BCH-001(BCH-001) - 药物靶点：PAPD5_在研适应症：先天性角化不良_专利_临床

概要

基本信息

药物类型

小分子化药

别名

靶点

PAPD5

作用机制

PAPD5抑制剂(Non canonical RNA polymerase PAPD5 inhibitors)

治疗领域

遗传病与畸形血液及淋巴系统疾病皮肤和肌肉骨骼疾病+ [1]

在研适应症

先天性角化不良

非在研适应症-

原研机构

The Children's Hospital Corp.

在研机构

The Children's Hospital Corp.

非在研机构-

最高研发阶段临床前

首次获批日期-

最高研发阶段(中国)-

特殊审评-

关联

100 项与 BCH-001 相关的临床结果

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100 项与 BCH-001 相关的转化医学

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100 项与 BCH-001 相关的专利（医药）

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1

项与 BCH-001 相关的文献（医药）

2020-06-01·Cell Stem Cell1区 · 医学

Small-Molecule PAPD5 Inhibitors Restore Telomerase Activity in Patient Stem Cells

1区 · 医学

Article

作者: Emily Lo ; Jing Zeng ; Roman O. Braun ; Suneet Agarwal ; Albert K. Tai ; Sioban B. Keel ; Christopher Reilly ; R. Coleman Lindsley ; Neha Nagpal ; Jianing Wang ; Lauri M. Burroughs ; Patrick Cahan ; Daniel E. Bauer ; Scot A. Wolfe ; Diane H. Moon ; Kevin Luk ; Yick W. Fong

Genetic lesions that reduce telomerase activity inhibit stem cell replication and cause a range of incurable diseases, including dyskeratosis congenita (DC) and pulmonary fibrosis (PF). Modalities to restore telomerase in stem cells throughout the body remain unclear. Here, we describe small-molecule PAPD5 inhibitors that demonstrate telomere restoration in vitro, in stem cell models, and in vivo. PAPD5 is a non-canonical polymerase that oligoadenylates and destabilizes telomerase RNA component (TERC). We identified BCH001, a specific PAPD5 inhibitor that restored telomerase activity and telomere length in DC patient induced pluripotent stem cells. When human blood stem cells engineered to carry DC-causing PARN mutations were xenotransplanted into immunodeficient mice, oral treatment with a repurposed PAPD5 inhibitor, the dihydroquinolizinone RG7834, rescued TERC 3' end maturation and telomere length. These findings pave the way for developing systemic telomere therapeutics to counteract stem cell exhaustion in DC, PF, and possibly other aging-related diseases.

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