained through optimization of a promising hydantoin series. The compound has shown biochemical activity against rat and human ADAMTS-5, and demonstrated anticatabolic and anticatabolic activity.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Letter
Biophysics
Laure Vincent, Luuk Gras, Patrice Ceballos, Juergen Finke, Jakob Passweg, Stephanie Harel, Laura Rosinol, Monique Minnema, Raphael Teipel, Jaap van Doesum, Mathias Haenel, Pascal Lenain, Carmen Botella-Garcia, Christian Koenecke, Sophie Ducastelle, Jaime Sanz, Wilfried Schroyens, Tsila Zuckerman, Federico Monaco, Linda Koster, Liesbeth de Wreede, Patrick J. Hayden, Stefan Schoenland, Ibrahim Yakoub-Agha, Meral Beksac
BONE MARROW TRANSPLANTATION
(2022)
Article
Biophysics
Juan-Carlos Hernandez-Boluda, Arturo Pereira, Nienke Zinger, Luuk Gras, Rodrigo Martino, Shankara Paneesha, Juergen Finke, Anabelle Chinea, Alessandro Rambaldi, Marie Robin, Riccardo Saccardi, Annalisa Natale, John A. Snowden, Panagiotis Tsirigotis, Carlos Vallejo, Gerald Wulf, Blanca Xicoy, Domenico Russo, Johan Maertens, Etienne Daguindau, Stig Lenhoff, Patrick Hayden, Tomasz Czerw, Donal P. McLornan, Ibrahim Yakoub-Agha
Summary: Allogeneic hematopoietic cell transplantation shows significant curative potential in patients with FGFR1-rearranged myeloid/lymphoid neoplasm. This study reports on the largest series of FGFR1-rearranged MLN patients undergoing allo-HCT, demonstrating promising overall results in the treatment of this aggressive disease.
BONE MARROW TRANSPLANTATION
(2022)
Article
Biophysics
Stavroula Masouridi-Levrat, Eduardo Olavarria, Simona Iacobelli, Mahmoud Aljurf, Elena Morozova, Riitta Niittyvuopio, Henrik Sengeloev, Peter Remenyi, Grzegorz Helbig, Paul Browne, Arnold Ganser, Arnon Nagler, John A. Snowden, Marie Robin, Jakob Passweg, Gwendolyn Van Gorkom, Helene Labussiere Wallet, Jennifer Hoek, Henric-Jan Blok, Theo De Witte, Nicolaus Kroeger, Patrick Hayden, Yves Chalandon, Ibrahim Yakoub Agha
Summary: This study demonstrates the feasibility of allo-HCT in patients previously treated with second-generation TKIs, with post-transplant complications rate comparable to that of TKI-naive or imatinib-treated patients.
BONE MARROW TRANSPLANTATION
(2022)
Letter
Rheumatology
Dominic Seet, Shir Ying Lee, Melissa Ooi, Ju Ee Seet, Jiacai Cho, Anselm Mak
ARTHRITIS & RHEUMATOLOGY
(2022)
Letter
Hematology
Bhagirathbhai Dholaria, Aleksandar Radujkovic, Noel Estrada-Merly, Tiarlan Sirait, Soyoung Kim, Juan Carlos Hernandez-Boluda, Tomasz Czerw, Patrick J. Hayden, Ankit Kansagra, Vincent T. Ho, Taiga Nishihori, Paul Shaughnessy, Bart Scott, Ryotaro Nakamura, Betul Oran, Mohamed Kharfan-Dabaja, Bipin N. Savani, Donal McLornan, Ibrahim Yakoub-Agha, Wael Saber
BRITISH JOURNAL OF HAEMATOLOGY
(2022)
Article
Hematology
Yves Chalandon, Giulia Sbianchi, Luuk Gras, Linda Koster, Jane Apperley, Jenny Byrne, Urpu Salmenniemi, Henrik Sengeloev, Mahmoud Aljurf, Grzegorz Helbig, Francesca Kinsella, Goda Choi, Peter Remenyi, John A. Snowden, Marie Robin, Stig Lenhoff, Stephan Mielke, Jakob Passweg, Annoek E. C. Broers, Nicolaus Kroeger, Zeynep Arzu Yegin, Sen Mui Tan, Patrick J. Hayden, Donal P. McLornan, Ibrahim Yakoub-Agha
Summary: With the introduction of TKI, the number of allo-HCT for CP CML patients has decreased significantly. The use of 1, 2, or 3 TKI prior to allo-HCT does not affect the overall survival, progression-free survival, relapse incidence, or non-relapse mortality. However, the disease stage and KPS score significantly influence the survival and progression-free survival, emphasizing the importance of careful candidate selection and performing allo-HCT during CP1 phase.
AMERICAN JOURNAL OF HEMATOLOGY
(2023)
Article
Biophysics
Anna Waszczuk-Gajda, Luuk Gras, Liesbeth C. de Wreede, Tiarlan Sirait, Arpad Illes, Zubeyde Nur Ozkurt, John A. Snowden, Mutlu Arat, Claude Eric Bulabois, Judith Niederland, Matjaz Sever, Shankara Paneesha, Victoria Potter, Alain Gadisseur, Thomas Chalopin, Gwendolyn Van Gorkom, Joaquin Martinez Lopez, Tessa Kerre, Joanna Drozd-Sokolowska, Kavita Raj, Patrick J. Hayden, Meral Beksac, Ibrahim Yakoub-Agha, Donal P. McLornan, Stefan Schoenland
Summary: The role of high-dose chemotherapy followed by autologous stem cell transplantation (ASCT) in the treatment of myeloma (MM) patients with severe and/or dialysis-dependent renal impairment remains uncertain. We report on the outcomes of 110 patients (median age 57 years) who had become dialysis-dependent pre-ASCT and who underwent a first ASCT between 1997 and 2017. Age at ASCT and response at ASCT (CR/VGPR/PR vs. MR/SD/progression) were significantly associated with better OS and PFS according to multivariate analyses.
BONE MARROW TRANSPLANTATION
(2023)
Letter
Biophysics
Joanna Drozd-Sokolowska, Luuk Gras, Nienke Zinger, Mohsen Al Zahrani, Jakob Passweg, Jenny Byrne, Aloysius Ho, Xiao-jun Huang, Nicolaus Kroeger, Jiri Mayer, Domenico Russo, Ann De Becker, Abdelghani Tbakhi, Aspasia Stamatoullas, Thomas Valerius, Patrick Hayden, Donal P. McLornan, Francesco Onida, Christof Scheid, Marie Robin, Ibrahim Yakoub-Agha
BONE MARROW TRANSPLANTATION
(2022)
Letter
Hematology
Dai Chihara, Luuk Gras, Nienke Zinger, Nicolaus Kroeger, Jiri Mayer, Jakob Passweg, Regis Peffault de Latour, Jenny Byrne, William Krueger, Jan-Paul Bohn, Uwe Platzbecker, Igor Wolfgang Blau, Francesca Bonifazi, Grzegorz Helbig, Andrew McDonald, Martin Mistrik, Mohamad Mohty, Ron Ram, Jaime Sanz, Carlos Vallejo Llamas, Robert J. Kreitman, Patrick J. Hayden, Donal McLornan, Olivier Tournilhac, Michel van Gelder, Ibrahim Yakoub-Agha
Editorial Material
Hematology
Meral Beksac, Patrick Hayden
LANCET HAEMATOLOGY
(2023)
Review
Hematology
Nicola Polverelli, Juan Carlos Hernandez-Boluda, Tomasz Czerw, Tiziano Barbui, Mariella D'Adda, Hans Joachim Deeg, Markus Ditschkowski, Claire Harrison, Nicolaus Martin Kroger, Ruben Mesa, Francesco Passamonti, Francesca Palandri, Naveen Pemmaraju, Uday Popat, Damiano Rondelli, Alessandro Maria Vannucchi, Srdan Verstovsek, Marie Robin, Antonio Colecchia, Luigi Grazioli, Enrico Damiani, Domenico Russo, Jessica Brady, David Patch, Slawomir Blamek, Gandhi Laurent Damaj, Patrick Hayden, Donal P. McLornan, Ibrahim Yakoub-Agha
Summary: Splenomegaly is a common complication in myelofibrosis patients and can negatively impact outcomes of allogeneic hematopoietic cell transplantation (HCT). This Position Paper provides a shared position statement on the management of splenomegaly before HCT. The assessment, prevalence, and clinical significance of splenomegaly are discussed, along with the need for therapeutic intervention. Specific scenarios, such as splanchnic vein thrombosis and COVID-19, are also addressed.
LANCET HAEMATOLOGY
(2023)
Editorial Material
Medicine, General & Internal
Yun Song Choo, Melissa Gaik-Ming Ooi, Shi Wang, James Thomas Patrick Decourcy Hallinan
Summary: Multiple myeloma, characterized by clonal proliferation of plasma cells and accumulation of monoclonal protein, primarily affects older adults and leads to a wide range of clinical manifestations and complications, such as hypercalcemia, renal dysfunction, anaemia, and bone destruction (known as CRAB features). This case report describes a 64-year-old man with no previous history of malignancy who presented with an enlarging precordial lump three years after a uncomplicated coronary artery bypass grafting surgery. Initial investigations revealed anaemia and impaired renal function. Further multimodal imaging identified radio-pathological features associated with haematological malignancies. Percutaneous biopsy confirmed the diagnosis of multiple myeloma, and prompt initiation of treatment resulted in resolution of the lesions, highlighting the significance of early diagnosis and treatment.
Letter
Hematology
Elyse A. Olesinski, Karanpreet S. Bhatia, Aarthi N. Mahesh, Shazwina Rosli, Jameelah S. Mohamed, Wei Y. Jen, Nitin Jain, Jacqueline S. Garcia, Gee C. Wong, Melissa Ooi, Anthony Letai, Marina Konopleva, Shruti Bhatt
Letter
Hematology
Marie Robin, Liesbeth C. de Wreede, Thomas Schroeder, Friedrich Stoelzel, Nicolaus Kroeger, Linda Koster, Uwe Platzbecker, Juergen Finke, Arnold Ganser, Didier Blaise, Fabio Ciceri, Johan Maertens, Helene Labussiere Wallet, Junfeng Wang, Patrice Chevallier, Jakob Passweg, Jan J. Cornelissen, Stephanie Nguyen, Edouard Forcade, Amandine Charbonnier, Francesca Bonifazi, Patrick Hayden, Donal P. McLornan, Ibrahim Yakoub-Agha
Article
Oncology
Quillan Huang, Irene Mitsiades, Heidi Dowst, Neda Zarrin-Khameh, Attiya Batool Noor, Patricia Castro, Michael E. Scheurer, Guilherme Godoy, Martha P. Mims, Nicholas Mitsiades
Summary: This report highlights the multifaceted utility of longitudinal ctDNA monitoring in early cancer diagnosis and monitoring of treatment response.
NPJ PRECISION ONCOLOGY
(2023)