The dual-channel target CDK7 R&D track is worthy of follow-up!

In 5 years, Ibrance, the first CDK4/6 inhibitor to be marketed, has achieved global sales of 5 billion US dollars.
In addition to the follow-up of similar drugs, the development of its surrounding targets has also risen, CDK7 Is one of them
.
With its role in both cell cycle and transcription, as well as high expression in some tumor cells, it has become one of the potential hot targets of cancer
.
Moreover, the current domestic research and development enthusiasm is in its infancy, and the track is not crowded yet, and it is worth setting up a project to follow up
.
01 Cell cycle/transcription&CDK7 role CDK7 is a member of the CDK family.
This target can activate other CDKs to participate in the regulation of the cell cycle, and at the same time participate in transcription, making CDK7 more special than other CDKs
.
During the cell cycle, CDK7 can activate multiple cyclin-related kinases including CDK1, CDK2, CDK4 and CDK6
.
During the transcription process, CDK7 combined with other transcription factors can phosphorylate the S5 and S7 sites of RNA polymerase II (RNP2), and also phosphorylate and activate CDK9, which has the activity of promoting S2 phosphorylation of CTD
.
Therefore, CDK7 directly or indirectly participates in the regulation of the initiation and elongation of intracellular transcription.
Inhibition of CDK7 will inhibit the phosphorylation of CTD, which will greatly interfere with the transcription process
.
Furthermore, CDK7 is overexpressed in a variety of tumors, such as oral squamous cell carcinoma and triple-negative breast cancer; therefore, CDK7 is considered a potential target for anti-tumor therapy
.
Figure 1.
1 The position of CDK7 in the cell cycle (see references for pictures) 02 CDK7 structural characteristics and mechanism of action On the structure, the crystal structure of CDK7-ATP complex has been determined, similar to the structure of CDK2-ATP complex, as shown in the figure below Show
.
Figure 2.
1 CDK7 protein structure (PDB database) Functionally, CDK7 requires active Cyclin H, and also requires another protein (MAT1) to form a ternary complex to perform physiological functions
.
In addition, CDK1 and CDK2 are also considered to be important factors in the phosphorylation and activation of CDK7
.
Figure 2.
2 The mechanism steps of CDK7 showing more physiological functions (see references for pictures) 03 Varieties entering the clinical stage worldwide According to reports, THZ1 is the first reported synthetic CDK7-specific covalent small molecule inhibitor in 2014, and it is also CDK12/ 13 Inhibitors: In vivo and in vitro, it can inhibit the proliferation of tumor cells of different genotypes and phenotypes.
It has been proven to have anti-tumor effects in cervical cancer, ovarian cancer, glioma and other cancers
.
Moreover, other studies have shown that THZI can pass through the blood-brain barrier, which makes THZ1 a potential drug for the treatment of gliomas, and can also change the cell cycle distribution and arrest cancer cells in the G2/M phase
.
Based on the problem of potential drug resistance, researchers have done a lot of optimization work on its structure
.
Currently, there are four main types of CDK7 inhibitors entering the clinical stage, namely CT7001, SY-5609, SY-1365, and BTX-A51
.
CT-7001, developed by the Imperial College Of Science, is a small molecule drug.
The highest research and development stage of the drug is clinical phase II, which is used to treat solid tumors
.
SY-5609, developed by Syros Pharmaceuticals, is a small molecule drug.
At present, the highest research and development stage of the drug is clinical phase I, which is used to treat breast cancer, solid tumors and small cell lung cancer; another variety, SY-1365, is the same Developed by Syros Pharmaceuticals, the highest stage of research and development is clinical phase I, which is used to treat solid tumors such as ovarian cancer and breast cancer
.
BTX-A51, developed by Biotheryx Inc, is a CDK7/CSNK1A1/CDK9 inhibitor.
The highest stage of development is clinical phase I for the treatment of non-Hodgkin’s lymphoma and solid tumors
.
Figure 3.
1 Chemical structure of THZ1 & CT7001 04 Domestic CDK7-related patent applications.
Through a simple search for CDK7-related patents, the main foreign applicants for patent applications in China are West Krassel Co.
, Ltd.
and Shiros Pharmaceuticals Co.
, Ltd.
, Argentina Knicks AG, Dana - Farber cancer Institute, Ltd.
and other
.
Domestic applicants mainly include Jinan University, Fudan University Affiliated Tumor Hospital, China Medical University, Zhejiang Tongkang Pharmaceutical Co.
, Ltd.
, Enrui Biomedical Technology (Shanghai) Co.
, Ltd.
, etc.

.
It is not difficult to see that the domestic research on CDK7, especially the development of inhibitors, is still at an early stage and it is worthy of follow-up! References: 1.
Cyclin dependent kinase (CDK) inhibitors as anticancer drugs: Recent advances (2015–2019).
Bioorganic & Medicinal Chemistry Letters 29 (2019).
doi.
org/10.
1016/j.
bmcl.
2019.
126637 2.
Recent development of CDK inhibitors: An overview of CDK/inhibitor co-crystal structures.
European Journal of Medicinal Chemistry 2019.
doi.
org/10.
1016/j.
ejmech.
2019.
01.
003 3.
Targeting cell-cycle machinery in cancer.
Cancer Cell 2021.
doi.
org/10.
1016/j.
ccell.
2021.
03.
010 4.
Recent advances in the development of cyclin-dependent kinase 7 inhibitors.
European Journal of Medicinal Chemistry (2019).
doi.
org/10.
1016/j.
ejmech.
2019.
111641 5.
http: // 6.
CNKI partial information