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
Yasutaka Hoashi, Takafumi Takai, Yohei Kosugi, Masato Nakashima, Masaharu Nakayama, Keisuke Hirai, Osamu Uchikawa, Tatsuki Koike
Summary: A novel series of 5-6-5 tricyclic derivatives were designed, synthesized, and evaluated as potent and orally bioavailable melatonin receptor agonists. Among these derivatives, (S)-3b showed potent binding affinity for MT1/MT2 receptors, good metabolic stability, and BBB permeability in rats, exhibiting in vivo pharmacological effects by promoting sleep in cats.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
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
Peng He, Aiwu Bian, Ying Miao, Wangrui Jin, Huang Chen, Jia He, Liting Li, Yue Sun, Jiangnan Ye, Zhengfang Yi, Wenbo Zhou, Yihua Chen
Summary: This study reports the discovery of a series of novel STAT3 dual phosphorylation inhibitors with an indole-containing tetra-aromatic heterocycle scaffold. The optimal compound 4c showed desirable ADME properties and highly potent antitumor activities in vitro and in vivo. It has the potential to be a useful treatment option for pancreatic cancer as a STAT3 dual phosphorylation inhibitor.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
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
Chemistry, Medicinal
Hefeng Zhang, Xia Peng, Yang Dai, Jingwei Shao, Yinchun Ji, Yiming Sun, Bo Liu, Xu Cheng, Jing Ai, Wenhu Duan
Summary: Compound 13c is a highly potent and orally bioavailable Axl inhibitor, showing inhibition of both Axl superfamily kinases and the oncogenic kinase Met. It exhibits significant antitumor efficacy in Axl-driven and Met-driven tumor models, making it a promising therapeutic candidate for cancer treatment.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Shingpan Chan, Yunong Zhang, Jie Wang, Qiuchun Yu, Xia Peng, Jian Zou, Licheng Zhou, Li Tan, Yunxin Duan, Yang Zhou, Hoon Hur, Jing Ai, Zhen Wang, Xiaomei Ren, Zhang Zhang, Ke Ding
Summary: The study describes the discovery of 3-aminopyrazole derivatives as potent and selective AXL kinase inhibitors. One representative compound, 6li, showed strong inhibitory activity against AXL enzymatic activity and demonstrated significant antitumor efficacy in vitro and in vivo.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Toshiya Ito, Kazutomo Kinoshita, Masaki Tomizawa, Shojiro Shinohara, Hiroki Nishii, Masayuki Matsushita, Kazuo Hattori, Yasunori Kohchi, Masami Kohchi, Tadakatsu Hayase, Fumio Watanabe, Kiyoshi Hasegawa, Hiroshi Tanaka, Shino Kuramoto, Kenji Takanashi, Nobuhiro Oikawa
Summary: In this study, chemical modification was employed to improve TRK inhibition and a potent inhibitor was identified.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Arindom Pal, Sadakatali Gori, Seung-wan Yoo, Ajit G. Thomas, Ying Wu, Jacob Friedman, Lukas Tenora, Harshit Bhasin, Jesse Alt, Norman Haughey, Barbara S. Slusher, Rana Rais
Summary: Extracellular vesicles (EVs) can carry pathological cargo and play an active role in disease progression. A series of prodrugs have been synthesized to overcome the poor oral pharmacokinetics (PK) of the potent nSMase2 inhibitor DPTIP, leading to the discovery of a potential DPTIP prodrug with clinical translation.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Multidisciplinary
Xingui Liu, Alexia F. Kalogeropulou, Sofia Domingos, Nikolai Makukhin, Raja S. Nirujogi, Francois Singh, Natalia Shpiro, Anton Saalfrank, Esther Sammler, Ian G. Ganley, Rui Moreira, Dario R. Alessi, Alessio Ciulli
Summary: This study reports the development of LRRK2 proteolysis targeting chimeras (PROTACs) and the discovery of a degrader XL01126 as an alternative LRRK2-targeting strategy. XL01126 shows fast and potent degradation of LRRK2 in multiple cell lines, high cell permeability, and oral bioavailability, as well as the ability to penetrate the blood-brain barrier in mice.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2022)
Article
Chemistry, Medicinal
James S. Scott, Darren Stead, Bernard Barlaam, Jason Breed, Rodrigo J. Carbajo, Elisabetta Chiarparin, Natalie Cureton, Paul R. J. Davey, David I. Fisher, Eric T. Gangl, Tyler Grebe, Ryan D. Greenwood, Sudhir Hande, Holia Hatoum-Mokdad, Samantha J. Hughes, Thomas A. Hunt, Tony Johnson, Stefan L. Kavanagh, Teresa C. M. Klinowska, Carrie J. B. Larner, Mandy Lawson, Andrew S. Lister, David Longmire, Stacey Marden, Thomas M. McGuire, Caroline McMillan, Lindsay McMurray, Christopher J. Morrow, J. Willem M. Nissink, Thomas A. Moss, Daniel H. O'Donovan, Radoslaw Polanski, Stephen Stokes, Kumar Thakur, Dawn Trueman, Caroline Truman, Michael J. Tucker, Haixia Wang, Nicky Whalley, Dedong Wu, Ye Wu, Bin Yang, Wenzhan Yang
Summary: In this study, we optimized a series of selective estrogen receptor degrader (SERD) antagonists for the treatment of ER+ breast cancer. Through structure-based design and the use of modeling and NMR, we obtained a highly potent series of basic SERDs with promising physicochemical properties. By forming a zwitterion, we successfully eliminated hERG activity and identified compound 38 as a highly potent SERD capable of effectively degrading ER alpha.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Review
Pharmacology & Pharmacy
Andrew Morris, Piyusha P. Pagare, Jiong Li, Yan Zhang
Summary: The Wnt/8-β-catenin pathway plays a crucial role in cancer treatment, but developing small-molecule inhibitors through traditional methods has proven difficult. Computer-aided drug discovery efforts have shown promise, and a more efficient and cost-effective approach to developing inhibitors for this pathway is needed.
DRUG DISCOVERY TODAY
(2022)
Article
Chemistry, Medicinal
Kevin B. Teuscher, Kenneth M. Meyers, Qiangqiang Wei, Jonathan J. Mills, Jianhua Tian, Joseph Alvarado, Jiqing Sai, Mayme Van Meveren, Taylor M. South, Tyson A. Rietz, Bin Zhao, William J. Moore, Gordon M. Stott, William P. Tansey, Taekyu Lee, Stephen W. Fesik
Summary: The study successfully optimized the drug structure of WDR5, improving its druglike properties and pharmacokinetic profile. A new series of compounds with strong binding affinity and high selectivity were generated, serving as useful tools for WDR5 inhibition research.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Shuo Yuan, Bo Wang, Qing-Qing Dai, Xiao-Nan Zhang, Jing-Ya Zhang, Jia-Hui Zuo, Hui Liu, Zhe-Sheng Chen, Guo-Bo Li, Shaomeng Wang, Hong-Min Liu, Bin Yu
Summary: YS-370 is a highly effective P-gp inhibitor capable of reversing multidrug resistance and achieving good results when administered orally. The inhibitor does not alter the expression or subcellular localization of P-gp, but increases the intracellular accumulation of drugs.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
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)
Article
Oncology
Elizabeth A. Coker, Adam Stewart, Bugra Ozer, Anna Minchom, Lisa Pickard, Ruth Ruddle, Suzanne Carreira, Sanjay Popat, Mary O'Brien, Florence Raynaud, Johann de Bono, Bissan Al-Lazikani, Udai Banerji
Summary: The study demonstrates that acute protein perturbation caused by targeted anticancer drugs can be used to predict drug sensitivity and rational combination therapy. Machine-learning approaches show better prediction results compared to mutation-based methods. These findings have implications for treatment selection in the clinic.
MOLECULAR CANCER THERAPEUTICS
(2022)
Editorial Material
Genetics & Heredity
Segun Fatumo, Aminu Yakubu, Olubukunola Oyedele, Jumi Popoola, Delali Attiogbe Attipoe, Golibe Eze-Echesi, Fatima Z. Modibbo, Nabila Ado-Wanka, Omolola Salako, Oyekanmi Nashiru, Babatunde L. Salako, Colm O'Dushlaine, Abasi Ene-Obong
Summary: The Non-Communicable Diseases Genetic Heritage Study (NCD-GHS) consortium was established to create a comprehensive catalog of human genetic variation in Nigeria and analyze the burden and etiological characteristics of non-communicable diseases in 100,000 adults.
Meeting Abstract
Oncology
C. Guo, A. Sharp, U. Vogl, I. Colombo, A. Stathis, S. Jain, K. Chandran, C. Tiu, A. Paschalis, R. E. Matthews, I. Figueiredo, J. Rekowski, C. Yap, M. de los Dolores Fenor de la Maza, A. Turner, H. C. Badham, M. Parmar, F. Raynaud, A. Alimonti, J. S. de Bono
ANNALS OF ONCOLOGY
(2022)
Article
Oncology
Susana Banerjee, Vasiliki Michalarea, Joo Ern Ang, Alvaro Ingles Garces, Andrea Biondo, Ionut-Gabriel Funingana, Martin Little, Ruth Ruddle, Florence Raynaud, Ruth Riisnaes, Bora Gurel, Sue Chua, Nina Tunariu, Joanna C. Porter, Toby Prout, Mona Parmar, Anna Zachariou, Alison Turner, Ben Jenkins, Stuart McIntosh, Ed Ainscow, Anna Minchom, Juanita Lopez, Johann de Bono, Robert Jones, Emma Hall, Natalie Cook, Bristi Basu, Udai Banerji
Summary: CT900 is a novel small molecule inhibitor that selectively targets α-folate receptor overexpressing tumors. A dose of 12 mg/m2 every 2 weeks was found to be well-tolerated and showed clinical benefit in patients with high/medium α-FR expression.
CLINICAL CANCER RESEARCH
(2022)
Article
Multidisciplinary Sciences
Olivier A. Pierrat, Manjuan Liu, Gavin W. Collie, Kartika Shetty, Matthew J. Rodrigues, Yann-Vai Le Bihan, Emma A. Gunnell, P. Craig McAndrew, Mark Stubbs, Martin G. Rowlands, Norhakim Yahya, Erald Shehu, Rachel Talbot, Lisa Pickard, Benjamin R. Bellenie, Kwai-Ming J. Cheung, Ludovic Drouin, Paolo Innocenti, Hannah Woodward, Owen A. Davis, Matthew G. Lloyd, Ana Varela, Rosemary Huckvale, Fabio Broccatelli, Michael Carter, David Galiwango, Angela Hayes, Florence Raynaud, Christopher Bryant, Steven Whittaker, Olivia W. Rossanese, Swen Hoelder, Rosemary Burke, Rob L. M. van Montfort
Summary: By recruiting corepressor proteins, B-cell lymphoma 6 (BCL6) protein controls gene transcription required for B-cell germinal center formation. This study aims to discover small molecule inhibitors that disrupt BCL6-corepressor protein interaction, as BCL6 deregulation is implicated in Diffuse Large B-Cell Lymphoma development. The researchers used high throughput screening and various assays to identify hit series, determined X-ray structures of BCL6 bound to compounds, and developed biochemical and cellular assays to optimize compound potency.
SCIENTIFIC REPORTS
(2022)
Article
Cell Biology
Afia Naseem, Akos Pal, Sharon Gowan, Yasmin Asad, Adam Donovan, Csilla Temesszentandrasi-Ambrus, Emese Kis, Zsuzsanna Gaborik, Gurdip Bhalay, Florence Raynaud
Summary: In this study, we used Caco-2 cell screening and targeted LC-MS to identify endogenous metabolites of P-gp, BCRP, and MRP2, and created a scoring system to differentiate among these three transporters. Network analysis revealed changes in enzymes involved in one-carbon metabolism that are associated with the inhibition of these transporters.
Meeting Abstract
Hematology
Sarah A. Bird, Amy Barber, Fernando J. Sialana, Marco P. Licciardello, Harvey Che, Habib Bouguenina, Yura Grabovska, Enze Liu, Yakinthi Chrisochoidou, Shannon Martin, Jyoti Choudhary, Brian A. Walker, Ian Collins, Paul Clarke, Charlotte Pawlyn
Article
Biochemical Research Methods
Rahul S. Samant, Silvia Batista, Mark Larance, Bugra Ozer, Christopher I. Milton, Isabell Bludau, Estelle Wu, Laura Biggins, Simon Andrews, Alexia Hervieu, Harvey E. Johnston, Bissan Al-Lazikhani, Angus I. Lamond, Paul A. Clarke, Paul Workman
Summary: The molecular chaperone HSP90 plays a role in stabilizing client proteins involved in oncogenesis and malignant progression. Inhibitors of HSP90 have diverse effects on the proteome, but previous studies have mainly focused on total protein levels rather than protein complex alterations. This study used SEC-MS to characterize early changes in native protein complexes after treatment with the HSP90 inhibitor tanespimycin in colon adenocarcinoma cells. The study identified novel HSP90 inhibitor-modulated proteins and provides a resource for further research in HSP90 pharmacology. The data is available via ProteomeXchange (identifier: PXD033459).
MOLECULAR & CELLULAR PROTEOMICS
(2023)
Article
Chemistry, Medicinal
Alice C. Harnden, Owen A. Davis, Gary M. Box, Angela Hayes, Louise D. Johnson, Alan T. Henley, Alexis K. de Haven Brandon, Melanie Valenti, Kwai-Ming J. Cheung, Alfie Brennan, Rosemary Huckvale, Olivier A. Pierrat, Rachel Talbot, Michael D. Bright, Hafize Aysin Akpinar, Daniel S. J. Miller, Dalia Tarantino, Sharon Gowan, Selby de Klerk, Peter Craig McAndrew, Yann-Vai Le Bihan, Mirco Meniconi, Rosemary Burke, Vladimir Kirkin, Rob L. M. van Montfort, Florence I. Raynaud, Olivia W. Rossanese, Benjamin R. Bellenie, Swen Hoelder
Summary: In this study, we optimized our previously reported tricyclic quinolinone series to improve the cellular potency and in vivo exposure of the non-degrading isomer, leading to the discovery of a potent BCL6 inhibitor, CCT374705, with good in vivo profile.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
A. Elisa Pasqua, Swee Y. Sharp, Nicola E. A. Chessum, Angela Hayes, Loredana Pellegrino, Michael J. Tucker, Asadh Miah, Birgit Wilding, Lindsay E. Evans, Carl S. Rye, N. Yi Mok, Manjuan Liu, Alan T. Henley, Sharon Gowan, Emmanuel De Billy, Robert te Poele, Marissa Powers, Suzanne A. Eccles, Paul A. Clarke, Florence I. Raynaud, Paul Workman, Keith Jones, Matthew D. Cheeseman
Summary: CCT251236, a potent chemical probe, was developed through a cell-based high-throughput screen to discover inhibitors of the transcription factor HSF1 that supports malignancy. The compound was optimized to mitigate P-glycoprotein efflux and eventually led to the design of a clinical candidate, CCT361814/NXP800 22, which demonstrated tumor regression in a human ovarian adenocarcinoma xenograft model. It has now progressed to phase 1 clinical trial as a potential treatment for refractory ovarian cancer and other malignancies.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Multidisciplinary Sciences
Tom Woelders, Victoria L. Revell, Benita Middleton, Katrin Ackermann, Manfred Kayser, Florence I. Raynaud, Debra J. Skene, Roelof A. Hut
Summary: Circadian rhythms have a significant impact on the human body, and estimating individual body time is crucial for optimizing behavior and for treating circadian rhythm disorders. This study presents a machine learning approach using plasma-derived metabolomics data to estimate circadian phase, which shows promising results compared to existing methods. Further validation is needed, but this technique has the potential to contribute to personalized optimization of behavior and clinical treatment.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Multidisciplinary Sciences
Christina Guo, Adam Sharp, Bora Gurel, Mateus Crespo, Ines Figueiredo, Suneil Jain, Ursula Vogl, Jan Rekowski, Mahtab Rouhifard, Lewis Gallagher, Wei Yuan, Suzanne Carreira, Khobe Chandran, Alec Paschalis, Ilaria Colombo, Anastasios Stathis, Claudia Bertan, George Seed, Jane Goodall, Florence Raynaud, Ruth Ruddle, Karen E. Swales, Jason Malia, Denisa Bogdan, Crescens Tiu, Reece Caldwell, Caterina Aversa, Ana Ferreira, Antje Neeb, Nina Tunariu, Daniel Westaby, Juliet Carmichael, Maria Dolores Fenor de la Maza, Christina Yap, Ruth Matthews, Hannah Badham, Toby Prout, Alison Turner, Mona Parmar, Holly Tovey, Ruth Riisnaes, Penny Flohr, Jesus Gil, David Waugh, Shaun Decordova, Anna Schlag, Bianca Cali, Andrea Alimonti, Johann S. de Bono
Summary: This study demonstrates the significance of myeloid inflammatory cells in driving disease progression and treatment resistance in prostate cancer, and proves that targeting these cells can be an effective therapeutic approach.
Article
Multidisciplinary Sciences
Habib Bouguenina, Stephanos Nicolaou, Yann-Vai Le Bihan, Elizabeth A. Bowling, Cheyenne Calderon, John J. Caldwell, Brinley Harrington, Angela Hayes, P. Craig Mcandrew, Costas Mitsopoulos, Fernando Jr Sialana, Andrea Scarpino, Mark Stubbs, Arjun Thapaliya, Siddhartha Tyagi, Hannah Z. Wang, Francesca Wood, Rosemary Burke, Florence Raynaud, Jyoti Choudhary, Rob L. M. van Montfort, Amine Sadok, Thomas F. Westbrook, Ian Collins, Rajesh Chopra
Summary: To address the limitations of degron-based systems, the iTAG synthetic tag has been developed based on the mechanism of action of IMiDs/CELMoDs. It improves on both PROTAC and previous IMiDs/CeLMoDs-based tags. Through analysis, an optimal chimeric iTAG (DCD23 60aa) has been identified, which robustly degrades targets in various cell types without the "hook effect" of PROTAC-based systems. The iTAG system is a versatile tool for degrading targets across the human and murine proteome.
Meeting Abstract
Oncology
P. Workman, P. A. Clarke, R. Te Poele, M. Powers, G. Box, E. De Billy, A. De Haven Brandon, A. Hallsworth, A. Hayes, H. McCann, S. Sharp, M. Valenti, F. I. Raynaud, S. A. Eccles, M. Cheeseman, K. Jones
EUROPEAN JOURNAL OF CANCER
(2022)