☆ 4.7 Article

Discovery of a Novel Class of Highly Potent, Selective, ATP-Competitive, and Orally Bioavailable Inhibitors of the Mammalian Target of Rapamycin (mTOR)

JOURNAL OF MEDICINAL CHEMISTRY (2013)

Journal

JOURNAL OF MEDICINAL CHEMISTRY

Volume 56, Issue 6, Pages 2218-2234

Publisher

AMER CHEMICAL SOC

DOI: 10.1021/jm3007933

Keywords

-

Categories

Chemistry, Medicinal

Ask authors/readers for more resources

Protocol

Community support

Reagent

Community support

Abstract

A series of novel, highly potent, selective, and ATP-competitive mammalian target of rapamycin (mTOR) inhibitors based on a benzoxazepine scaffold have been identified. Lead optimization resulted in the discovery of inhibitors with low nanomolar activity and greater than 1000-fold selectivity over the closely related PI3K kinases. Compound 28 (XL388) inhibited cellular phosphorylation of mTOR complex 1 (p-p70S6K, pS6, and p-4E-BP1) and mTOR complex 2 (pAKT (S473)) substrates. Furthermore, this compound displayed good pharmacokinetics and oral exposure in multiple species with moderate bioavailability. Oral administration of compound 28 to athymic nude mice implanted with human tumor xenografts afforded significant and dose-dependent antitumor activity.

Authors

I am an author on this paper

Click your name to claim this paper and add it to your profile.

Reviews

Primary Rating

4.7

Not enough ratings

Secondary Ratings

Novelty

-

Significance

-

Scientific rigor

-

Rate this paper

Recommended

Article Chemistry, Medicinal

Discovery of a Potent and Orally Bioavailable Melatonin Receptor Agonist

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)

Add to Collection

Article Chemistry, Medicinal

Discovery of a Pyrimidinedione Derivative as a Potent and Orally Bioavailable Axl Inhibitor

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)

Add to Collection

Article Chemistry, Medicinal

Discovery of 3-Aminopyrazole Derivatives as New Potent and Orally Bioavailable AXL Inhibitors

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)

Add to Collection

Article Chemistry, Medicinal

Discovery of CH7057288 as an Orally Bioavailable, Selective, and Potent pan-TRK Inhibitor

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)

Add to Collection

Article Chemistry, Medicinal

Discovery of Orally Bioavailable and Brain-Penetrable Prodrugs of the Potent nSMase2 Inhibitor DPTIP

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)

Add to Collection

Article Chemistry, Medicinal

From PROTAC to inhibitor: Structure-guided discovery of potent and orally bioavailable BET inhibitors

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)

Add to Collection

Article Chemistry, Medicinal

Discovery of a Potent and Orally Bioavailable Zwitterionic Series of Selective Estrogen Receptor Degrader-Antagonists

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)

Add to Collection

Article Chemistry, Medicinal

Discovery of a Highly Potent and Orally Bioavailable STAT3 Dual Phosphorylation Inhibitor for Pancreatic Cancer Treatment

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)

Add to Collection

Article Chemistry, Medicinal

Discovery of Potent Orally Bioavailable WD Repeat Domain 5(WDR5) Inhibitors Using a Pharmacophore-Based Optimization

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)

Add to Collection

Article Chemistry, Medicinal

Discovery of New 4-Indolyl Quinazoline Derivatives as Highly Potent and Orally Bioavailable P-Glycoprotein Inhibitors

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)

Add to Collection

Article Biochemistry & Molecular Biology

Discovery and optimization of orally bioavailable and potent plasma Kallikrein inhibitors bearing a quaternary carbon

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)

Add to Collection

Article Chemistry, Medicinal

Synthesis and evaluation of piperazinotriazoles. Discovery of a potent and orally bioavailable neurokinin-3 receptor inhibitor

Liang Ye, Yifei yang, Chunmei Li, Jianzhao Zhang, Wenyan Wang, Mingxu Ma, Hengwei Xu, Wenjing Zhang, Fangxia Zou, Zhengping Hu, Hongbo Wang, Jingwei Tian

Summary: The study found that pharmacological blockade of neurokinin B (NKB) signaling with an oral NK3R antagonist significantly improved hot flash symptoms, suggesting NK3R as a viable drug target. A series of novel imidazolepiperazine derivatives were designed and synthesized, among which compound 16x showed promising inhibitory activity against NK3R. In vivo studies demonstrated that 16x was orally active, efficacious, and well-tolerated in a specific model, indicating its potential for further development.

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY (2023)

Add to Collection

Article Chemistry, Medicinal

Discovery of Potent, Selective, and Orally Bioavailable Small-Molecule Inhibitors of CDK8 for the Treatment of Cancer

Yangguang Li, Yingtao Liu, Jianping Wu, Xiaosong Liu, Lin Wang, Ju Wang, Jiaojiao Yu, Hongyun Qi, Luoheng Qin, Xiao Ding, Feng Ren, Alex Zhavoronkov

Summary: Cyclin-dependent kinase 8 (CDK8), a kinase subunit of the Mediator complex, is involved in regulating RNA polymerase II-mediated transcription and plays a role in oncogenic control. CDK8 deregulation is associated with human diseases, particularly acute myeloid leukemia (AML) and advanced solid tumors. In this study, an azaindole series of CDK8 inhibitors were successfully optimized using a structure-based generative chemistry approach. Compound 23, the most promising inhibitor, demonstrated robust tumor growth inhibition in multiple in vivo models after oral administration.

JOURNAL OF MEDICINAL CHEMISTRY (2023)

Add to Collection

Article Chemistry, Medicinal

Discovery of Pyridinone Derivatives as Potent, Selective, and Orally Bioavailable Adenosine A2A Receptor Antagonists for Cancer Immunotherapy

Chenyu Zhu, Shuyin Ze, Ronghui Zhou, Xinyu Yang, Haojie Wang, Xiaolei Chai, Meimiao Fang, Mingyao Liu, Yonghui Wang, Weiqiang Lu, Qiong Xie

Summary: Recent studies and clinical evidence have shown that adenosine A2A receptor (A2AR) antagonists have great potential in cancer immunotherapy. Through screening, compound 38, a pyridinone derivative, was identified as a potent A2AR antagonist with good stability and high bioavailability. Furthermore, compound 38 effectively enhanced the activation of T cells in vitro and demonstrated excellent antitumor activity in vivo, making it a promising candidate for cancer immunotherapy.

JOURNAL OF MEDICINAL CHEMISTRY (2023)

Add to Collection

Article Chemistry, Medicinal

Discovery of Pyridinone Derivatives as Potent, Selective, and Orally Bioavailable Adenosine A2A Receptor Antagonists for Cancer Immunotherapy

Chenyu Zhu, Shuyin Ze, Ronghui Zhou, Xinyu Yang, Haojie Wang, Xiaolei Chai, Meimiao Fang, Mingyao Liu, Yonghui Wang, Weiqiang Lu, Qiong Xie

Summary: Recent studies and clinical evidence have shown that adenosine A2A receptor (A2AR) antagonists have great potential as novel approaches for cancer immunotherapy. Through the screening of a compound library, a pyridinone hit compound with weak A2AR antagonistic activity was identified, and further studies led to the discovery of a series of pyridinone derivatives with strong potency. Compound 38 demonstrated potent A2AR antagonistic activity, good metabolic stability, and excellent oral bioavailability, and also effectively enhanced the activation and killing ability of T cells. In addition, it exhibited excellent in vivo antitumor activity, making it a promising candidate for cancer immunotherapy.

JOURNAL OF MEDICINAL CHEMISTRY (2023)

Add to Collection

No Data Available

No Data Available

© Peeref 2019-2024. All rights reserved.