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)
Review
Immunology
Rongxiu Huo, Xinxiang Huang, Yang Yang, Jinying Lin
Summary: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by cytokine imbalance. Dysregulation of the JAK/STAT pathway plays a role in SLE pathogenesis. JAK inhibitors (JAKis) show promise in reducing corticosteroid and immunosuppressant use in SLE treatment. Clinical trials are ongoing, and JAKis may improve traditional treatment strategies for SLE.
JOURNAL OF INFLAMMATION RESEARCH
(2023)
Review
Immunology
Dawei Huang, Yuexin Zhang, Luyang Kong, Jiajing Lu, Yuling Shi
Summary: Autoimmune bullous disease (AIBD) is a severe skin disorder caused by autoantibodies that target intercellular or cell-matrix adhesion proteins. The current treatment options include glucocorticoids, traditional immunosuppressants, and the utilization of biological agents. The Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway has been implicated in AIBD, and JAK inhibitors have shown potential in treating this disease.
FRONTIERS IN IMMUNOLOGY
(2023)
Review
Oncology
Boheng Li, Qin Wan, Zhubo Li, Wee-Joo Chng
Summary: Janus kinases (JAKs) are transmembrane receptors that play a role in lymphoid cancer pathogenesis by mediating gene expression through the JAK/STAT pathway. JAK abnormalities can lead to over-activation of the JAK/STAT pathway and the nuclear role of JAK tyrosine kinases. Anti-JAK therapeutics have been developed to effectively target lymphoid cancer cells.
Article
Chemistry, Medicinal
Mikhail Krasavin, Maria Adamchik, Andrey Bubyrev, Christopher Heim, Samuel Maiwald, Daniil Zhukovsky, Petr Zhmurov, Alexander Bunev, Marcus D. Hartmann
Summary: In order to enhance the chemical toolkit for targeted protein degradation, the authors developed a new series of non-thalidomide Cereblon (CRBN) ligands. By using a thio-Michael addition reaction, readily available 2-methylidene glutarimide was converted to a series of 2-((hetero)aryl(methyl))thio glutarimides. These compounds were evaluated for their affinity to human CRBN and their binding modes were studied through X-ray crystallography. The newly identified Cereblon ligands show promising potential for the synthesis of novel PROTAC protein degraders.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Review
Immunology
Fei Qi, Fang Liu, Ling Gao
Summary: Vitiligo is a reversible skin disorder characterized by white patches resulting from destruction of melanocytes. JAK inhibitors have shown effectiveness in treating vitiligo by targeting the JAK/STAT pathway, but further studies are needed to determine optimal dosage and identify other inflammatory pathways involved in the pathogenesis of the condition.
FRONTIERS IN IMMUNOLOGY
(2021)
Review
Pharmacology & Pharmacy
Nem Kumar Jain, Mukul Tailang, Hemant Kumar Jain, Balakumar Chandrasekaran, Biswa Mohan Sahoo, Anandhalakshmi Subramanian, Neelaveni Thangavel, Afaf Aldahish, Kumarappan Chidambaram, M. Alagusundaram, Santosh Kumar, Palani Selvam
Summary: Severe cases of COVID-19 are characterized by hyperinflammation and multiorgan failure. JAK-STAT signaling plays a role in the immunopathogenesis of COVID-19. Jakinibs, small molecules that target proinflammatory cytokines, are being investigated as potential treatments through clinical trials. Baricitinib is currently the only FDA-approved Jakinib for treating critical COVID-19 patients. Further studies are needed to understand the pathogenesis of COVID-19 and determine the optimal duration and combination therapy of Jakinibs. This review article provides important insights into the therapeutic implications of Jakinibs for COVID-19 treatment.
FRONTIERS IN PHARMACOLOGY
(2023)
Editorial Material
Hematology
Carol Fries, Michelle L. Hermiston
Summary: In this issue of Blood, Courtois et al. identified interleukin-7 receptor (IL-7R) expression as a potential biomarker for predicting sensitivity to JAK pathway inhibition in T-cell acute lymphoblastic leukemia (T-ALL).
Review
Dermatology
Stephanie Chapman, Michael Kwa, Linda Stein Gold, Henry W. Lim
Summary: The JAK-STAT pathway is important in inflammatory dermatoses, and JAK inhibitors have shown efficacy in treating various dermatologic conditions.
JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY
(2022)
Article
Allergy
William Damsky, Danielle Peterson, Julie Ramseier, Badr Al-Bawardy, Hyung Chun, Deborah Proctor, Vibeke Strand, Richard A. Flavell, Brett King
Summary: Autoimmune and inflammatory diseases are commonly treated by targeting dysregulated cytokine activity, with the emergence of JAK inhibitors offering a new approach that simultaneously blocks multiple pathogenic cytokines. These small molecule inhibitors show promising results and are becoming increasingly important in the treatment of various autoimmune and inflammatory disorders.
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
(2021)
Review
Immunology
Hongda Li, Honglei Wang, Guizhi Qiao, Yongxia Liu, Furen Zhang, Futang Pan
Summary: This article describes the first report of the use of tofacitinib in treating bullous pemphigoid combined with psoriasis vulgaris with significant results. Tofacitinib may be a safe and effective treatment option for patients suffering from both conditions, with important implications for treatment strategies.
INTERNATIONAL IMMUNOPHARMACOLOGY
(2023)
Review
Dermatology
Stephanie Chapman, Linda Stein Gold, Henry W. Lim
Summary: The Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway is important in the development of inflammatory skin conditions, and JAK inhibitors have shown efficacy in treating various dermatologic diseases. This review focuses on JAK inhibitors being investigated for the treatment of alopecia areata, vitiligo, sarcoidosis, necrobiosis lipoidica, granuloma annulare, and systemic lupus erythematosus, with a discussion on safety and the implications of JAK inhibitors during the COVID-19 pandemic.
JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY
(2022)
Review
Oncology
Dipanjan Karati, Kakasaheb Ramoo Mahadik, Piyush Trivedi, Dileep Kumar
Summary: Cancer is a leading cause of death worldwide, and abnormal activation of the JAK-STAT signaling pathway plays an important role in carcinogenesis. JAK inhibitors have shown promising anticancer effects, but clinical trials are still ongoing.
CURRENT CANCER DRUG TARGETS
(2022)
Article
Cell Biology
Nathanael A. Caveney, Robert A. Saxton, Deepa Waghray, Caleb R. Glassman, Naotaka Tsutsumi, Stevan R. Hubbard, Christopher Garcia
Summary: Janus kinases (JAKs) play a key role in cytokine signaling by mediating the transduction of signals downstream of cytokine receptors. The cryoelectron microscopy structure of a mouse JAK1 complex provides insights into the trans-activation step of JAK signaling and the allosteric mechanisms of JAK inhibition.
Article
Immunology
Chun Dang, Yaoheng Lu, Xingyu Chen, Qian Li
Summary: Baricitinib, a JAK 1/2 inhibitor, was shown to significantly delay onset, decrease severity of symptoms, shorten EAE duration, and alleviate demyelination and immune cell infiltration in EAE mice. Baricitinib treatment also reduced the proportion of proinflammatory Th1 and Th17 cells, inhibiting lymphocyte proliferation and decreasing expression of proinflammatory cytokines and chemokines, indicating its potential as a candidate for treating MS.
FRONTIERS IN IMMUNOLOGY
(2021)
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
Daniel A. Arber, Attilio Orazi, Robert P. Hasserjian, Michael J. Borowitz, Katherine R. Calvo, Hans-Michael Kvasnicka, Sa A. Wang, Adam Bagg, Tiziano Barbui, Susan Branford, Carlos E. Bueso-Ramos, Jorge E. Cortes, Paola Dal Cin, Courtney D. DiNardo, Herve Dombret, Eric J. Duncavage, Benjamin L. Ebert, Elihu H. Estey, Fabio Facchetti, Kathryn Foucar, Naseema Gangat, Umberto Gianelli, Lucy A. Godley, Nicola Gokbuget, Jason Gotlib, Eva Hellstrom-Lindberg, Gabriela S. Hobbs, Ronald Hoffman, Elias J. Jabbour, Jean-Jacques Kiladjian, Richard A. Larson, Michelle M. Le Beau, Mignon L. -C. Loh, Bob Lowenberg, Elizabeth Macintyre, Luca Malcovati, Charles G. Mullighan, Charlotte Niemeyer, Olatoyosi M. Odenike, Seishi Ogawa, Alberto Orfao, Elli Papaemmanuil, Francesco Passamonti, Kimmo Porkka, Ching-Hon Pui, Jerald P. Radich, Andreas Reiter, Maria Rozman, Martina Rudelius, Michael R. Savona, Charles A. Schiffer, Annette Schmitt-Graeff, Akiko Shimamura, Jorge Sierra, Wendy A. Stock, Richard M. Stone, Martin S. Tallman, Juergen Thiele, Hwei-Fang Tien, Alexandar Tzankov, Alessandro M. Vannucchi, Paresh Vyas, Andrew H. Wei, Olga K. Weinberg, Agnieszka Wierzbowska, Mario Cazzola, Hartmut Dohner, Ayalew Tefferi
Summary: In 2016, the WHO, Society for Hematopathology, and European Association for Haematopathology collaborated to update the classification of myeloid neoplasms and acute leukemias, advancing the field of myeloid neoplasms and acute leukemias.
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
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
Hematology
Yunchao Chang, Fatemeh Keramatnia, Pankaj S. Ghate, Gisele Nishiguchi, Qingsong Gao, Ilaria Iacobucci, Lei Yang, Divyabharathi Chepyala, Ashutosh Mishra, Anthony A. High, Hiroaki Goto, Koshi Akahane, Junmin Peng, Jun J. Yang, Marcus Fischer, Zoran Rankovic, Charles G. Mullighan
Summary: This study developed a novel cereblon modulator named SJ6986, which effectively degrades GSPT1 and GSPT2 and exhibits cytotoxic activity against childhood cancer cell lines. In vitro and in vivo testing showed that SJ6986 has similar cytotoxicity to the previously described GSPT1 degrader CC-90009, but is more effective in suppressing leukemic cell growth and does not significantly impair differentiation of human CD34(+) cells. Genome-wide CRISPR/Cas9 screening confirmed the involvement of components of the CRL4CRBN complex in mediating the action of SJ6986. SJ6986 is a potent and selective GSPT1/2 degrader with broad antileukemic activity and potential for clinical development.
Article
Chemistry, Medicinal
Mladen Koravovic, Anand Mayasundari, Gordana Tasic, Fatemeh Keramatnia, Timothy R. Stachowski, Huarui Cui, Sergio C. Chai, Barbara Jonchere, Lei Yang, Yong Li, Xiang Fu, Ryan Hiltenbrand, Leena Paul, Vibhor Mishra, Jeffery M. Klco, Martine F. Roussel, William CK. Pomerantz, Marcus Fischer, Zoran Rankovic, Vladimir Savic
Summary: An X-ray structure of a CLICK chemistry-based BET PROTAC bound to BRD2(BD2) inspired the synthesis of JQ1 derived heterocyclic amides. These compounds displayed improved profiles compared to JQ1 and birabresib as potent BET inhibitors. A specific compound 1q (SJ1461) showed excellent affinity to both BRD4 and BRD2 and high potency in acute leukaemia and medulloblastoma cell lines. The co-crystal structure of 1q with BRD4-BD1 revealed polar interactions, explaining the observed affinity improvements. Furthermore, pharmacokinetic studies suggested that the heterocyclic amide moiety improved drug-like features. Our study led to the discovery of the potent and orally bioavailable BET inhibitor 1q (SJ1461) as a promising candidate for further development.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(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.
Article
Biochemistry & Molecular Biology
Timothy R. R. Stachowski, Stanley Nithianantham, Murugendra Vanarotti, Karlo Lopez, Marcus Fischer
Summary: Isoforms of HSP90 play a role in facilitating cancer development, but their therapeutic potential remains unfulfilled due to lack of FDA-approved drugs. The challenge lies in selective targeting of isoforms with high structural similarity and side effects caused by pan-HSP90 inhibition. This study presents a three-pronged approach to understand the HSP90 landscape and explore isoform-specific accommodations, shedding light on ligand discovery and design for potential drug development.
Article
Biochemical Research Methods
Timothy R. Stachowski, Marcus Fischer
Summary: Researchers have developed an automated multi-conformer modeling program, FLEXR, to detect and include hidden protein conformational dynamics in high-resolution electron-density maps. The program reveals new structural details that are missed by manual modeling or current tools, such as hidden side chains and backbone conformations in ligand-binding sites, which may redefine protein-ligand binding mechanisms. FLEXR is an open-source tool available for crystallographers.
ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY
(2023)
Meeting Abstract
Oncology
Lindsey Montefiori, Ilaria Iacobucci, Amit Budhraja, Jamila Moore, Rebekah Baskin, Rebekah DeVries, Emily Backhaus, Melissa Johnson, Walter Akers, Divyabharathi Chepyala, Cyrus Mehr, Aman Seth, Paul Mead, Joseph Opferman, Charles Mullighan
CLINICAL LYMPHOMA MYELOMA & LEUKEMIA
(2022)
Article
Oncology
Robert J. Vanner, Stephanie M. Dobson, Olga Gan, Jessica McLeod, Erwin M. Schoof, Ildiko Grandal, Jeff A. Wintersinger, Laura Garcia-Prat, Mohsen Hosseini, Stephanie Z. Xie, Liqing Jin, Nathan Mbong, Veronique Voisin, Michelle Chan-Seng-Yue, James A. Kennedy, Esme Waanders, Quaid Morris, Bo Porse, Steven M. Chan, Cynthia J. Guidos, Jayne S. Danska, Mark D. Minden, Charles G. Mullighan, John E. Dick
Summary: In B-ALL CNS disease, the leptomeningeal environment selects cells with unique functional dependencies. Pharmacologic inhibition of mRNA translation signaling treats CNS disease and offers a new therapeutic approach for this condition.
BLOOD CANCER DISCOVERY
(2022)
