The CDK family is in full bloom. Dozens of domestic pharmaceutical companies have entered the track!

It has been quietly 6 years since the first CDK4/6 inhibitor was launched.

Function distribution of 20 CDKs

CDK, short for cyclin-dependent kinase, belongs to the serine/threonine protein kinase family; both contain a homologous sequence of PSTAIRE and form a heterodimer with the corresponding cyclin; and currently Nearly 20 CDKs have been found, as shown in the figure below

Figure 1.

CDK1, CDK2, CDK4, CDK6, etc.

CDK monomers are usually inactive, and can only become active and stable conformation when combined with the corresponding cyclin

Figure 1.

Listed drugs

At present, the CDK inhibitors that have been marketed are all CDK4/6 inhibitors, which are Palbocicilib, Ribociclib, Abemaciclib, and Trilaciclib in the order of listing time

Palbocicilib: CDK4/6 inhibitor, developed by Pfizer, trade name Ibrance; in 2015, this product was approved by the US FDA for the first-line treatment of advanced breast cancer; in February 2016, the FDA approved its combination with fulvestrant for endocrine After treatment, HR-positive/HER2-negative metastatic breast cancer; in March 2017, the FDA approved the expansion of its combined use with letrozole to be used with aromatase inhibitors; in April 2019, the FDA approved the drug for the treatment of men Patients with HER2-negative advanced or metastatic breast cancer; Ibrance is an oral capsule, each containing 75mg, 100mg or 125mg Palbociclib; the recommended starting dose is once a day, 125mg each time, combined with letrozole, taken with meals , A total of 21 days, after which the medication was stopped for 7 days

Ribociclib: CDK4/6 inhibitor, developed by Novartis; In March 2017, it was approved by the U.

Abemaciclib: oral CDK4/6 inhibitor, the development company is Eli Lilly; in October 2017, the US FDA approved its single drug or combined with Fulvestrant for second-line HR-positive and HER2-negative advanced metastatic breast cancer; 2018.

Trilaciclib: a small molecule CDK4/6 inhibitor, developed by G1Therapeutics Inc; in July 2019, the FDA recognized it as a breakthrough therapy for the treatment of SCLC; in July 2021, the FDA approved its combination chemotherapy for the treatment of locally advanced stages through fast track Or metastatic TNBC

Figure 2.

Clinical Drugs Under Research

For the development of CDK inhibitors, a number of highly selective subtypes have been used in clinical research, such as CDK1, CDK7, CDK9, CDK12 inhibitors, etc.

➣ Dalpiciclib (SHR-6390)

In June 2014, it was declared as a class 1.

Table 3.

(Information source:addition to the above-mentioned SHR-6390 of Jiangsu Hengrui, CDKs currently under research in the world still focus on target 4/6 as the main research and development focus, such as lerociclib, MM-D37K, ebvaciclib, vicoryx, TQB3616, GLR-2007, NUV-422, alvocidib, ON-123300, BPI-1178, XZP-3287, FCN-437, CS-3002, TY-302, PF-06842874, ETH-155008, PF-07220060, voruciclib, BEBT-209, BPI-16350, HS-10342

Other CDKs are mainly CDK1, CDK7, CDK8, CDK9, and CDK11; for example, CDK1 inhibitors have been developed to clinical phase II, and CDK9 has also been developed to clinical phase II; and CDK7, CDK8, and CDK11 have all entered clinical I Period
.

Development of CDK inhibitors by domestic pharmaceutical companies

Through clinical data query, domestic pharmaceutical companies have developed CDK inhibitors and have entered clinical trials, including Jiangsu Hengrui, Zhengda Tianqing, Jiangsu Hexion, Jiahe Biological, Betta Pharmaceuticals, Chongqing Fuchuang, and CStone Pharmaceuticals.
, Benny pharmaceutical, biotechnology and other real king
.

Further inquiring about patent information, the development companies for CDK inhibitors include Suzhou Southeast Pharmaceutical, Wuhan Jiuzhou Yumin, Guangzhou Weirongte, Nerviano, Jiangxi Runze Pharmaceutical, Beijing Shiantai, Suzhou Jingyun, Shenzhen City Somerset biological, Shanghai Xun and medicine, Kai complex (Suzhou) biological, Beijing Sailin Tai, Ya Sheng medicine, bio-Taji Rui Shenzhen, Hangzhou, a British medicine
.

references:

1.
Structural insights of cyclin dependent kinases: Implications in design of selective inhibitors.
EJMC

2.
Cyclin dependent kinase (CDK) inhibitors as anticancer drugs: Recent advances (2015–2019).
BMC

3.
Cyclin-dependent protein serine/threonine kinase inhibitors as anticancer drugs.
Pharmacological Research

4.
Recent development of CDK inhibitors: An overview of CDK/inhibitor co-crystal structures.
EJMC

5.
The development of CDK inhibitors in the field of anti-tumor.
Pharmaceutical progress

6.