Article
Biochemistry & Molecular Biology
Yuhei Horai, Naoki Suda, Shinsuke Uchihashi, Mayako Katakuse, Tomomi Shigeno, Takashige Hirano, Junichi Takahara, Tomoyuki Fujita, Yohei Mukoyama, Yuji Haga
Summary: The discovery of a novel BRD4 inhibitor for melanoma therapy is outlined in this study. Through modifications of existing molecules and the introduction of new structures, a compound with potent inhibitory activity and favorable pharmacokinetic properties was successfully developed. This compound demonstrated significant antitumor efficacy in a mouse melanoma model, indicating its potential as a therapeutic agent for melanoma treatment.
BIOORGANIC & MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Hongchao Zheng, Jichen Zhao, Bing Li, Weihe Zhang, Michael A. Stashko, Katherine A. Minson, Madeline G. Huey, Yubai Zhou, Henry Shelton Earp, Dmitri Kireev, Douglas K. Graham, Deborah DeRyckere, Stephen Frye, Xiaodong Wang
Summary: Inhibition of MER receptor tyrosine kinase (MERTK) contributes to tumor cell killing and stimulation of the immune response. UNC5293 is a highly selective MERTK inhibitor with potent and selective inhibition in cell-based assays, excellent mouse PK properties, and activity in leukemia cells in a murine model.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Zenichi Ikeda, Taku Kamei, Yusuke Sasaki, Matthew Reynolds, Nozomu Sakai, Masato Yoshikawa, Michiko Tawada, Nao Morishita, Douglas R. Dougan, Chien-Hung Chen, Irena Levin, Hua Zou, Masako Kuno, Naoto Arimura, Yusuke Kikukawa, Mitsuyo Kondo, Kimio Tohyama, Kenjiro Sato
Summary: We explored a novel series of non-amidine-based C1s inhibitors. By replacing isoquinoline with 1-aminophthalazine, we enhanced the C1s inhibitory activity while maintaining good selectivity against other serine proteases. Through structure-based optimization around the S2 and S3 sites and improving membrane permeability, we identified (R)-8 as a potent, selective, orally available, and brain-penetrable C1s inhibitor, which effectively blocked the classical complement pathway.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Andrew Novak, David Laughton, Rebecca Lane, Emma Blackham, Jennifer Thomas, Elli Chatzopoulou, Joseph Wrigglesworth, Abdul Quddus, Saleh Ahmed, David Cousin, Lorna Duffy, Nathalie Dubois, John Unitt, Katalin Orban, Edward Browne, Michelle Ward, David Mycock, Maria Ieva, Nicholas Bland, Pascal George, Timothy Bourne, Helene Asnagli, Louise Birch, Geraint Jones
Summary: In this study, we reported the discovery of a novel chemotype, 2-(alkylsulfonamido)thiazol-4-yl)acetamides, which act as pan-selective inhibitors of cytidine 5'-triphosphate synthetase (CTPS1/2), critical enzymes in the de novo pyrimidine synthesis pathway. Through optimization, compound 27 has been developed into a potent, orally active agent, showing significant pharmacological responses in a well-established animal model of inflammation.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Changwei Chen, Xin Chai, Xueping Hu, Shengying Lou, Dan Li, Tingjun Hou, Sunliang Cui
Summary: A new core structure for androgen receptor antagonists was designed and synthesized, which showed antiandrogen resistance activity at a non-traditional targeting site and effectively inhibited tumor growth in an animal study. This study provides new possibilities for the development of prostate cancer therapy.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
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
Chemistry, Medicinal
Wataru Kawahata, Tokiko Asami, Takao Kiyoi, Takayuki Irie, Shigeki Kashimoto, Hatsuo Furuichi, Masaaki Sawa
Summary: The study identified a series of novel noncovalent BTK inhibitors, among which 13f (AS-1763) as a next-generation noncovalent BTK inhibitor, showed good oral availability, potency, and selectivity, with significant efficacy in in vivo tumor xenograft models, and has advanced to phase 1 clinical trials.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Xishan Wu, Hui Shen, Yan Zhang, Chao Wang, Qiu Li, Cheng Zhang, Xiaoxi Zhuang, Chenchang Li, Yudan Shi, Yanli Xing, Qiuping Xiang, Jinxin Xu, Donghai Wu, Jinsong Liu, Yong Xu
Summary: The study reports a novel inverse agonist as a therapeutic target for ROR gamma, showing potent inhibition activity and selectivity, as well as good suppression in prostate cancer cell lines, along with good pharmacokinetic properties.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Multidisciplinary Sciences
Keith Woodley, Laura S. Dillingh, George Giotopoulos, Pedro Madrigal, Kevin M. Rattigan, Celine Philippe, Vilma Dembitz, Aoife M. S. Magee, Ryan Asby, Louie N. van de Lagemaat, Christopher Mapperley, Sophie C. James, Jochen H. M. Prehn, Konstantinos Tzelepis, Kevin Rouault-Pierre, George S. Vassiliou, Kamil R. Kranc, G. Vignir Helgason, Brian J. P. Huntly, Paolo Gallipoli
Summary: Metabolic rewiring through inhibition of mannose-6-phosphate isomerase sensitizes acute myeloid leukemia (AML) to FLT3-tyrosine kinase inhibitor and standard chemotherapy by enhancing lipid peroxidation and ferroptotic cell death. Resistance to standard and novel therapies in AML is driven by metabolic adaptations, and here the authors identify mannose-6-phosphate isomerase (MPI) inhibition as a sensitizer to cytarabine and FLT3 inhibitors. This metabolic rewiring leads to the activation of the ATF6 arm of the unfolded protein response (UPR), resulting in the accumulation of polyunsaturated fatty acids, lipid peroxidation and ferroptotic cell death in AML cells. These findings emphasize the importance of rewired metabolism in AML therapy resistance and support efforts to sensitize therapy-resistant AML cells to ferroptotic cell death.
NATURE COMMUNICATIONS
(2023)
Review
Biochemistry & Molecular Biology
Maria Giulia Nizi, Chiara Sarnari, Oriana Tabarrini
Summary: The discovery of new targets for personalized treatment in addressing unmet medical needs is urgent. The introduction of PARP1 inhibitors as innovative cancer treatments has been a significant step forward in precision medicine. The PARP family consists of 17 members, with PARP1 being the only enzyme targeted for therapy. Other members, known as mono-ARTs enzymes, have also been found to have extensive pathophysiological roles and potential therapeutic applications. Recent studies have identified several mono-ARTs inhibitors, highlighting the importance of further research in this field.
Article
Chemistry, Medicinal
Donghui Qin, Xiaojuan Lin, Zhi Liu, Yan Chen, Zhiliu Zhang, Chengde Wu, Linlin Liu, Yan Pan, Sylvie Laquerre, John Emery, Jeff Fergusson, Kimberly Roland, Rick Keenan, Allen Oliff, Sanjay Kumar, Mui Cheung, Dai-Shi Su
Summary: The discovery of quinazolindiones as potent and selective tankyrase inhibitors has led to the development of truncated analogues with good potency in cells and excellent selectivity. Compound 21 showed excellent potencies in cells, good selectivity, in vitro activities, and an excellent PK profile, as well as inhibiting H292 xenograft tumor growth in nude mice. The synthesis, biological, pharmacokinetic, in vivo efficacy studies, and safety profiles of compounds are presented.
ACS MEDICINAL CHEMISTRY LETTERS
(2021)
Article
Chemistry, Medicinal
Martin A. . Lowe, Alvaro Cardenas, Jean-Pierre Valentin, Zhaoning Zhu, Jan Abendroth, Jose L. Castro, Reiner Class, Annie Delaunois, Renaud Fleurance, Helga Gerets, Vitalina Gryshkova, Lloyd King, Donald D. Lorimer, Malcolm MacCoss, Julian H. Rowley, Marie-Luce Rosseels, Leandro Royer, Richard D. Taylor, Melanie Wong, Oliver Zaccheo, Vishal P. Chavan, Gokul A. . Ghule, Bapusaheb K. Tapkir, Jeremy N. Burrows, Maelle Duffey, Matthias Rottmann, Sergio Wittlin, Inigo Angulo-Barturen, Maria Belen Jimenez-Diaz, Josefine Striepen, Kate J. Fairhurst, Tomas Yeo, David A. . Fidock, Alan F. Cowman, Paola Favuzza, Benigno Crespo-Fernandez, Francisco Javier Gamo, Daniel E. Goldberg, Dominique Soldati-Favre, Benoit Laleu, Teresa de Haro
Summary: This study optimized Plasmepsin X (PMX) and identified potent PMX inhibitors with potential efficacy in treating malaria.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Gianni Chessari, Ian R. Hardcastle, Jong Sook Ahn, Burcu Anil, Elizabeth Anscombe, Ruth H. Bawn, Luke D. Bevan, Timothy J. Blackburn, Ildiko Buck, Celine Cano, Benoit Carbain, Juan Castro, Ben Cons, Sarah J. Cully, Jane A. Endicott, Lynsey Fazal, Bernard T. Golding, Roger J. Griffin, Karen Haggerty, Suzannah J. Harnor, Keisha Hearn, Stephen Hobson, Rhian S. Holvey, Steven Howard, Claire E. Jennings, Christopher N. Johnson, John Lunec, Duncan C. Miller, David R. Newell, Martin E. M. Noble, Judith Reeks, Charlotte H. Revill, Christiane Riedinger, Jeffrey D. St Denis, Emiliano Tamanini, Huw Thomas, Neil T. Thompson, Mladen Vinkovic, Stephen R. Wedge, Pamela A. Williams, Nicola E. Wilsher, Bian Zhang, Yan Zhao
Summary: In this study, novel isoindolinone-based MDM2 inhibitors were designed with rational structure guidance and showed potent inhibition of MDM2-p53 interaction, leading to cytostasis in an osteosarcoma xenograft model. These findings highlight the potential of targeting MDM2 in cancer therapy.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Pharmacology & Pharmacy
Jia-Luo Huang, Xue-Long Yan, Dong Huang, Lu Gan, Huahua Gao, Run-Zhu Fan, Shen Li, Fang-Yu Yuan, Xinying Zhu, Gui-Hua Tang, Hong-Wu Chen, Junjian Wang, Sheng Yin
Summary: The study optimized a natural importin-beta 1 inhibitor DD1 to improve its tolerability and oral bioavailability, resulting in an analog called DD1-Br. DD1-Br exhibited potent inhibition of survival in castration-resistant prostate cancer cells and effectively prevented tumor growth in resistant CRPC models. Mechanistic study revealed that DD1-Br targeted importin-beta 1 and suppressed the nuclear accumulation of key CRPC drivers, including AR-V7, thereby inhibiting oncogenic signaling.
ACTA PHARMACEUTICA SINICA B
(2023)
Article
Chemistry, Medicinal
Yingchao Duan, Tong Yu, Linfeng Jin, Shaojie Zhang, Xiaojing Shi, Yizhe Zhang, Nanqian Zhou, Yongtao Xu, Wenfeng Lu, Huimin Zhou, Huijuan Zhu, Suping Bai, Kua Hu, Yuanyuan Guan
Summary: Compound 5e, a highly potent inhibitor of HDACs and LSD1, showed significant antiproliferative activity in multiple cancer cell lines and induced mitochondrial apoptosis with cell cycle arrest. It demonstrated higher in vivo antitumor efficacy compared to SAHA in xenograft tumor models. This study provides a novel lead compound for the development of epigenetic drugs for solid tumor therapy.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Pharmacology & Pharmacy
R. Jason Kirby, Daniela B. Divlianska, Kanupriya Whig, Nadezda Bryan, Camilo J. Morfa, Ada Koo, Becky L. Hood, Kevin H. Nguyen, Patrick Maloney, Satayamaheshwar Peddibhotla, E. Hampton Sessions, Paul M. Hershberger, Layton H. Smith, Siobhan Malany
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
(2018)
Review
Neurosciences
Samuel A. Barnes, Douglas J. Sheffler, Svetlana Semenova, Nicholas D. P. Cosford, Anton Bespalov
BIOLOGICAL PSYCHIATRY
(2018)
Article
Chemistry, Medicinal
Katherine Krajnak, Russell Dahl
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2018)
Article
Chemistry, Medicinal
Katherine Krajnak, Russell Dahl
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2018)
Article
Chemistry, Medicinal
Anthony B. Pinkerton, Eduard Sergienko, Yalda Bravo, Russell Dahl, Chen-Ting Ma, Qing Sun, Michael R. Jackson, Nicholas D. P. Cosford, Jose Luis Millan
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2018)
Article
Chemistry, Organic
Raveendra Panickar Dhanya, Ananda Herath, Douglas J. Sheffler, Nicholas D. P. Cosford
Article
Biochemical Research Methods
Camilo J. Morfa, Daniel Bassoni, Andras Szabo, Danielle McAnally, Haleli Sharir, Becky L. Hood, Stefan Vasile, Tom Wehrman, Jane Lamerdin, Layton H. Smith
ASSAY AND DRUG DEVELOPMENT TECHNOLOGIES
(2018)
Article
Multidisciplinary Sciences
Danielle McAnally, Khandaker Siddiquee, Ahmed Gomaa, Andras Szabo, Stefan Vasile, Patrick R. Maloney, Daniela B. Divlianska, Satyamaheshwar Peddibhotla, Camilo J. Morfa, Paul Hershberger, Rebecca Falter, Robert Williamson, David B. Terry, Rafal Farjo, Anthony B. Pinkerton, Xiaping Qi, Judith Quigley, Michael E. Boulton, Maria B. Grant, Layton H. Smith
Review
Pharmacology & Pharmacy
Allison S. Limpert, Lester J. Lambert, Nicole A. Bakas, Nicole Bata, Sonja N. Brun, Reuben J. Shaw, Nicholas D. P. Cosford
TRENDS IN PHARMACOLOGICAL SCIENCES
(2018)
Article
Biochemistry & Molecular Biology
Apirat Chaikuad, Sebastian E. Koschade, Alexandra Stolz, Katarina Zivkovic, Christian Pohl, Shabnam Shaid, Huiyu Ren, Lester J. Lambert, Nicholas D. P. Cosford, Christian H. Brandts, Stefan Knapp
BIOCHEMICAL JOURNAL
(2019)
Article
Chemistry, Medicinal
Anthony B. Pinkerton, Satyamaheshwar Peddibhotla, Fusayo Yamamoto, Lauren M. Slosky, Yushi Bai, Patrick Maloney, Paul Hershberger, Michael P. Hedrick, Bekhi Falter, Robert J. Ardecky, Layton H. Smith, Thomas D. Y. Chung, Michael R. Jackson, Marc G. Caron, Lawrence S. Barak
JOURNAL OF MEDICINAL CHEMISTRY
(2019)
Article
Chemistry, Medicinal
Satyamaheshwar Peddibhotla, Paul M. Hershberger, R. Jason Kirby, Eliot Sugarman, Patrick R. Maloney, E. Hampton Sessions, Daniela Divlianska, Camilo J. Morfa, David Terry, Anthony B. Pinkerton, Layton H. Smith, Siobhan Malany
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2020)
Article
Biochemistry & Molecular Biology
Nicholas Pagano, Peter Teriete, Margrith E. Mattmann, Li Yang, Beth A. Snyder, Zhaohui Cai, Marintha L. Heil, Nicholas D. P. Cosford
BIOORGANIC & MEDICINAL CHEMISTRY
(2017)
Article
Biochemistry & Molecular Biology
Russell Dahl
BIOORGANIC & MEDICINAL CHEMISTRY
(2017)