Article
Chemistry, Medicinal
Menglan Luo, Qian Wu, Yueyue Yang, Lin Sun, Xiajuan Huan, Changqing Tian, Bing Xiong, Zehong Miao, Yingqing Wang, Danqi Chen
Summary: Bromodomain and extraterminal domain (BET) subfamily members are potential targets for cancer treatment. This study presents a series of novel bivalent inhibitors with short and hydrophilic linkers, which exhibit improved activities and pharmacokinetic properties.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Ryutaro Kanada, Yoshiko Kagoshima, Takashi Suzuki, Akifumi Nakamura, Hideaki Funami, Jun Watanabe, Masayoshi Asano, Mizuki Takahashi, Osamu Ubukata, Kanae Suzuki, Tomoya Aikawa, Kazumi Sato, Megumi Goto, Genzui Setsu, Kentaro Ito, Kawori Kihara, Mutsumi Kuroha, Takashi Kohno, Hideaki Ogiwara, Takeshi Isoyama, Yuichi Tominaga, Saito Higuchi, Hiroyuki Naito
Summary: In this study, a novel, potent, and selective EP300/CBP HAT inhibitor DS-9300 was identified, which effectively inhibits the acetylation of histone H3K27 and shows significant antitumor effects in a mouse model.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Junius Eugene Thomas, Mi Wang, Wei Jiang, Meilin Wang, Lu Wang, Bo Wen, Duxin Sun, Shaomeng Wang
Summary: The study describes the design, synthesis, and evaluation of potent PROTAC degraders (JET-209) targeting the transcriptional coactivators CBP and p300. JET-209 achieved high degradation potency for CBP and p300 in leukemia cell lines and demonstrated inhibition of tumor growth in xenograft models. JET-209 shows promise as a lead compound for developing CBP/p300 degraders for cancer treatment.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Natsuki Imayoshi, Makoto Yoshioka, Kuniaki Tanaka, Shyh-Ming Yang, Koshi Akahane, Yuki Toda, Shigekuni Hosogi, Takeshi Inukai, Seiji Okada, David J. Maloney, Tatsutoshi Nakahata, Junko Takita, Itaru Kato, Eishi Ashihara
Summary: This study demonstrates that the BET/CBP/p300 multi-bromodomain inhibitor, CN470, has anti-tumor activity against MLL-r ALL by inhibiting cell growth, inducing apoptosis, and showing potential therapeutic advantages.
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
(2022)
Article
Chemistry, Medicinal
Anthony Mastracchio, Chunqiu Lai, Enrico Digiammarino, Damien B. Ready, Loren M. Lasko, Kenneth D. Bromberg, William J. McClellan, Debra Montgomery, Vlasios Manaves, Bailin Shaw, Mikkel Algire, Melanie J. Patterson, Chaohong C. Sun, Saul Rosenberg, Albert Lai, Michael R. Michaelides
Summary: The development of a covalent inhibitor targeting p300/CBP has been reported in this study, demonstrating selective binding to C1450. Mass spectrometry and kinetics experiments were used to confirm the covalent binding of the inhibitor, providing a unique tool for studying p300/CBP biology.
ACS MEDICINAL CHEMISTRY LETTERS
(2021)
Article
Biochemistry & Molecular Biology
Hong Ding, Yuan Pei, Yuanqing Li, Wen Xu, Lianghe Mei, Zeng Hou, Yiman Guang, Liyuan Cao, Peizhuo Li, Haijing Cao, Jinlei Bian, Kaixian Chen, Cheng Luo, Bing Zhou, Ting Zhang, Zhiyu Li, Yaxi Yang
Summary: This study modified the p300/CBP HAT domain inhibitor and obtained a highly active small molecule that showed significant anti-proliferation activity on ovarian cancer cells. The discovery provides a novel idea for the application of epigenetic inhibitors in the treatment of ovarian cancer.
BIOORGANIC & MEDICINAL CHEMISTRY
(2021)
Article
Multidisciplinary Sciences
Kee-Beom Kim, Ashish Kabra, Dong-Wook Kim, Yongming Xue, Yuanjian Huang, Pei-Chi Hou, Yunpeng Zhou, Leilani J. Miranda, Jae-Il Park, Xiaobing Shi, Timothy P. Bender, John H. Bushweller, Kwon-Sik Park
Summary: EP300, an important transcription coactivator in proliferation and differentiation, is frequently mutated in various cancer types. This study found that EP300 mutants without acetyltransferase domain accelerate tumor development in small cell lung cancer (SCLC) mouse models, while complete EP300 knockout suppresses SCLC development and proliferation. The kinase inducible domain-interacting (KIX) domain of EP300, specifically its interaction with transcription factors including MYB, was identified as the determinant of protumorigenic activity. Inhibition of KIX-mediated interactions inhibits SCLC development and cell growth.
Article
Immunology
Shicheng Huo, Xuesong Liu, Shutao Zhang, Zhuocheng Lyu, Jue Zhang, You Wang, Bin'en Nie, Bing Yue
Summary: Our study shows that A-485 has a protective effect in osteoporosis and can inhibit RANKL-induced osteoclast differentiation while reducing the expression of genes associated with osteoporosis. Additionally, A-485 also attenuated OVX-induced bone loss in a mouse model by inhibiting MAPK pathway phosphorylation.
INTERNATIONAL IMMUNOPHARMACOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Xue Zhong, Huiwen Deng, Min Long, Honglu Yin, Qiu Zhong, Shilong Zheng, Tao Gong, Ling He, Guangdi Wang, Qiu Sun
Summary: Berberine was discovered as a potent p300/CBP HAT inhibitor and showed inhibition of tumor growth. Novel analog 5d, derived from berberine, demonstrated high selectivity towards p300/CBP HAT and effectively suppressed tumor growth in animal models. Furthermore, liposomes-encapsulated 5d showed increased inhibition of tumor growth with good absorption properties in vivo.
BIOORGANIC CHEMISTRY
(2023)
Article
Hematology
Katie R. Ryan, Francis Giles, Gareth J. Morgan
Summary: The dual inhibition of BET and CBP/EP300 may have potential therapeutic benefits for patients with MM. The dual inhibitor NEO2734 showed strong anti-tumor activity, independent of a specific MM molecular subgroup, and correlated with c-MYC protein expression levels.
EUROPEAN JOURNAL OF HAEMATOLOGY
(2021)
Article
Multidisciplinary Sciences
Bradley M. Dickson, Ariana Kupai, Robert M. Vaughan, Scott B. Rothbart
Summary: This study introduces a quantitative scale for chromatin immunoprecipitation followed by sequencing (ChIP-seq) called siQ-ChIP, which does not require additional reagents or spike-ins. The authors simplify the calculations for the quantitative scale and introduce a new scheme for generating 'tracks'. They apply siQ-ChIP to analyze p300/CBP inhibition and provide new interpretations of the outcomes.
SCIENTIFIC REPORTS
(2023)
Article
Chemistry, Medicinal
Shenyou Nie, Fangrui Wu, Jingyu Wu, Xin Li, Chao Zhou, Yuan Yao, Yongcheng Song
Summary: Acetylation of histone lysine residues by p300 and CBP plays important roles in gene regulation. Compound 29 is a potential inhibitor of p300 HAT with activity against cancer cells.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Meng Wang, Zhiyuan Chen, Yi Zhang
Summary: Epigenome reprogramming after fertilization is crucial for early embryonic development. The chromatin marker H3K27ac undergoes three waves of global transitions during this process. CBP/p300 acetyltransferase deposits H3K27ac and promotes chromatin opening, while HDAC prevents premature expression of developmental genes.
Article
Pharmacology & Pharmacy
Qian Wu, Dan-Qi Chen, Lin Sun, Xia-Juan Huan, Xu-Bin Bao, Chang-Qing Tian, Jianping Hu, Kai-Kai Lv, Ying-Qing Wang, Bing Xiong, Ze-Hong Miao
Summary: Bromodomain and extra-terminal domain (BET) family proteins are promising anticancer targets. The novel bivalent BET inhibitor N2817 showed greater potency in inhibiting proliferation, arresting cell-cycle, inducing apoptosis, and suppressing tumor growth, with high metabolic stability and no brain penetration after oral administration. This study introduces a new paradigm for designing bivalent BET inhibitors and a novel potent bivalent BET inhibitor with a new anticancer mechanism.
BIOCHEMICAL PHARMACOLOGY
(2021)
Article
Cell Biology
Linlin Zhang, Chunxiang Sheng, Feiye Zhou, Kecheng Zhu, Shushu Wang, Qianqian Liu, Miaomiao Yuan, Zhaoqian Xu, Yun Liu, Jieli Lu, Jianmin Liu, Libin Zhou, Xiao Wang
Summary: In this study, it was found that the HAT activity of CBP/p300 plays a dominant role in maintaining the identity of insulin-secreting β cells by regulating the expression of functional genes through transcriptional networks.
CELL DEATH & DISEASE
(2021)
