2115897-23-7Relevant articles and documents
Identifying transcriptional programs underlying cancer drug response with TraCe-seq
Chang, Matthew T.,Shanahan, Frances,Nguyen, Thi Thu Thao,Staben, Steven T.,Gazzard, Lewis,Yamazoe, Sayumi,Wertz, Ingrid E.,Piskol, Robert,Yang, Yeqing Angela,Modrusan, Zora,Haley, Benjamin,Evangelista, Marie,Malek, Shiva,Foster, Scott A.,Ye, Xin
, p. 86 - 93 (2021/09/25)
Genetic and non-genetic heterogeneity within cancer cell populations represent major challenges to anticancer therapies. We currently lack robust methods to determine how preexisting and adaptive features affect cellular responses to therapies. Here, by conducting clonal fitness mapping and transcriptional characterization using expressed barcodes and single-cell RNA sequencing (scRNA-seq), we have developed tracking differential clonal response by scRNA-seq (TraCe-seq). TraCe-seq is a method that captures at clonal resolution the origin, fate and differential early adaptive transcriptional programs of cells in a complex population in response to distinct treatments. We used TraCe-seq to benchmark how next-generation dual epidermal growth factor receptor (EGFR) inhibitor–degraders compare to standard EGFR kinase inhibitors in EGFR-mutant lung cancer cells. We identified a loss of antigrowth activity associated with targeted degradation of EGFR protein and an essential role of the endoplasmic reticulum (ER) protein processing pathway in anti-EGFR therapeutic efficacy. Our results suggest that targeted degradation is not always superior to enzymatic inhibition and establish TraCe-seq as an approach to study how preexisting transcriptional programs affect treatment responses.
BIFUNCTIONAL DEGRADERS OF INTERLEUKIN-1 RECEPTOR-ASSOCIATED KINASES AND THERAPEUTIC USE THEREOF
-
Page/Page column 125; 127, (2021/08/27)
The present disclosure provides bifunctional compounds as IRAK4 degraders via ubiquitin proteasome pathway, and method for treating diseases modulated by IRAK4.
BIFUNCTIONAL COMPOUNDS
-
, (2021/05/07)
The invention provides a bifunctional compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein said Targeting Ligand, Linker and Degron are as described herein.
Design, Synthesis, and Evaluation of VHL-Based EZH2 Degraders to Enhance Therapeutic Activity against Lymphoma
Tu, Yalin,Sun, Yameng,Qiao, Shuang,Luo, Yao,Liu, Panpan,Jiang, Zhong-Xing,Hu, Yumin,Wang, Zifeng,Huang, Peng,Wen, Shijun
, p. 10167 - 10184 (2021/07/26)
Traditional EZH2 inhibitors are developed to suppress the enzymatic methylation activity, and they may have therapeutic limitations due to the nonenzymatic functions of EZH2 in cancer development. Here, we report proteolysis-target chimera (PROTAC)-based EZH2 degraders to target the whole EZH2 in lymphoma. Two series of EZH2 degraders were designed and synthesized to hijack E3 ligase systems containing either von Hippel-Lindau (VHL) or cereblon (CRBN), and some VHL-based compounds were able to mediate EZH2 degradation. Two best degraders, YM181 and YM281, induced robust cell viability inhibition in diffuse large B-cell lymphoma (DLBCL) and other subtypes of lymphomas, outperforming a clinically used EZH2 inhibitor EPZ6438 (tazemetostat) that was only effective against DLBCL. The EZH2 degraders displayed promising antitumor activities in lymphoma xenografts and patient-derived primary lymphoma cells. Our study demonstrates that EZH2 degraders have better therapeutic activity than EZH2 inhibitors, which may provide a potential anticancer strategy to treat lymphoma.
TAU-PROTEIN TARGETING COMPOUNDS AND ASSOCIATED METHODS OF USE
-
, (2021/02/12)
The present disclosure relates to bifunctional compounds, which find utility as modulators of tan protein. In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a VHL or cereblon ligand which binds to the E3 ubiquitin ligase and on the other end a moiety which binds tan protein, such that tan protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of tan. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of tan protein. Diseases or disorders that result from aggregation or accumulation of tan protein are treated or prevented with compounds and compositions of the present disclosure.
BIFUNCTIONAL MOLECULES CONTAINING AN E3 UBIQUITINE LIGASE BINDING MOIETY LINKED TO A BCL6 TARGETING MOIETY
-
Paragraph 00355; 00356, (2021/04/23)
Bifunctional compounds, which find utility as modulators of B-cell lymphoma 6 protein (BCL6; target protein), are described herein. In particular, the bifunctional compounds of the present disclosure contain on one end a Von Hippel-Lindau, cereblon, Inhibitors of Apotosis Proteins or mouse double-minute homolog 2 ligand that binds to the respective E3 ubiquitin ligase and on the other end a moiety which binds the target protein, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The bifunctional compounds of the present disclosure exhibit a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aggregation or accumulation of the target protein are treated or prevented with compounds and compositions of the present disclosure.
COMPOUNDS AND METHODS FOR THE TARGETED DEGRADATION OF INTERLEUKIN-1 RECEPTOR-ASSOCIATED KINASE 1 PROTEINS
-
Page/Page column 53; 55; 56, (2021/02/05)
The present invention relates to compounds comprising an interleukin-1 receptor-associated kinase 1 (IRAK1) protein binding moiety and a Von Hippel-Lindau (VHL) E3 ubiquitin ligase binding moiety, and associated methods of use. The compounds are useful as modulators of targeted ubiquitination, especially with respect to IRAK1, which is degraded by the compounds according to the invention.
SMARCA2-VHL DEGRADERS
-
Page/Page column 34-36, (2021/07/17)
The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, pharmaceutical compositions comprising a compound of the invention, a method for manufacturing compounds of the invention and therapeutic uses thereof.
Discovery of Highly Potent and Selective IRAK1 Degraders to Probe Scaffolding Functions of IRAK1 in ABC DLBCL
Fu, Liqiang,Zhang, Jing,Shen, Bin,Kong, Linglong,Liu, Yingtao,Tu, Wangyang,Wang, Wenqian,Cai, Xin,Wang, Xiaotao,Cheng, Na,Xia, Mingxuan,Zhou, Tianyuan,Liu, Qian,Xu, Yanping,Yang, Jennifer,Gavine, Paul,Philippar, Ulrike,Attar, Ricardo,Edwards, James P.,Venable, Jennifer D.,Dai, Xuedong
, p. 10878 - 10889 (2021/08/03)
MyD88 gene mutation has been identified as one of the most prevalent driver mutations in the activated B-cell-like diffuse large B-cell lymphoma (ABC DLBCL). The published literature suggests that interleukin-1 receptor-associated kinase 1 (IRAK1) is an essential gene for ABC DLBCL harboring MyD88 mutation. Importantly, the scaffolding function of IRAK1, rather than its kinase activity, is required for tumor cell survival. Herein, we present our design, synthesis, and biological evaluation of a novel series of potent and selective IRAK1 degraders. One of the most potent compounds, Degrader-3 (JNJ-1013), effectively degraded cellular IRAK1 protein with a DC50 of 3 nM in HBL-1 cells. Furthermore, JNJ-1013 potently inhibited IRAK1 downstream signaling pathways and demonstrated strong anti-proliferative effects in ABC DLBCL cells with MyD88 mutation. This work suggests that IRAK1 degraders have the potential for treating cancers that are dependent on the IRAK1 scaffolding function.
SYSTEMS AND METHODS TO TRACK THE EVOLUTION OF SINGLE CELLS
-
Paragraph 0142-0144, (2021/09/26)
Cells in a given population often display heterogeneity that may affect how each cell responds to a particular treatment or growth condition. The methods described herein allow determination of which cells from an initial population survive a treatment or condition, and how surviving cells evolve over time. For example, the methods described herein may be used to model drug resistance, response and/or adaptation in a cell population.
