Gluetacs Therapeutics has co-published a paper in Nature Communications, reporting on CDK9-targeted degraders and their application in the treatment of cutaneous T-cell lymphoma

ON：2024-12-13 TAGS：GLUETACS THERAPEUTICS

Recently, Gluetacs Therapeutics, in collaboration with Lu Ying’s research group from the Xinhua Hospital affiliated with Shanghai Jiao Tong University School of Medicine and other domestic research teams, published a research paper titled “CDK9 recruits HUWE1 to degrade RARα and offers therapeutic opportunities for cutaneous T-cell lymphoma” in the international journal Nature Communications. The study discovered that cyclin-dependent kinase 9 (CDK9) is a driving factor in the growth of T-cell lymphoma (TCL). Inhibition of kinase activity, gene knockout, or degradation of CDK9 protein using proteolysis-targeting chimeras (PROTACs) can significantly reduce the growth of TCL cells both in vitro and in mouse models. Researchers synthesized, optimized, and screened a lead compound GT-02897 that targets and degrades CDK9 protein at nanomolar concentrations, killing TCL tumor cells. The combination of GT-02897 with all-trans retinoic acid (ATRA) synergistically inhibits tumor growth in vitro and in xenograft models, providing a therapeutic strategy with promising clinical translation prospects for the complete eradication of TCL.

T-cell lymphoma (TCL) is a category of malignant tumors characterized by the clonal proliferation of T-lymphocytes. It exhibits highly aggressive and heterogeneous biological behavior and clinical manifestations, lacking efficient and specific treatment methods. The research team initially used a small molecule compound library to screen for high sensitivity of TCL cells to CDK9 inhibitors. Furthermore, to elucidate the mechanism by which CDK9 drives the development of TCL, the team revealed a novel function of CDK9 beyond its kinase activity, which is to enhance the ubiquitination level and proteasomal degradation of retinoic acid receptor RARα protein at the K360 site by recruiting the E3 ubiquitin ligase HUWE1. Correspondingly, targeting the degradation of CDK9 protein using PROTACs can increase RARα protein levels, thereby endowing tumor cells with sensitivity to RARα ligand ATRA. Based on this new mechanism, the team developed a sequential treatment plan targeting the degradation of CDK9 with the small molecule GT-02897 combined with ATRA, achieving good efficacy in preclinical models. Therefore, this research not only provides a more comprehensive theoretical basis for developing CDK9-targeting therapeutic strategies but also expands the spectrum of effect of differentiation therapy, holding significant potential for clinical translation.

This work was completed by Gluetacs in collaboration with multiple research teams, including Xinhua Hospital affiliated with Shanghai Jiao Tong University School of Medicine, Hainan Medical University (Hainan Province Medical Science Academy), ShanghaiTech University, and Dalian Medical University. The project was funded by the National Natural Science Foundation of China.

Gluetacs, as the corresponding unit, has once again published an article in collaboration with academic institutions, further demonstrating the rich technical reserves and translational potential of the GlueTacs^®platform, as well as its significant academic and commercial value.