Article
Biochemistry & Molecular Biology
William M. Marsiglia, Arthur Chow, Zaigham M. Khan, Liu He, Arvin C. Dar
Summary: This study presents a NanoBRET-based assay to quantify the direct target engagement of MEK inhibitors on MEK1 and its complexes with ARAF, BRAF, CRAF, KSR1 and KSR2 in living cells. The study reveals the preferences of MEK inhibitors among these complexes and their binding profiles. Furthermore, the assay can also report on the effect of pathogenic mutations on MEK inhibitor binding. These methods are important for screening compounds targeting specific complexes in the RAS-MAPK cascade.
NATURE CHEMICAL BIOLOGY
(2023)
Article
Multidisciplinary Sciences
Shotaro Tsujioka, Ayumi Sumino, Yutaro Nagasawa, Takashi Sumikama, Holger Flechsig, Leonardo Puppulin, Takuya Tomita, Yudai Baba, Takahiro Kakuta, Tomoki Ogoshi, Kenichi Umeda, Noriyuki Kodera, Hideji Murakoshi, Mikihiro Shibata
Summary: CaMKII plays a crucial role in synaptic plasticity and its molecular behavior has been observed using high-speed atomic force microscopy. The dynamic behavior is dependent on CaM binding and pT286 phosphorylation. Rat CaMKIIa exhibited kinase domain oligomerization, which was not observed in other species. Sensitivity to PP2A also differs between the three species.
Article
Biochemistry & Molecular Biology
Jakob Fleischmann, Andreas Feichtner, Louis DeFalco, Valentina Kugler, Selina Schwaighofer, Roland G. Huber, Eduard Stefan
Summary: Mutations in the MAPK signaling pathway can lead to abnormal activation of protein kinases, with targeted MEK inhibition causing qualitative changes in carcinogenic MAPK signals. By phosphorylating MEK1 at specific sites, RAF kinases trigger conformational changes that enable substrate phosphorylation. Allosterically acting MEK inhibitors can reverse the conformational changes induced by phosphorylation, indicating their potential efficacy in cancer therapy.
Article
Multidisciplinary Sciences
Hayarpi Torosyan, Michael D. Paul, Antoine Forget, Megan Lo, Devan Diwanji, Krzysztof Pawlowski, Nevan J. Krogan, Natalia Jura, Kliment A. Verba
Summary: In this study, the cryo-EM structure of the PEAK3/14-3-3 complex was presented, revealing the asymmetric binding mode and the unique secondary interaction between PEAK3 and 14-3-3. It was also found that PKD regulates the binding of PEAK3 and 14-3-3, and disruption of this binding leads to nuclear enrichment of PEAK3 and distinct protein-protein interactions. The results demonstrate how 14-3-3 modulates PEAK3 localization and protein-protein interactions.
NATURE COMMUNICATIONS
(2023)
Article
Chemistry, Multidisciplinary
Wei Yu, Min Liao, Yang Chen, Rui Xue, Xiao-Meng Shi, Dan Liu, Fang-Fang Zhuo, Hui Tang, Zhi-Yuan Lu, Peng-Fei Tu, Bo Han, Xin Jia, Ke-Wu Zeng
Summary: This study identified phosphatidyl-ethanolamine binding protein1 (PEBP1) as a cellular target of ethyl gallate (EG), a natural small molecule for ulcerative colitis (UC) treatment. EG inhibited the phosphorylation of PEBP1 and enhanced PEBP1-Raf-1 interaction to block the NF-kappa B inflammatory pathway in macrophages. It was also found that PEBP1 serves as an essential anti-inflammation mechanism in UC therapy.
CHEMICAL COMMUNICATIONS
(2023)
Article
Chemistry, Medicinal
Peng Zhao, Linghang Zhuang, Xiangzhu Wang, Song Huang, Heping Wu, Yu Zhou, Yuna Yan, Fan Zhang, Ru Shen, Jing Li, Suxing Liu, Rumin Zhang, Ping Dong, Yuchang Mao, Yuanmin Fan, Chunyong He, Jiakang Sun, Lei Zhang, Qiyue Hu, Hong Wan, Jun Feng, Chang Bai, Feng He, Weikang Tao
Summary: A molecule called SHR902275 (or molecule 33) has been discovered with significantly improved potency and solubility, which shows potential for targeting cancers with mutant RAS and wild type RAF activity. In vivo experiments have demonstrated dose dependent efficacy of molecule 33.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Katarzyna Malarz, Jacek Mularski, Marcin Pacholczyk, Robert Musiol
Summary: We synthesized a series of styrylquinazolines with a thioaryl moiety in the C4 position and evaluated their biological activity. The compounds showed high inhibition potential against non-receptor tyrosine kinases and differential binding to the DFG conformational states of ABL kinase. They exhibited sub-micromolar activity against leukemia. In-depth cellular studies revealed the mechanism of action of the most active compounds. S-4-substituted styrylquinazolines can be considered as promising multi-kinase inhibitors for effective anticancer drugs.
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Weixue Wang, Laurence Mevellec, Annie Liu, Geoff Struble, Robyn Miller, Samantha J. Allen, Kelly Federowicz, Berthold Wroblowski, Jorge Vialard, Kay Ahn, Daniel Krosky
Summary: Targeting inactive kinase conformations can lead to more selective kinase inhibitors. By applying cascade assays, a highly selective inhibitor for the cancer immunotherapy target kinase HPK1 was discovered, indicating the potential for further development of potent and selective inhibitors.
Article
Biochemistry & Molecular Biology
Ryan C. Maloney, Mingzhen Zhang, Hyunbum Jang, Ruth Nussinov
Summary: Oncogenic mutations in B-Raf, especially the V600E mutation, are common in cancer and are a major drug target. This study found that the V600E mutation destabilizes the inactive state while stabilizing the active state, providing insights for the development of new Raf inhibitors.
COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL
(2021)
Article
Biochemistry & Molecular Biology
Coralie Dorard, Claire Madry, Olivier Buhard, Stefanie Toifl, Sebastian Didusch, Toky Ratovomanana, Quentin Letourneur, Helmut Dolznig, Mathew J. Garnett, Alex Duval, Manuela Baccarini
Summary: This study shows that RAF1 plays a crucial role in the proliferation of colorectal cancer and is independent of KRAS mutation status. RAF1 ablation decreases proliferation and STAT3 phosphorylation, indicating that RAF1 could be a therapeutic target for colorectal cancer.
Article
Biochemistry & Molecular Biology
Mohammad Reza Amiran, Majid Taghdir, Farzane Abasi Joozdani
Summary: AKT1 is a family of kinases that regulate cell growth, proliferation, metabolism, and survival. This study investigated the effects of different inhibitors on two conformations of AKT1 through computational simulations. The results showed that each inhibitor forms a stable complex with AKT1, with some complexes showing less stability. MK2206 exhibited a stronger binding affinity in the inactive conformation, and van der Waals interactions were found to contribute more to the binding energy.
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
(2023)
Review
Biochemistry & Molecular Biology
Lianbo Li, Cynthia Meyer, Zhi-Wei Zhou, Ammar Elmezayen, Kenneth Westover
Summary: Allosteric mechanisms are common in nature but rare in human-designed perturbagens. The development of KRAS(G12C) inhibitors suggests that covalent chemistry could expand the use of allosteric inhibitors. This study explores the feasibility of extending this approach to other proteins in the RAS and kinase family, which play important roles in cellular processes, especially in cancer therapy.
JOURNAL OF MOLECULAR BIOLOGY
(2022)
Article
Multidisciplinary Sciences
Lorena Gonzalez, Lucia Diaz, Joan Pous, Blazej Baginski, Anna Duran-Corbera, Margherita Scarpa, Isabelle Brun-Heath, Ana Igea, Pau Martin-Malpartida, Lidia Ruiz, Chiara Pallara, Mauricio Esguerra, Francesco Colizzi, Cristina Mayor-Ruiz, Ricardo M. Biondi, Robert Soliva, Maria J. Macias, Modesto Orozco, Angel R. Nebreda
Summary: p38 alpha is a versatile protein kinase that plays important roles in cellular stress responses. Dysregulation of p38 alpha signaling is linked to several diseases, making it a potential therapeutic target.
NATURE COMMUNICATIONS
(2023)
Article
Chemistry, Medicinal
Peng Zhao, Xiangzhu Wang, Linghang Zhuang, Song Huang, Yu Zhou, Yuna Yan, Ru Shen, Fan Zhang, Jie Li, Qiyue Hu, Suxing Liu, Rumin Zhang, Ping Dong, Hong Wan, Chang Bai, Feng He, Weikang Tao
Summary: In this study, a series of RAF inhibitors with a novel spiro structure were discovered and optimized. The most potent compound 9 showed excellent in vitro potency against b/c RAF enzymes and RAS mutant cancer cells, with minimal paradoxical RAF signaling activation. Compound 9 also exhibited good drug-like properties with in vitro cytochrome P450 (CYP) data, liver microsome stability (LMS) data, and moderate oral pharmacokinetics (PK) profiles in rat and mouse.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2022)
Article
Chemistry, Medicinal
Seyed-Omar Zaraei, Nour N. Al-Ach, Hanan S. Anbar, Randa El-Gamal, Hamadeh Tarazi, Rimas T. Tokatly, Rawan R. Kalla, Mouna A. Munther, Marwa M. Wahba, Aya M. Alshihabi, Mahmoud K. Shehata, Rawan M. Sbenati, Afnan I. Shahin, Raafat El-Awady, Taleb H. Al-Tel, Mohammed I. El-Gamal
Summary: This article presents the design, synthesis, and biological screening results of a new series of diarylurea and diarylamide derivatives with a quinoline core armed with dimethylamino or morpholino side chains. The compounds showed broad-spectrum antiproliferative activity against a panel of 60 cancer cell lines, with three of them demonstrating higher potency than the reference drug, sorafenib. The compounds also exhibited high selectivity for C-RAF kinase, making them potential inhibitors for this molecular target.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Yang W. Zhang, Zhihong Wang, Wenbing Xie, Yi Cai, Limin Xia, Hariharan Easwaran, Jianjun Luo, Ray-Whay Chiu Yen, Yana Li, Stephen B. Baylin
Article
Biochemistry & Molecular Biology
Zhihong Wang, Min-Sik Kim, Isabel Martinez-Ferrando, Anthony J. Koleske, Akhilesh Pandey, Philip A. Cole
Article
Biochemistry & Molecular Biology
Nicholas Cope, Christine Candelora, Kenneth Wong, Sujeet Kumar, Haihan Nan, Michael Grasso, Borna Novak, Yana Li, Ronen Marmorstein, Zhihong Wang
Article
Biochemistry & Molecular Biology
Zhihong Wang, Lily L. Raines, Richard M. Hooy, Heather Roberson, Daniel J. Leahy, Philip A. Cole
ACS CHEMICAL BIOLOGY
(2013)
Article
Biochemistry & Molecular Biology
Kathryn E. Muratore, Markus A. Seeliger, Zhihong Wang, Dina Fomina, Johnathan Neiswinger, James J. Havranek, David Baker, John Kuriyan, Philip A. Cole
Article
Biochemistry & Molecular Biology
Zhihong Wang, Yuxin Wang, Eric L. Hegg
JOURNAL OF BIOLOGICAL CHEMISTRY
(2009)
Article
Biochemistry & Molecular Biology
Zhihong Wang, Patti A. Longo, Mary Katherine Tarrant, Kwangsoo Kim, Sarah Head, Daniel J. Leahy, Philip A. Cole
NATURE STRUCTURAL & MOLECULAR BIOLOGY
(2011)
Article
Biology
Jennifer M. Kavran, Jacqueline M. McCabe, Patrick O. Byrne, Mary Katherine Connacher, Zhihong Wang, Alexander Ramek, Sarvenaz Sarabipour, Yibing Shan, David E. Shaw, Kalina Hristova, Philip A. Cole, Daniel J. Leahy
Article
Biochemistry & Molecular Biology
Amber Y. Gunderwala, Anushri A. Nimbvikar, Nicholas J. Cope, Zhijun Li, Zhihong Wang
ACS CHEMICAL BIOLOGY
(2019)
Article
Biochemistry & Molecular Biology
Nicholas Cope, Borna Novak, Christine Candelora, Kenneth Wong, Maria Cavallo, Amber Gunderwala, Zhiwei Liu, Yana Li, Zhihong Wang
Review
Biochemistry & Molecular Biology
Amber Gunderwala, Nicholas Cope, Zhihong Wang
Summary: Recent structural studies have uncovered the mechanism of autoinhibition in BRAF, providing a more complete understanding of the regulation cycle of RAF kinases. While specific inhibitors targeting BRAFV600E have proven effective, they are less potent against other BRAF mutants due to paradoxical activation of the MAPK pathway caused by RAS-driven diseases. New generation inhibitors without paradoxical activation have been developed, and efforts are underway to develop inhibitors targeting the dimer interface of BRAF.
CURRENT OPINION IN CHEMICAL BIOLOGY
(2022)
Meeting Abstract
Chemistry, Multidisciplinary
Christine Candelora, Nicholas Cope, Kenneth Wong, Yana Li, Philip Cole, Zhihong Wang
ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY
(2016)
Meeting Abstract
Chemistry, Multidisciplinary
Eric L. Hegg, Zhihong Wang, Behzad Khodaverdian
ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY
(2008)
Article
Biochemistry & Molecular Biology
Jinyou Zhuang, Amit R. Reddi, Zhihong Wang, Behzad Khodaverdian, Eric L. Hegg, Brian R. Gibney