Article
Biochemistry & Molecular Biology
Willem F. J. Karstens, Wiro M. B. P. Menge, Gijs Martens, Sanne J. N. Op Het Veld, Jacobus Th. H. van Eupen, Marco Demon, Tanja A. E. van Achterberg, Monica J. Arisse-Thijssen, Ellen W. H. Santegoeds-Lenssen, Miranda M. C. van der Lee, Ruud Ubink, Roel J. Arends, Aloys Sesink, Marion Blomenrohr, C. Marco Timmers
Summary: This paper describes the discovery of a novel small molecule TSH-R antagonist, SYD5115 (67), with nanomolar potency. SYD5115 also blocks the synthesis of thyroid hormone T4 induced by stimulating antibodies after a single oral dose. During optimization, issues such as low metabolic stability and potential mutagenicity of the initial compounds had to be addressed.
BIOORGANIC & 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
Obstetrics & Gynecology
Tasuku Harada, Yutaka Osuga, Yusuke Suzuki, Masaki Fujisawa, Motoko Fukui, Jo Kitawaki
Summary: This study evaluated the efficacy and safety of 40-mg relugolix compared with leuprorelin in treating endometriosis-associated pain. The results demonstrated that relugolix was noninferior to leuprorelin in relieving pelvic pain, and both medications had comparable safety profiles.
FERTILITY AND STERILITY
(2022)
Article
Obstetrics & Gynecology
Yutaka Osuga, Yoshifumi Seki, Masataka Tanimoto, Takeru Kusumoto, Kentarou Kudou, Naoki Terakawa
Summary: This study evaluated the efficacy and safety of relugolix in treating endometriosis-associated pain, showing that oral administration of relugolix alleviated pain in a dose-response manner and was generally well tolerated. Relugolix demonstrated efficacy and safety comparable to leuprorelin, another treatment option.
FERTILITY AND STERILITY
(2021)
Article
Geriatrics & Gerontology
Dorota Walkiewicz, Zofia Wicik, Monika Puzianowska-Kuznicka
Summary: The study identified pathways associated with age-related changes in human B lymphocytes, including the gonadotropin-releasing hormone receptor (GnRHR) pathway, which is involved in both aging and lymphocyte activation. Inhibition of the GnRHR pathway reduced cell proliferation, increased apoptosis, and led to decreased immunoglobulin G synthesis in B lymphocytes, with a more pronounced effect in centenarian cells compared to young cells.
EXPERIMENTAL GERONTOLOGY
(2021)
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)
Article
Chemistry, Medicinal
Michael G. Yang, Zili Xiao, Rulin Zhao, Andrew J. Tebben, Bei Wang, Robert J. Cherney, Douglas G. Batt, Gregory D. Brown, Mary Ellen Cvijic, John Duncia, Michael A. Gallela, Daniel S. Gardner, Purnima Khandelwal, Mary F. Malley, Jian Pang, Anne Rose, Joseph B. Santella, Amy A. Sarjeant, Songmei Xu, Arvind Mathur, Sandhya Mandlekar, Ragini Vuppugalla, Qihong Zhao, Percy H. Carter
Summary: Through a structure-activity relationship study, the discovery of BMS-753426 (2d) as a potent CCR2 antagonist was made, showing significant improvements in pharmacokinetic properties compared to the previous clinical candidate la, and exhibiting good activity in a multiple sclerosis model.
ACS MEDICINAL CHEMISTRY LETTERS
(2021)
Article
Pharmacology & Pharmacy
Susan J. Keam
Summary: Linzagolix is an orally administered drug developed for the treatment of uterine fibroids and endometriosis, with approval in the EU and undergoing regulatory review in the USA.
Article
Pharmacology & Pharmacy
Motohiro Tezuka, Yasuaki Tamai, Yu Kuramochi, Kaoru Kobayashi, Nobuhiko Fushimi, Sumiyoshi Kiguchi
Summary: Control of GnRH signaling is effective for treating sex hormone-dependent diseases. Linzagolix, a potent and selective GnRH antagonist, inhibits GnRH-stimulated signaling and suppresses hormone activity in animal models, making it a potential treatment for reproductive-age women suffering from such diseases.
CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY
(2022)
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
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
Biochemistry & Molecular Biology
Douglas L. Orsi, Steven J. Ferrara, Stephan Siegel, Anders Friberg, Lea Bouche, Elisabeth Pook, Philip Lienau, Joseph P. Bluck, Christopher T. Lemke, Gizem Akcay, Timo Stellfeld, Hanna Meyer, Vera Puetter, Simon J. Holton, Daniel Korr, Isabel Jerchel-Furau, Constantia Pantelidou, Craig A. Strathdee, Matthew Meyerson, Knut Eis, Jonathan T. Goldstein
Summary: PPAR gamma (PPARG) is a ligand activated transcription factor that regulates genes involved in various biological processes. Inverse agonists of PPARG offer a potential avenue to modulate PPARG biology in vivo, but current inverse agonists lack favorable in vivo properties. The discovery and characterization of a series of orally bioavailable 4-chloro-6-fluoroisophthalamides as covalent PPARG inverse-agonists provide new tools for future studies to explore their potential utility for treatment of disorders related to hyperactivated PPARG.
BIOORGANIC & MEDICINAL CHEMISTRY
(2023)
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
Pharmacology & Pharmacy
Yi Xu, Wei Hu, Jian Li, Xin Jiang, Ping Shi, Kai Shen, Yu Shen, Lingyu Ma, Yu Cao
Summary: This study evaluated the safety, pharmacokinetics, and pharmacodynamics of SHR7280 in healthy premenopausal women. The results showed that SHR7280 had tolerable toxicity, rapid onset of action, and dose-dependent plasma exposure. The pharmacodynamic results demonstrated that SHR7280 effectively suppressed estrogen concentration, inhibited the peak of luteinizing hormone and the concentration of follicle stimulating hormone, and maintained progesterone concentration in an anovulatory state.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Chemistry, Medicinal
Jason R. Zbieg, Jun Liang, Jun Li, Robert A. Blake, Jae Chang, Lori Friedman, Simon Goodacre, Steven J. Hartman, Ellen Rei Ingalla, James R. Kiefer, Tracy Kleinheinz, Sharada Labadie, Tommy Lai, Jiangpeng Liao, Nev McLean, Ciara Metcalfe, Vidhi Mody, Michelle Nannini, Daniel F. Ortwine, Yingqing Ran, Nick Ray, Fabien Roussel, Amy Sambrone, Deepak Sampath, Maia Vinogradova, John Wai, Tao Wang, Kuen Yeap, Birong Zhang, Xiaoping Zheng, Yu Zhong, Xiaojing Wang
Summary: Researchers aimed to develop an orally bioavailable drug with a dual mechanism of action similar to Fulvestrant, in order to overcome the limitations of intramuscular injections required for Fulvestrant dosing. They made progress and developed a new lead compound, GNE-502, which addressed some of the issues with the previously reported GNE-149.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2021)
Article
Biochemistry & Molecular Biology
Ho Yeon Nam, Dasom Song, Jinny Eo, Na-Eun Choi, Jong-Ah Hong, Kyung Tae Hong, Jun-Seok Lee, Jiwon Seo, Jiyoun Lee
ACS CHEMICAL BIOLOGY
(2020)
Article
Biochemistry & Molecular Biology
Ha-Rim Lee, Jihyae Ann, Young Min Kim, Jeewoo Lee, Hyun-Jung Kim
Summary: Members of the KDM5/JARID1 family have been found to be crucial in determining the fate of stem cells, with KDM5 inhibitor C70 (KDM5-C70) showing that the demethylase activity of KDM5 is essential in repressing astrocytic differentiation of neural stem cells (NSCs). Treatment with KDM5-C70 activated the Gfap gene and JAK-STAT3 signaling pathway, leading to astrocytogenesis in NSCs. This study provides evidence that KDM5 is a promising target for modulating NSC fate and highlights the importance of epigenetic regulation in determining NSC fate.
ACS CHEMICAL NEUROSCIENCE
(2021)
Article
Chemistry, Medicinal
Shivaji A. Thorat, Yoonji Lee, Aeran Jung, Jihyae Ann, Songyeon Ahn, Jisoo Baek, Dongxu Zuo, Nayeon Do, Jin Ju Jeong, Peter M. Blumberg, Timothy E. Esch, Noe A. Turcios, Larry Pearce, Hee-Jin Ha, Young Dong Yoo, Sunhye Hong, Sun Choi, Jeewoo Lee
Summary: Among benzopyridone-based scaffolds investigated as TRPV1 ligands, two isomeric scaffolds displayed distinct functional profiles - one with high affinity and potent antagonism, the other with full agonism. Computational models suggest the importance of the Arg557 residue in sensing agonist binding and signal transmission. These findings offer structural insights into TRPV1 and protein-ligand interactions at a molecular level.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Review
Biochemistry & Molecular Biology
Na-Eun Choi, Ji-Yu Lee, Eun-Chae Park, Ju-Hee Lee, Jiyoun Lee
Summary: This review summarizes the recent reports on organelle-targeted fluorescent probes, evaluating their strategies and structural features based on their target organelles. The article discusses the advantages of the currently used probes, the potential challenges in their application, and future directions for development.
Article
Chemistry, Medicinal
Juyoung Jung, Hongchul Yoon, Te-ik Sohn, Kyusic Jang, Yeongran Yoo, Ilji Jeong, Jae Eui Shin, Jin Hee Lee, Jihyae Ann, Jeewoo Lee
Summary: Through a structure-activity relationship study, the N-3-bromophenyl derivative 19 was identified as the most potent inhibitor of IDO1, with an IC50 value of 0.44 μM. Molecular modeling revealed that interactions with heme iron, halogen bonding with Cys129, and hydrophobic interactions were crucial for the high potency of compound 19.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2021)
Article
Chemistry, Medicinal
Cong-Truong Nguyen, Minh Thanh La, Jihyae Ann, Gibeom Nam, Hyun-Ju Park, Jung Min Park, Yoon-Jae Kim, Ji Young Kim, Jae Hong Seo, Jeewoo Lee
Summary: The investigation showed that compound 37, designed as a HSP90 C-terminal inhibitor, displayed significant antitumor activity against HER2-positive breast cancer cells by destabilizing and inactivating HSP90 client proteins through binding to the C-terminal domain of HSP90.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2021)
Article
Chemistry, Medicinal
Jin Mi Kang, Sun Ok Kwon, Jihyae Ann, Sunho Lee, Changhoon Kim, Nayeon Do, Jin Ju Jeong, Peter M. Blumberg, Heejin Ha, Thi Ngoc Lan Vu, Sanghee Yoon, Sun Choi, Robert Frank-Foltyn, Bernhard Lesch, Gregor Bahrenberg, Hannelore Stockhausen, Thomas Christoph, Jeewoo Lee
Summary: The series of 117 2-(halogenated phenyl) acetamide and propanamide analogs were investigated as TRPV1 antagonists, with halogenated phenyl A-region analogs showing a broad functional profile. Antagonists 28 and 92 exhibited potent antagonism against capsaicin for hTRPV1, with antagonist 92 displaying promising analgesic activity in vivo. Molecular modeling of compound 92 suggested that the two fluoro groups in the A-region interacted hydrophobically with the receptor.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2021)
Article
Biochemistry & Molecular Biology
Soyoung Kim, Ji-Yu Lee, Jieun Choi, Ho Yeon Nam, Jiwon Seo, Jiyoun Lee
Summary: Two types of mitochondria-targeted delivery methods are discussed in the text. Peptoids, biocompatible peptidomimetics, may have potential applications in various fields such as anti-cancer or antibacterial activity. Increasing hydrophobicity did not enhance mitochondrial localization, while a positive net charge was crucial for the process.
Article
Chemistry, Medicinal
Nguyen Van Manh, Van-Hai Hoang, Van T. H. Ngo, Jihyae Ann, Tae-Ho Jang, Jung-Hye Ha, Jae Young Song, Hee-Jin Ha, Hee Kim, Young-Ho Kim, Jiyoun Lee, Jeewoo Lee
Summary: Inhibition of glutaminyl cyclase (QC) shows promise in treating early Alzheimer's disease by reducing toxic beta-amyloid in patients' brains. Among the tested compounds, one derivative (227) exhibited strong in vivo efficacy and may provide a potential therapeutic option for early-stage AD treatment. This study suggests small molecule-based QC inhibitors could be a viable approach for AD therapy.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Cell Biology
Soeun Park, Yoon-Jae Kim, Jung Min Park, Minsu Park, Kee Dal Nam, Lee Farrand, Cong-Truong Nguyen, Minh Thanh La, Jihyae Ann, Jeewoo Lee, Ji Young Kim, Jae Hong Seo
Summary: NCT-58, a C-terminal HSP90 inhibitor, kills trastuzumab-resistant HER2-positive breast cancer stem-like cells by downregulating HER family members and inhibiting Akt phosphorylation, without inducing heat shock response. The treatment also suppresses tumor growth and angiogenesis in a trastuzumab-resistant xenograft model by downregulating ICD-HER2 and HSF-1/HSP70/HSP90.
CELL DEATH DISCOVERY
(2021)
Article
Multidisciplinary Sciences
Sachin S. Katti, Inna Krieger, Jihyae Ann, Jeewoo Lee, James C. Sacchettini, Tatyana I. Igumenova
Summary: This study reveals the structures of C1 domain complexes with DAG and agonists, providing insights into the mechanisms of DAG recognition and capture by C1 domains in the complex environment of a biological membrane. The findings offer guidance for the design of agents that modulate the activities of DAG effector proteins.
NATURE COMMUNICATIONS
(2022)
Article
Chemistry, Medicinal
Juyoung Jung, Yoonsuk Lee, An-Na Moon, Jihyae Ann, Jin Ju Jeong, Nayeon Do, Jeewoo Lee
Summary: This study synthesized new compounds and discovered one compound with potential for treating Parkinson's disease, showing good pharmacokinetic properties and low safety risk in vivo.
Article
Chemistry, Medicinal
Dasom Song, Ji-Yu Lee, Eun-Chae Park, Na-Eun Choi, Ho-Yeon Nam, Jiwon Seo, Jiyoun Lee
Summary: HTRA is a serine protease that participates in protein quality control and cellular stress responses, and is associated with several clinical disorders. Recent studies have identified HTRA as an important biomarker and potential therapeutic target, necessitating the development of an effective detection method. We have developed a series of HTRA-targeting activity-based probes with enhanced subtype selectivity and reactivity. These probes are cell-permeable and inhibit HTRA1 and HTRA2, making them valuable for identifying and validating HTRAs as important biomarkers.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2023)
Article
Biochemistry & Molecular Biology
Jung-Eun Park, Jiyoun Lee, Soonhyuck Ok, Seunghee Byun, Eun-Ju Chang, Sung-Eun Yoon, Young-Joon Kim, Min-Ji Kang
Summary: A study with a Drosophila model of autosomal dominant retinitis pigmentosa (ADRP) identified the Wg/Wnt1 signaling pathway and ER stress-associated serine protease (Erasp) as important regulators of apoptosis induced by ER stress. Knocking down Erasp suppressed apoptosis and alleviated retinal degeneration, while overexpression of Erasp enhanced caspase activity. These findings provide insights into the mechanism of retinal degeneration in ADRP.
EXPERIMENTAL AND MOLECULAR MEDICINE
(2023)
Article
Chemistry, Multidisciplinary
Na-Eun Choi, Eun-Ji Kim, Jiyoun Lee
Summary: Efficient techniques for developing latent fingerprints are crucial for solving crimes. In this study, we developed a fluorescent molecular rotor probe that can visualize latent fingerprints with detailed information. We believe that the simple and convenient features of the LFP-1 will benefit forensic practice.
