靶点- |
作用机制- |
在研机构 |
原研机构 |
在研适应症 |
非在研适应症- |
最高研发阶段临床1/2期 |
首次获批国家/地区- |
首次获批日期- |
靶点- |
作用机制- |
在研机构 |
原研机构 |
非在研适应症- |
最高研发阶段临床1期 |
首次获批国家/地区- |
首次获批日期- |
靶点 |
作用机制 FER抑制剂 |
在研机构 |
原研机构 |
在研适应症 |
非在研适应症- |
最高研发阶段临床前 |
首次获批国家/地区- |
首次获批日期- |
开始日期2024-02-27 |
申办/合作机构 |
开始日期2023-07-03 |
申办/合作机构 |
Cutaneous T-cell lymphoma (CTCL) is a highly heterogeneous non-Hodgkin lymphoma that originates from the skin and invades the systemic hematopoietic system. Current skin-directed or systemic treatment including chemotherapy, retinoid analogs, interferons, HDAC inhibitors and monoclonal antibodies yielded limited clinical responses with high incidence of side effects, emphasizing urgent clinical need for more effective targeted therapy. Here, through small inhibitors library screening, we identify cyclin dependent kinase 9 (CDK9) as a driver for growth of CTCL. Single-cell RNA-seq data analyses reveal a CDK9high malignant T cell cluster with a unique actively proliferating feature. Pharmacological inhibition, genetic depletion or proteolysis targeting chimera (PROTAC)-medicated degradation of CDK9 significantly inhibit the growth of CTCL cells in vitro and in preclinical murine models. Beyond established kinase-dependent modulation on RNA polymerase II activity, CDK9 protein promotes degradation of retinoid acid receptor α (RARα) at lysine 360 in a kinase-independent manner via recruiting the HECT domain containing E3 ligase HUWE1. Depletion of CDK9 protein thus accumulates RARα and enhances the sensitivity of CTCL cells to all-trans retinoid acid (ATRA) which induces growth arrest and T cell differentiation. Co-administration of CDK9-PROTAC (GT-02897) with ATRA leads to synergistic attenuation of tumor growth in vitro and in xenograft models, providing a potential translational treatment for complete eradication of CTCL.
药物(靶点) | 适应症 | 全球最高研发状态 |
---|---|---|
GT-929 | 难治性非霍奇金淋巴瘤 更多 | 临床2期 |
GT-919 | 血液肿瘤 更多 | 临床1期 |
PROTAC 632005 ( NAMPT ) | 肿瘤 更多 | 临床前 |
SIAIS-352008 ( FER ) | 卵巢癌 更多 | 临床前 |
SIAIS262039 ( FER ) | 卵巢癌 更多 | 临床前 |