Highly functionalized skeletons of macrolide natural products gain access to rare spatial arrangements of atoms, where changes in stereochemistry can have a profound impact on the structure and function. Spliceosome modulators present a unique consensus motif, with the majority targeting a key interface within the SF3B spliceosome complex. Our recent preparative-scale synthetic campaign of 17S-FD-895 provided unique access to stereochemical analogues of this complex macrolide. Here, we report on the preparation and systematic activity evaluation of multiple FD-895 analogues. These studies examine the effects of modifications at specific stereocenters within the molecule and highlight future directions for medicinal chemical optimization of spliceosome modulators.

2023-03-01·Cell Stem Cell

Reversal of malignant ADAR1 splice isoform switching with Rebecsinib

Article

作者: Diep, Raymond H ; Mondala, Phoebe K ; Jiang, Qingfei ; Pineda, Gabriel ; La Clair, James J ; Crews, Leslie A ; Jamieson, Catriona H M ; Wentworth, Peggy ; van der Werf, Inge ; Pham, Jessica ; Whisenant, Thomas C ; Balaian, Larisa ; Steel, S Kathleen ; Ma, Wenxue ; Burkart, Michael D ; Reynoso, Eduardo ; Ladel, Luisa ; Wu, Christina N ; Mason, Cayla N ; Oliver, Isabelle

Adenosine deaminase acting on RNA1 (ADAR1) preserves genomic integrity by preventing retroviral integration and retrotransposition during stress responses. However, inflammatory-microenvironment-induced ADAR1p110 to p150 splice isoform switching drives cancer stem cell (CSC) generation and therapeutic resistance in 20 malignancies. Previously, predicting and preventing ADAR1p150-mediated malignant RNA editing represented a significant challenge. Thus, we developed lentiviral ADAR1 and splicing reporters for non-invasive detection of splicing-mediated ADAR1 adenosine-to-inosine (A-to-I) RNA editing activation; a quantitative ADAR1p150 intracellular flow cytometric assay; a selective small-molecule inhibitor of splicing-mediated ADAR1 activation, Rebecsinib, which inhibits leukemia stem cell (LSC) self-renewal and prolongs humanized LSC mouse model survival at doses that spare normal hematopoietic stem and progenitor cells (HSPCs); and pre-IND studies showing favorable Rebecsinib toxicokinetic and pharmacodynamic (TK/PD) properties. Together, these results lay the foundation for developing Rebecsinib as a clinical ADAR1p150 antagonist aimed at obviating malignant microenvironment-driven LSC generation.

2023-03-01·Cell Reports Medicine

Detection and targeting of splicing deregulation in pediatric acute myeloid leukemia stem cells

Article

作者: Chan, Warren C ; Cloos, Jacqueline ; Fisch, Kathleen M ; Balaian, Larisa ; Mark, Adam ; Jamieson, Catriona H M ; Pham, Jessica ; Crews, Leslie A ; Burkart, Michael D ; Steel, S Kathleen ; Whisenant, Thomas C ; Mason, Cayla N ; Ladel, Luisa ; Wentworth, Peggy ; Donohoe, Mary E ; Kaspers, Gertjan J L ; van der Werf, Inge ; Diep, Raymond H ; La Clair, James J ; Mondala, Phoebe K

Pediatric acute myeloid leukemia (pAML) is typified by high relapse rates and a relative paucity of somatic DNA mutations. Although seminal studies show that splicing factor mutations and mis-splicing fuel therapy-resistant leukemia stem cell (LSC) generation in adults, splicing deregulation has not been extensively studied in pAML. Herein, we describe single-cell proteogenomics analyses, transcriptome-wide analyses of FACS-purified hematopoietic stem and progenitor cells followed by differential splicing analyses, dual-fluorescence lentiviral splicing reporter assays, and the potential of a selective splicing modulator, Rebecsinib, in pAML. Using these methods, we discover transcriptomic splicing deregulation typified by differential exon usage. In addition, we discover downregulation of splicing regulator RBFOX2 and CD47 splice isoform upregulation. Importantly, splicing deregulation in pAML induces a therapeutic vulnerability to Rebecsinib in survival, self-renewal, and lentiviral splicing reporter assays. Taken together, the detection and targeting of splicing deregulation represent a potentially clinically tractable strategy for pAML therapy.

项与 Rebecsinib 相关的新闻（医药）

2023-10-06

·Endpoints

The researchers who resurrected Inrebic are testing a new bone marrow cancer drug in space

It was 4:45 a.m. on May 27. Cat Jamieson, a prominent cancer stem cell researcher, was at her home in San Diego wrapping up a call with astronaut Peggy Whitson. Whitson was in space, carrying out an experiment that Jamieson had sent up to the International Space Station. Right before the call ended, Whitson shared a microscope image of the experiment, which was housed in a small cube. They were looking at the effects of a drug candidate called rebecsinib on cancer cell regeneration. In space, stem cells face more stressors at once, so researchers can do an experiment that would take at least a year on Earth in just a few days.

细胞疗法

100 项与 Rebecsinib 相关的药物交易

登录后查看更多信息

研发状态

10 条进展最快的记录,

后查看更多信息

适应症	最高研发状态	国家/地区	公司	日期
急性髓性白血病	临床前	荷兰	Vrije Universiteit Amsterdam	-
急性髓性白血病	临床前	美国	University of California San Diego	-
急性髓性白血病	临床前	美国	Aspera Biomedicines, Inc.	-