Article
Cell Biology
Avinashnarayan Venkatanarayan, Jason Liang, Ivana Yen, Frances Shanahan, Benjamin Haley, Lilian Phu, Erik Verschueren, Trent B. Hinkle, David Kan, Ehud Segal, Jason E. Long, Tony Lima, Nicholas P. D. Liau, Jawahar Sudhamsu, Jason Li, Christiaan Klijn, Robert Piskol, Melissa R. Junttila, Andrey S. Shaw, Mark Merchant, Matthew T. Chang, Donald S. Kirkpatrick, Shiva Malek
Summary: CRAF is necessary for the growth of KRAS mutant tumors and its dimerization plays a vital role. Lack of CRAF leads to sustained ERK activation and cell cycle arrest, and the CRAF-loss phenotype can be rescued by inhibiting MEK or ERK.
Article
Chemistry, Multidisciplinary
Charles W. Morgan, Ian L. Dale, Andrew P. Thomas, James Hunt, Jason W. Chin
Summary: In this study, bio-orthogonal ligand tethering (BOLT) was used to selectively target inhibitors to CRAF, showing that selective CRAF inhibition promotes paradoxical activation. This suggests that BOLT may be used to triage potential targets for drug discovery before any target-selective small molecules are known.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2021)
Article
Immunology
Honglin Jiang, Ryan K. Muir, Ryan L. Gonciarz, Adam B. Olshen, Iwei Yeh, Byron C. Hann, Ning Zhao, Yung-Hua Wang, Spencer C. Behr, James E. Korkola, Michael J. Evans, Eric A. Collisson, Adam R. Renslo
Summary: KRAS mutations are a major driver of cancer mortality, but most of them cannot be targeted by drugs. This study discovered that oncogenic KRAS signaling leads to the accumulation of ferrous iron (Fe-2(+)). By converting an FDA-approved MEK inhibitor into a ferrous iron-activatable drug conjugate (FeADC), the researchers were able to effectively block MAPK signaling in tumor cells and improve systemic tolerability. FeADC holds promise for improving the treatment of KRAS-driven solid tumors.
JOURNAL OF EXPERIMENTAL MEDICINE
(2022)
Article
Chemistry, Multidisciplinary
Lan-song Xu, Su-xin Zheng, Liang-he Mei, Ke-xin Yang, Ya-fang Wang, Qiang Zhou, Xiang-tai Kong, Ming-yue Zheng, Hua-liang Jiang, Cheng-ying Xie
Summary: A novel and highly potent KRAS(G12C) inhibitor, 143D, was identified through a structure-based and focused chemical library analysis. It showed comparable antitumor efficacy to AMG510 and MRTX849 and selectively inhibited cell proliferation by downregulating KRAS(G12C)-dependent signal transduction, inducing cell cycle arrest and apoptosis.
ACTA PHARMACOLOGICA SINICA
(2023)
Review
Oncology
Sarah M. Trinder, Campbell McKay, Phoebe Power, Monique Topp, Bosco Chan, Santosh Valvi, Geoffrey McCowage, Dinisha Govender, Maria Kirby, David S. Ziegler, Neevika Manoharan, Tim Hassall, Stewart Kellie, John Heath, Frank Alvaro, Paul Wood, Stephen Laughton, Karen Tsui, Andrew Dodgshun, David D. Eisenstat, Raelene Endersby, Stephen J. Luen, Eng-Siew Koh, Hao-Wen Sim, Benjamin Kong, Nicholas G. Gottardo, James R. Whittle, Dong-Anh Khuong-Quang, Jordan R. Hansford
Summary: The MAPK pathway is frequently mutated in human cancers, and BRAF alterations play a crucial role in oncogenesis. While targeted therapies have shown success, the outcomes for glioma patients have not significantly improved. Recent studies have revealed that MAPK dysregulation is almost universally present in pediatric and adult gliomas, opening up new opportunities for clinical trials.
FRONTIERS IN ONCOLOGY
(2023)
Article
Oncology
Meghan J. Mooradian, James M. Cleary, Anita Giobbie-Hurder, Lancia N. F. Darville, Aparna Parikh, Elizabeth I. Buchbinder, Justine V. Cohen, Donald P. Lawrence, Geoffrey I. Shapiro, Harold Keer, Helen X. X. Chen, Susan Percy Ivy, Keiran S. M. Smalley, John M. Koomen, Ryan J. Sullivan
Summary: This study showed that the combination of HSP90 inhibitor AT13387 with dabrafenib and trametinib was safe and led to modest disease control in heavily pretreated patients with BRAF V600E/K-mutant solid tumors. Further research is needed to identify tumor types and resistance mechanisms that are most sensitive to this approach.
Article
Oncology
Nobumichi Ohoka, Masanori Suzuki, Takuya Uchida, Yoshinori Tsukumo, Masayuki Yoshida, Takao Inoue, Hitoshi Ohki, Mikihiko Naito
Summary: This study developed proteolysis targeting chimeras (PROTACs) that can degrade BRAF(V600E) protein, providing a promising strategy to treat cancer caused by this mutation. Compared to current inhibitors, targeted degradation showed more potent and sustained suppression of downstream signaling, avoiding the issue of paradoxical activation.
Review
Multidisciplinary Sciences
Yoshiro Niitsu, Yasushi Sato, Tetsuji Takayama
Summary: GSTP1, a glutathione-S transferase isozyme, is highly expressed in malignant tissues and serves as a tumor marker and a refractory factor against certain types of anticancer drugs. Recent studies have also identified its chaperone activity in regulating intracellular protein function.
PROCEEDINGS OF THE JAPAN ACADEMY SERIES B-PHYSICAL AND BIOLOGICAL SCIENCES
(2022)
Article
Chemistry, Multidisciplinary
Zong-jun Xia, Yin-chun Ji, De-qiao Sun, Xia Peng, Ying-lei Gao, Yan-fen Fang, Xing-dong Zhao, Wei-bo Wang, Jian Ding, Mei-yu Geng, Jing Ai
Summary: SAF-189s, a novel ROS1/ALK inhibitor, shows promising antitumor efficacy against both wild-type and crizotinib-resistant mutants of ROS1 fusion, indicating its potential for treating patients with the G2032R mutation and its recruitment in a phase II clinical trial for NSCLC patients.
ACTA PHARMACOLOGICA SINICA
(2021)
Article
Biochemistry & Molecular Biology
Namkyoung Kim, Injae Shin, Jiwon Lee, Eunhye Jeon, Younghoon Kim, Seongshick Ryu, Eunhye Ju, Wonjeong Cho, Taebo Sim
Summary: This study identified six pyrimido[4,5-d]pyrimidin-2-one derivatives with highly potent anti-proliferative activities against melanoma cells harboring BRAF class I/II/III mutations. The novel compound SIJ1777 showed the most potent effects and outperformed vemurafenib and PLX8394 in inhibiting the proliferation of melanoma cells.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Medicine, Research & Experimental
Raie T. Bekele, Amruta S. Samant, Amin H. Nassar, Jonathan So, Elizabeth P. Garcia, Catherine R. Curran, Justin H. Hwang, David L. Mayhew, Anwesha Nag, Aaron R. Thorner, Judit Borcsok, Zsofia Sztupinszki, Chong-Xian Pan, Joaquim Bellmunt, David J. Kwiatkowski, Guru P. Sonpavde, Eliezer M. Van Allen, Kent W. Mouw
Summary: The study identified RAF1 activation as a dependency in a subset comprising nearly 20% of urothelial tumors, suggesting that targeting RAF1-mediated signaling may represent a rational therapeutic strategy.
JOURNAL OF CLINICAL INVESTIGATION
(2021)
Article
Chemistry, Multidisciplinary
Ronan P. Hanley, David Y. Nie, John R. Tabor, Fengling Li, Amin Sobh, Chenxi Xu, Natalie K. Barker, David Dilworth, Taraneh Hajian, Elisa Gibson, Magdalena M. Szewczyk, Peter J. Brown, Dalia Barsyte-Lovejoy, Laura E. Herring, Gang Greg Wang, Jonathan D. Licht, Masoud Vedadi, Cheryl H. Arrowsmith, Lindsey I. James
Summary: Nuclear receptor-binding SET domain-containing 2 (NSD2) is involved in gene regulation by dimethylating lysine 36 of histone 3 (H3K36me2). UNC8153 is a novel NSD2-targeted degrader that effectively reduces NSD2 protein and H3K36me2 levels. It works by degrading NSD2 through a unique mechanism and has demonstrated positive effects on pathological phenotypes in multiple myeloma cells.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2023)
Article
Biochemistry & Molecular Biology
Hui Dang, Mengjun Sui, Qingyuan He, Jingyi Xie, Yan Liu, Peng Hou, Meiju Ji
Summary: This study shows that Pin1 inhibitor API-1 has strong antitumor activity against thyroid cancer and improves the sensitivity of BRAF-mutant thyroid cancer cells to BRAF inhibitor PLX4032. The combination therapy of API-1 and PLX4032 offers an alternative therapeutic strategy for BRAF-mutant thyroid cancers.
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
(2023)
Article
Dermatology
Jonathan I. I. Silverberg, Lars E. E. French, Richard B. B. Warren, Bruce Strober, Kim Kjoller, Morten O. A. Sommer, Philippe Andres, Jakob Felding, Anne Weiss, Deniz Tutkunkardas, Tine Skak-Nielsen, Emma Guttman
Summary: This study examined the PDE4 enzymatic activity and anti-inflammatory effects of orismilast in vitro, ex vivo, and in vivo. The results showed that orismilast selectively and potently inhibited PDE4 and demonstrated broad-spectrum anti-inflammatory activity. These findings support the clinical development of oral orismilast as a novel treatment option for chronic inflammatory skin diseases.
JOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY AND VENEREOLOGY
(2023)
Article
Chemistry, Medicinal
Hoi-Yee Chow, Sofiia Karchugina, Brian J. Groendyke, Sean Toenjes, John Hatcher, Katherine A. Donovan, Eric S. Fischer, Gleb Abalakov, Bulat Faezov, Roland Dunbrack, Nathanael S. Gray, Jonathan Chernoff
Summary: This study reports the development of a new Pak1 selective degrader, BJG-05-039, achieved by conjugating NVS-PAK1-1 with lenalidomide. BJG-05-039 showed enhanced anti-proliferative effects compared to its parent compound in Pak1-dependent cell lines. These findings suggest that selective degradation of Pak1 may have more potent pharmacological effects compared to catalytic inhibition and highlight the potential advantages of Pak1-targeted degradation.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)