Author: Zhou, Beiyun ; Offringa, Ite A ; Calvert, Ben A ; Meier, Angela ; St Pierre, Laurence ; Alvarez, Juan R ; Afshar, Kamyar ; Ji, Yanbin ; Liu, Yixin ; Wang, Hongjun ; Lin, Grace Y ; Marconett, Crystal N ; Borok, Zea ; Ryan, Amy ; Yu, Haoze ; Berhan, Asres ; Castaldi, Alessandra ; Sung, Eun K ; Golts, Eugene M

Idiopathic pulmonary fibrosis (IPF) is a lethal progressive lung disease urgently needing new therapies. Current treatments only delay disease progression, leaving lung transplant as the sole remaining option. Recent studies support a model whereby IPF arises because alveolar epithelial type II (AT2) cells, which normally mediate distal lung regeneration, acquire airway and/or mesenchymal characteristics, preventing proper repair. Mechanisms driving this abnormal differentiation remain unclear. We performed integrated transcriptomic and epigenomic analysis of purified AT2 cells which revealed genome-wide alterations in IPF lungs. The most prominent epigenetic alteration was activation of an enhancer in thyroid receptor interactor 13 (TRIP13), although TRIP13 was not the most significantly transcriptionally upregulated gene. TRIP13 is broadly implicated in epithelial-mesenchymal plasticity. In cultured human AT2 cells and lung slices, small molecule TRIP13 inhibitor DCZ0415 prevented acquisition of the mesenchymal gene signature characteristic of IPF, suggesting TRIP13 inhibition as a potential therapeutic approach to fibrotic disease.

01 Oct 2024·Bioorganic Chemistry

TRIP13 − a potential drug target in cancer pharmacotherapy

Review

Author: Xu, Zhijian ; Zhu, Weiliang ; Jacob Bunu, Samuel ; Shi, Jumei ; Zhou, Zhaoyin ; Cai, Haiyan ; Wu, Leyun ; Zhang, Hui

ATPases Associated with Diverse Cellular Activity (AAA⁺ATPases) are important enzymatic functional proteins in human cells. Thyroid Hormone Receptor Interacting Protein-13 (TRIP13) is a member of this protein superfamily, that partly regulates DNA repair pathways and spindle assembly checkpoints during mitosis. TRIP13 is reported as an oncogene involving multiple pathways in many human malignancies, including multiple myeloma, brain tumors, etc. The structure of TRIP13 reveals the mechanisms for ATP binding and how TRIP13 recognizes the Mitotic Arrest Deficiency-2 (MAD2) protein, with p31^comet acting as an adapter protein. DCZ0415, TI17, DCZ5417, and DCZ5418 are the reported small-molecule inhibitors of TRIP13, which have been demonstrated to inhibit TRIP13's biological functions significantly and effective in suppressing various types of malignant cells, indicating that TRIP13 is a significant anticancer drug target. Currently, no systematic reviews are cutting across the functions, structure, and novel inhibitors of TRIP13. This review provides a comprehensive overview of TRIP13's biological functions, its roles in eighteen different cancers, four small molecule inhibitors, different underlying molecular mechanisms, and its functionality as a potential anticancer drug target.

01 Sep 2024·Bioorganic & Medicinal Chemistry

Design, synthesis, and biological evaluation of novel 1-amido-2-one-4-thio-deoxypyranose as potential antitumor agents for multiple myeloma

Article

Author: Sun, Haiguo ; Xu, Zhijian ; Shi, Jumei ; Zhu, Weiliang ; Guo, Shushan ; Cai, Haiyan ; Hu, Ke ; Zhang, Qikai ; Zhang, Yong ; Akber Aisa, Haji ; Li, Bo ; Zhang, Hui ; Zhu, Jianming ; Shen, Jingshan ; Li, Xiaomei ; Guo, Zhufeng ; Zhou, Zhaoyin ; Gao, Xuejie ; Jacob Bunu, Samuel ; Dong, Sanfeng

This study reported the design and synthesis of novel 1-amido-2-one-4-thio-deoxypyranose as inhibitors of potential drug target TRIP13 for developing new mechanism-based therapeutic agents in the treatment of multiple myeloma (MM). In comparison with the positive control DCZ0415, the most active compounds C16, C18, C20 and C32 exhibited strong anti-proliferative activity against human MM cell lines (ARP-1 and NCI-H929) with IC₅₀ values of 1 ∼ 2 μM. While the surface plasmon resonance (SPR) and ATPase activity assays demonstrated that the representative compound C20 is a potent inhibitor of TRIP13, C20 also showed good antitumor activity in vivo on BALB/c nude mice xenografted with MM tumor cells. An initial structure-activity study showed that the carbonyl group is crucial for anticancer activity. Overall, this study provided novel 1-amido-2-one-4-thio-deoxypyranoses, which are entirely different from previously reported potent inhibitor structures of TRIP13, and thus would aid the development of carbohydrate-based novel agents in MM pharmacotherapy.

100 Deals associated with DCZ0415

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Indication	Highest Phase	Country/Location	Organization	Date
Multiple Myeloma	Preclinical	China	Tongji University	01 Apr 2024
Acute Megakaryoblastic Leukemia	Preclinical	Germany	Martin-Luther-Universität Halle-Wittenberg	11 Dec 2023
Prostatic Cancer	Preclinical	United States	Morehouse School of Medicine	18 Apr 2023

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