Article
Multidisciplinary Sciences
Kee-Beom Kim, Ashish Kabra, Dong-Wook Kim, Yongming Xue, Yuanjian Huang, Pei-Chi Hou, Yunpeng Zhou, Leilani J. Miranda, Jae-Il Park, Xiaobing Shi, Timothy P. Bender, John H. Bushweller, Kwon-Sik Park
Summary: EP300, an important transcription coactivator in proliferation and differentiation, is frequently mutated in various cancer types. This study found that EP300 mutants without acetyltransferase domain accelerate tumor development in small cell lung cancer (SCLC) mouse models, while complete EP300 knockout suppresses SCLC development and proliferation. The kinase inducible domain-interacting (KIX) domain of EP300, specifically its interaction with transcription factors including MYB, was identified as the determinant of protumorigenic activity. Inhibition of KIX-mediated interactions inhibits SCLC development and cell growth.
Article
Multidisciplinary Sciences
Angelique N. Masibag, Christopher J. Bergin, Joshua R. Haebe, Aicha Zouggar, Muhammad S. Shah, Tamara Sandouka, Amanda Mendes da Silva, Francois M. Desrochers, Aube Fournier-Morin, Yannick D. Benoit
Summary: Cancer stem cells play a key role in tumorigenesis and therapy resistance, and disrupting CBP/beta-Catenin interactions with reverse-turn peptidomimetics shows promise in curbing hyperactive Wnt/beta-Catenin signaling in CSCs. Recent studies have identified Sam68 as a critical mediator of the response to these peptidomimetics in CSC populations. Through in silico drug discovery, YB-0158 was identified as a small molecule with enhanced translational potential in altering key hallmarks of human colorectal CSCs.
Article
Chemistry, Medicinal
Shenyou Nie, Fangrui Wu, Jingyu Wu, Xin Li, Chao Zhou, Yuan Yao, Yongcheng Song
Summary: Acetylation of histone lysine residues by p300 and CBP plays important roles in gene regulation. Compound 29 is a potential inhibitor of p300 HAT with activity against cancer cells.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Junius Eugene Thomas, Mi Wang, Wei Jiang, Meilin Wang, Lu Wang, Bo Wen, Duxin Sun, Shaomeng Wang
Summary: The study describes the design, synthesis, and evaluation of potent PROTAC degraders (JET-209) targeting the transcriptional coactivators CBP and p300. JET-209 achieved high degradation potency for CBP and p300 in leukemia cell lines and demonstrated inhibition of tumor growth in xenograft models. JET-209 shows promise as a lead compound for developing CBP/p300 degraders for cancer treatment.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Jang-Hyun Choi, Tae-Young Jang, So-El Jeon, Jee-Heun Kim, Choong-Jae Lee, Hyeon-Ji Yun, Ji-Youn Jung, So-Yeon Park, Jeong-Seok Nam
Summary: Recurrence and metastasis are main challenges in CRC treatment, driven by a small subpopulation of cells called cancer stem-like cells (CSCs). Transcriptomic profiling showed upregulation of Wnt pathway and stemness genes in metastatic tumors, and treatment with small-molecule Wnt inhibitor ICG-001 effectively suppressed CSC behavior and metastasis.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Immunology
Shicheng Huo, Xuesong Liu, Shutao Zhang, Zhuocheng Lyu, Jue Zhang, You Wang, Bin'en Nie, Bing Yue
Summary: Our study shows that A-485 has a protective effect in osteoporosis and can inhibit RANKL-induced osteoclast differentiation while reducing the expression of genes associated with osteoporosis. Additionally, A-485 also attenuated OVX-induced bone loss in a mouse model by inhibiting MAPK pathway phosphorylation.
INTERNATIONAL IMMUNOPHARMACOLOGY
(2021)
Article
Multidisciplinary Sciences
Bradley M. Dickson, Ariana Kupai, Robert M. Vaughan, Scott B. Rothbart
Summary: This study introduces a quantitative scale for chromatin immunoprecipitation followed by sequencing (ChIP-seq) called siQ-ChIP, which does not require additional reagents or spike-ins. The authors simplify the calculations for the quantitative scale and introduce a new scheme for generating 'tracks'. They apply siQ-ChIP to analyze p300/CBP inhibition and provide new interpretations of the outcomes.
SCIENTIFIC REPORTS
(2023)
Article
Biochemistry & Molecular Biology
Natsuki Imayoshi, Makoto Yoshioka, Kuniaki Tanaka, Shyh-Ming Yang, Koshi Akahane, Yuki Toda, Shigekuni Hosogi, Takeshi Inukai, Seiji Okada, David J. Maloney, Tatsutoshi Nakahata, Junko Takita, Itaru Kato, Eishi Ashihara
Summary: This study demonstrates that the BET/CBP/p300 multi-bromodomain inhibitor, CN470, has anti-tumor activity against MLL-r ALL by inhibiting cell growth, inducing apoptosis, and showing potential therapeutic advantages.
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
(2022)
Article
Oncology
Michael Bordonaro
Summary: Dietary fiber has a preventive effect against colorectal cancer due to the fermentation product butyrate inducing CRC cell growth arrest and apoptosis. The interaction of CBP and p300 with beta-catenin influences CRC cell physiology, with CBP-Wnt vs. p300-Wnt activity ratio impacting the outcomes. Sam68 and Pygo2 are hypothesized to be responsible for the cell type-specific response of CRC cell lines to ICG-001 and butyrate cotreatment.
Review
Oncology
Francesco Tamiro, Andrew P. Weng, Vincenzo Giambra
Summary: Leukemia-initiating cells (LIC) are unique cells in different types of leukemia that have self-renewing capabilities and produce tumors, which are functionally distinct from bulk leukemia cells. Current conventional treatments are not effective in eliminating LICs, hence innovative therapeutics targeting LICs hold promise for developing an effective cure for ALL.
Review
Biochemistry & Molecular Biology
Hyeon Jin Kim, Mi Suk Jeong, Se Bok Jang
Summary: The influenza virus causes significant human morbidity and mortality worldwide. Developing new anti-influenza drugs is urgently needed, with small molecules targeting NS1 being identified as a potential pathway for drug development. NS1 plays a crucial role in host antiviral responses, making it a key target for new therapeutic interventions against the virus.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Chemistry, Multidisciplinary
Xiao-ru Zhou, Xiao Li, Li-ping Liao, Jie Han, Jing Huang, Jia-cheng Li, Hong-ru Tao, Shi-jie Fan, Zhi-feng Chen, Qi Li, Shi-jie Chen, Hong Ding, Ya-xi Yang, Bing Zhou, Hua-liang Jiang, Kai-xian Chen, Yuan-yuan Zhang, Chuan-xin Huang, Cheng Luo
Summary: Mantle cell lymphoma lacks reliable therapies, but a p300/CBP inhibitor A-485 has been found to overcome resistance to idelalisib by inhibiting MAPK/ERK signaling and reducing histone acetylation, ultimately suppressing cell growth and tumor progression. This study highlights the potential of epigenetic inhibitors targeting p300/CBP to reverse drug resistance in tumors.
ACTA PHARMACOLOGICA SINICA
(2022)
Review
Biochemistry & Molecular Biology
Qingmei Zeng, Kun Wang, Yongxiang Zhao, Qingzhi Ma, Zhinan Chen, Wan Huang
Summary: p300 acts as a transcription coactivator and an acetyltransferase that plays a crucial role in tumourigenesis and progression. It has been proven to regulate various pathophysiological processes and function as an acetyltransferase that drives malignant tumours. In addition, p300 is involved in posttranslational modifications that promote malignant biological behaviors.
Review
Chemistry, Multidisciplinary
Miquel Duran-Frigola, Marko Cigler, Georg E. Winter
Summary: Only 20% of the human proteome is considered druggable, but targeted protein degradation (TPD) offers a solution to this limitation. TPD relies on small molecules to induce the proximity between a protein of interest (POI) and an E3 ubiquitin ligase, leading to degradation of the POI. Advances in multiomics profiling, artificial intelligence, and machine learning (AI/ML) will play a crucial role in overcoming challenges in this field.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2023)
Review
Oncology
Ziting Zhang, Kun Yang, Han Zhang
Summary: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive and heterogeneous subtype of cancer. Recent studies have shown the important roles of leukemia-initiating cells (LICs) and leukemic niches in the initiation and progression of T-ALL, leading to the development of targeted therapies.
Review
Oncology
Richard Rosenquist, Edwin Cuppen, Reinhard Buettner, Carlos Caldas, Helene Dreau, Olivier Elemento, Geert Frederix, Sean Grimmond, Torsten Haferlach, Vaidehi Jobanputra, Manja Meggendorfer, Charles G. Mullighan, Sarah Wordsworth, Anna Schuh
Summary: Precision diagnostics is an important aspect of precision medicine, and whole-genome sequencing can be used to predict and respond to cancer treatment. National initiatives aim to introduce clinical whole-genome sequencing as a rational and effective diagnostic tool, but there is a lack of systematic evaluation of the clinical utility of whole-genome sequencing.
SEMINARS IN CANCER BIOLOGY
(2022)
Review
Hematology
Ilaria Iacobucci, Matthew T. Witkowski, Charles G. Mullighan
Summary: Despite advances in identifying genetic drivers of ALL, prognosis for disease recurrence remains poor. Single-cell sequencing approaches are being used to explore various aspects of ALL biology, such as cell of origin, molecular heterogeneity, and interactions between leukemia cells and the microenvironment. These approaches have provided insights into gene expression, cellular differentiation, and clonal architecture in ALL, but there are still limitations to consider.
Article
Hematology
Eric J. Duncavage, Adam Bagg, Robert P. Hasserjian, Courtney D. DiNardo, Lucy A. Godley, Ilaria Iacobucci, Siddhartha Jaiswal, Luca Malcovati, Alessandro M. Vannucchi, Keyur P. Patel, Daniel A. Arber, Maria E. Arcila, Rafael Bejar, Nancy Berliner, Michael J. Borowitz, Susan Branford, Anna L. Brown, Catherine A. Cargo, Hartmut Dohner, Brunangelo Falini, Guillermo Garcia-Manero, Torsten Haferlach, Eva Hellstrom-Lindberg, Annette S. Kim, Jeffery M. Klco, Rami Komrokji, Mignon Lee-Cheun Loh, Sanam Loghavi, Charles G. Mullighan, Seishi Ogawa, Attilio Orazi, Elli Papaemmanuil, Andreas Reiter, David M. Ross, Michael Savona, Akiko Shimamura, Radek C. Skoda, Francesc Sole, Richard M. Stone, Ayalew Tefferi, Matthew J. Walter, David Wu, Benjamin L. Ebert, Mario Cazzola
Summary: Myeloid neoplasms and acute leukemias are caused by somatic gene mutations that drive the clonal expansion of hematopoietic cells. Genomic characterization plays a crucial role in diagnosis, risk assessment, and clinical decision making. Conventional cytogenetics has been the main method for genomic testing, but recent advances in sequencing technology allow for more accurate detection of somatic mutations. Whole-genome sequencing shows potential as a replacement for traditional methods in patients with myeloid neoplasms, providing rapid and comprehensive genomic profiling.
Letter
Oncology
Kentaro Ohki, Ellie R. Butler, Nobutaka Kiyokawa, Shinsuke Hirabayashi, Anke K. Bergmann, Anja Moericke, Judith M. Boer, Helene Cave, Giovanni Cazzaniga, Allen Eng Juh Yeoh, Masashi Sanada, Toshihiko Imamura, Hiroto Inaba, Charles G. Mullighan, Mignon L. Loh, Ulrika Noren-Nystrom, Lee-Yung Shih, Marketa Zaliova, Ching-Hon Pui, Oskar A. Haas, Christine J. Harrison, Anthony V. Moorman, Atsushi Manabe
Meeting Abstract
Hematology
Lauren K. Meyer, Ritu P. Roy, Petri Polonen, Abdelrahman Elsayed, Benjamin J. Huang, Shunsuke Kimura, Cristina Delgado-Martin, Tiffaney L. Vincent, Theresa Ryan, Brent L. Wood, Zhiguo Chen, Yu Liu, Jinghui Zhang, Terzah M. Horton, Mignon L. Loh, Meenakshi Devidas, Elizabeth A. Raetz, Robert J. Hayashi, Stuart S. Winter, Kimberly P. Dunsmore, Stephen P. Hunger, Stanley B. Pounds, Michelle L. Hermiston, Jun J. Yang, Charles G. Mullighan, David T. Teachey, Adam B. Olshen
Article
Hematology
David Spencer Mangum, Johnathon D. Bishop, Yinmei Zhou, Cheng Cheng, Seth E. Karol, Jeffrey E. Rubnitz, Raul C. Ribeiro, Jun J. Yang, Charles G. Mullighan, Sima Jeha, Ching-Hon Pui, Hiroto Inaba
Summary: Among children with acute lymphoblastic leukaemia, about 14.7% presented without peripheral blood blasts. While absence of blasts did not affect survival outcomes, these patients had distinct genetic and clinical characteristics, with a higher incidence of hyperdiploid B-ALL and lower rates of central nervous system involvement.
BRITISH JOURNAL OF HAEMATOLOGY
(2023)
Review
Pathology
Amy S. Duffield, Charles G. Mullighan, Michael J. Borowitz
Summary: The updated International Consensus Classification (ICC) of B-acute lymphoblastic leukemia (B-ALL) and T-acute lymphoblastic leukemia (T-ALL) includes revisions to previous subtypes and new entities. The classification incorporates recent clinical, cytogenetic, and molecular data, emphasizing whole transcriptome analysis and gene expression clustering studies. The new classification allows for improved risk stratification and optimized treatment plans for ALL patients.
Letter
Hematology
Sai Prasad Desikan, Jayastu Senapati, Elias Jabbour, Tareq Abuasab, Nicholas Short, Guilin Tang, Sa Wang, Partow Kebriaei, Tapan Kadia, Gautam Borthakur, Farhad Ravandi, Kathryn Roberts, Charles Mullighan, Marina Konopleva, Hagop Kantarjian, Nitin Jain
AMERICAN JOURNAL OF HEMATOLOGY
(2023)
Letter
Hematology
Olga K. Weinberg, Daniel A. Arber, Hartmut Doehner, Charles G. Mullighan, Etan Orgel, Anna Porwit, Richard M. Stone, Michael J. Borowitz
Article
Biochemistry & Molecular Biology
Lin Kang, Ai-Lun Yang, Chao-Han Lai, Tsan-Ju Chen, Sung-Yen Lin, Yan-Hsiung Wang, Chau-Zen Wang, Edward M. Conway, Hua-Lin Wu, Mei-Ling Ho, Je-Ken Chang, Chung-Hwan Chen, Tsung-Lin Cheng
Summary: The study found that thrombomodulin (TM) plays a crucial protective role in osteoarthritis (OA) by enhancing chondrocyte growth and migration, blocking inflammatory signaling, and protecting knee function and bone integrity. Increasing TM expression can effectively protect cartilage from damage. These findings contribute to the development of novel therapeutic approaches against OA.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Oncology
Satoshi Yoshimura, John C. Panetta, Jianzhong Hu, Lie Li, Yoshihiro Gocho, Guoqing Du, Akihiro Umezawa, Seth E. Karol, Ching-Hon Pui, Charles G. Mullighan, Marina Konopleva, Wendy Stock, David T. Teachey, Nitin Jain, Jun J. Yang
Summary: LCK is a therapeutic target in T-cell acute lymphoblastic leukemia (T-ALL), and dasatinib and ponatinib are effective inhibitors of LCK. This study evaluates the pharmacokinetics and pharmacodynamics of dasatinib and ponatinib in LCK-activated T-ALL. Both drugs demonstrate similar cytotoxic activity, with ponatinib being slightly more potent. Ponatinib exhibits slower clearance and higher exposure compared to dasatinib. Exposure-to-response models suggest that both drugs achieve significant pLCK inhibition, comparable to their effects in other leukemias. Additionally, ponatinib retains partial activity against LCK in a dasatinib-resistant T-ALL cell line model. Overall, this study provides crucial data for the development of human trials involving dasatinib and ponatinib in T-ALL.
Editorial Material
Pharmacology & Pharmacy
Mark Thomas Shaw Williams, Yong-Mi Kim, Monica L. Guzman
FRONTIERS IN PHARMACOLOGY
(2023)
Article
Cell Biology
Chau Ly, Heather Ogana, Hye Na Kim, Samantha Hurwitz, Eric J. Deeds, Yong-Mi Kim, Amy C. Rowat
Summary: This study investigates the physical properties of chemotherapy-treated leukemia cells using microfluidic technology. The findings show that chemotherapy-treated B-ALL cells are more deformable than control cells. Furthermore, machine learning algorithms applied to physical phenotyping data can predict the presence of chemotherapy-surviving cells in a mixed population.
INTEGRATIVE BIOLOGY
(2023)
Meeting Abstract
Hematology
Oscar Molina, Namitha Thampi, Juan Trincado, Carmen Ortega-Sabater, Gabriel Fernandez-Calvo, Paola Romecin, Alba Martinez-Moreno, Talia Velasco-Hernandez, Meritxell Vinyoles, Victor Perez-Garcia, Angelika Merkel, Isabel Granada, Mireia Camos, Jose Fuster, Paola Ballerini, Franco Locatelli, Charles Mullighan, Clara Bueno, Pablo Menendez
EXPERIMENTAL HEMATOLOGY
(2022)
Meeting Abstract
Oncology
Katelyn Purvis, Yinmei Zhou, Seth Karol, Jeffrey Rubnitz, Raul Ribeiro, Shawn Lee, Jun Yang, Cheng Cheng, Charles Mullighan, Sima Jeha, Ching-Hon Pui, Hiroto Inaba
PEDIATRIC BLOOD & CANCER
(2022)