Small-Molecule Inhibitors of Transcription Factor PU.1 for the Treatment of Acute T Cell Lymphoblastic Leukemia and Organ Fibrosis

Xin Wang, Liuzhen Zhang, Fusheng Guo, Ningning Yao, Zhenpeng Wu, Libing He, Dan Xu,Haichuan Zhu, Zhou Gong, Shuai Yang, Wenjun Xie, Yafen Wang, Liyun Zhang, Xiang Zhou10, Chun Tang,Rong Mu, Hong Wu* & Xiaoguang Lei*

CCS Chem. 2025, Just Published.

Transcription factors (TFs) play essential roles in cancer and metabolic diseases, and targeting TFs with small molecules remains a significant challenge. The TF PU.1 is critical for maintaining leukemia initiation cells (LICs) “stemness” in acute T cell lymphoblastic leukemia (T-ALL) and is also a key regulator of fibroblast polarization and organ fibrosis. Herein we rationally designed and synthesized a variety of diamidines with rigid and AT-selective linkers as PU.1 inhibitors. The compound PKU0140 displayed the highest potency in reducing the expression of PU.1 target genes. Significantly, PKU0140 allosterically disrupted the PU.1-chromatin interaction by binding to the minor groove of DNA. In the Pten-null T-ALL mouse model, PKU0140, combined with rapamycin, could significantly decrease leukemic blasts and LICs, alleviate leukemia progression, and prolong the survival of mice. Furthermore, PKU0140 showed preventive and therapeutic effects on fibrotic lesions in various organs by inhibiting the activation of myofibroblasts. This work provides a new small-molecule PU.1 inhibitor with the potential for the treatment of T-ALL and organ fibrosis.

https://www.chinesechemsoc.org/doi/10.31635/ccschem.025.202405360