The transcription and transportation of mRNA are coupled processes; however, the mechanisms linking these processes remain unclear. Additionally, the significance of this connection in cancer drug development is poorly understood. To address these issues, we investigated the role of CDK12 kinase, which regulates RNA transcription through the phosphorylation of RNA polymerase II (Pol II) and has a repeated serine-arginine dipeptide (RS domain) involved in mRNA transport. Despite the anticipated uniqueness of CDK12 function, the mechanism by which CDK12 bridges and manages mRNA transcription and transport has not been fully analyzed. Our study revealed that CDK12 interacts with NXF1, a key molecule involved in the export of mRNA from the nucleus to the cytosol. Although CDK12 does not phosphorylate NXF1, we found that NXF1 unexpectedly stabilized the CDK12 protein, suggesting that NXF1 mRNA export activity indirectly affects mRNA transcriptional activity by modifying the protein level of CDK12. Furthermore, CDK12 recruited other essential RNA transporters, specifically the exon junction complex (EJC) and THO complexes, into the CDK12-NXF1 axis through its kinase activity. These observations provide insights into the mechanisms linking mRNA transcription and transport through the formation of a novel CDK12-NXF1 complex that involves EJC and THO. Importantly, the expression level of NXF1 influences sensitivity to CDK12 inhibitors, which are emerging as novel anti-cancer drug candidates. This highlights the importance of considering the relationship between mRNA transcription and transport when targeting RNA transcription in cancer therapy.

01 Sep 2024·Biomedicine & Pharmacotherapy

Antitumoral activity of a CDK12 inhibitor in colorectal cancer through a liposomal formulation

Article

Author: Paniagua-Herranz, Lucía ; Ocaña, Alberto ; Clemente-Casares, Pilar ; Bravo, Ivan ; Nieto-Jiménez, Cristina ; Arenas-Moreira, María ; Sanvicente, Adrián ; Alonso-Moreno, Carlos ; Díaz-Tejeiro, Cristina

Colorectal cancer (CRC) is the third most common cancer worldwide. Recent experiments suggest that CDK12 can be a good therapeutic target in CRC, and therefore, novel inhibitors targeting this protein are currently in preclinical development. Lipid-based formulations of chemical entities have demonstrated the ability to enhance activity while improving the safety profile. In the present work, we explore the antitumor activity of a new CDK12 inhibitor (CDK12-IN-E9, CDK12i) and its lipid-based formulation (LP-CDK12i) in CRC models, to increase efficacy. SW620, SW480 and HCT116 CRC cell lines were used to evaluate the inhibitor and the liposomal formulation using MTT proliferation assay, 3D invasion cultures, flow cytometry, Western blotting and immunofluorescence experiments. Free-cholesterol liposomal formulations of CDK12i (LP-CDK12i) were obtained by solvent injection method and fully characterized by size, shape, polydispersity, encapsulation efficiency, and release profile and stability assessments. LP-CDK12i induced a higher antiproliferative effect compared with CDK12i as a free agent. The IC₅₀ value was lower across all cell lines tested, leading to a reduction in cell proliferation and the formation of 3D structures. Evaluation of apoptosis revealed an increase in cell death, while biochemical studies demonstrated modifications of apoptosis and DNA damage components. In conclusion, we confirm the role of targeting CDK12 for the treatment of CRC and describe, for the first time, a liposomal formulation of a CDK12i with higher antiproliferative activity compared with the free compound.

01 Nov 2023·European Journal of Medicinal Chemistry

Discovery of a novel dual-target inhibitor of CDK12 and PARP1 that induces synthetic lethality for treatment of triple-negative breast cancer

Article

Author: Zhang, Lan ; Wang, Guan ; Zhen, Yongqi ; Ouyang, Liang ; Li, Zhijia ; Lu, Yingying ; Feng, Lu

Triple negative breast cancer (TNBC) is one of the most aggressive breast tumors, with a high rate of recurrence and metastasis as well as a poor prognosis. Consequently, it is urgent to find new targeted therapeutic strategies and development of corresponding drugs. Previous studies have shown that CDK12 inhibitors in combination with PARP1 inhibitors is able to induce synthetic lethality in TNBC cells. Here, we reported simultaneously inhibition of CDK12 and PARP1 by genetic or pharmacological approaches synergistically inhibited the proliferation of TNBC cells. Then, a series of small molecule inhibitors targeting both CDK12 and PARP1 were designed and synthesized. The new dual-target inhibitor (12e) showed potent inhibitory activity against CDK12 (IC₅₀ = 285 nM) and PARP1 (IC₅₀ = 34 nM), as well as good anti-proliferative effects in TNBC cell lines. Meanwhile, compound 12e showed favorable synergistic anti-tumor efficacy in cells and xenografts by inhibiting DNA damage repair, promoting cell cycle arrest and apoptosis. Taken together, we successfully synthesized the ﬁrst effective CDK12-PARP1 dual inhibitor, which is expected to be an attractive therapeutic strategy for TNBC.

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Preclinical	CN	Chupu Chuang (Wuhan) Pharmaceutical Technology Co., Ltd.	04 Apr 2024

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