Why did the CDKs family only succeed with CDK4/6 inhibitors?

Recently, the CDK4/6 inhibitor SHR-6390 developed by Jiangsu Hengrui was included in the CDE's list of varieties to be reviewed.
It is expected to become the first domestically produced Class 1 new drug in the field of CDK4/6 inhibitors; and the world's first CDK4/ 6 Inhibitor Palbociclib, in the past 2020, has achieved a brilliant record of annual sales of more than 5 billion US dollars
.

So, how important is CDK4/6 in the CDK family and even the entire cell cycle? What is the development history of CDK4/6 inhibitors? What are the CDK4/6 inhibitors currently on the market? Please see this manuscript

1.
The position of CDK4/6 in the cell cycle

The normal cell cycle, including DNA synthesis pre-stage G1, synthesis stage S, post-synthesis stage G2 and mitotic stage M, has three main checkpoints in preventing abnormal replication of cells, namely G1/S checkpoint, G2/M checkpoint and Mid-late mitosis checkpoint
.

The G1/S checkpoint is also called the starting point or restriction point, where various signals inside and outside the cell are integrated, which determines the cell to start the first round of proliferation, differentiation, death, or exit the cell cycle and enter the G0 phase
.

The interaction of cyclin and CDK controls the G1/S checkpoint

CDK4 and CDK6 have 71% amino acid homology, and can bind to the three subtypes of cyclinD (cyclinD1; cyclinD2; cyclinD3)
.

Under the induction of mitogenic signals, cyclinD binds to CDK4/6 to form a complex, which promotes phosphorylation of the tumor suppressor gene Rb, which causes the transcription factor E2F to dissociate from the Rb-E2F complex, activates gene transcription, and makes the cell enter S from the G1 phase.

2.
Discovery and development of CDK4/6 inhibitors

The research on CDKs can be traced back to the 1970s.
In 1985, it was confirmed that CDKs belonged to protein kinases.
In 1992, the first generation CDK inhibitor flavopirdol was discovered.
In 1998, the crystal structure of CDK was identified.
In 2001, the discoverer was awarded the Nobel Physiology Or medical awards to recognize their outstanding contributions in understanding CDK and cyclin proteins; later clinical trials have entered the research phase one after another
.

       In 2015, the first CDK4/6 inhibitor, pambociclib, was approved for marketing (approved for first-line and second-line treatment of hormone receptor-positive, human epidermal growth factor receptor-2 (HER-2)-negative advanced breast cancer ), after that, ribociclib and abemaciclib have been approved for marketing (approved for first-line and subsequent-line treatment of hormone receptor-positive and HER-2 negative advanced breast cancer); 2021 Trilaciclib has also been approved by the FDA for marketing
.

       3.
CDK4/6 inhibitors already on the market

       Pimbociclib (palbociclib)

       The development company is Pfizer, with the permission of Onyx, to develop the CDK4/6 inhibitor palbociclib
.

In the United States, accelerated approval in February 2015 for first-line advanced breast cancer; approved in February 2016 for use in combination with fulvestrant for the treatment of HR-positive/HER2-negative metastatic breast cancer in women with disease progression after endocrine therapy; 2017 Expanded to use in combination with aromatase inhibitors in March, 2019; in April 2019, the FDA approved the drug for the treatment of HER2-negative advanced or metastatic breast cancer in male patients

       The variety was approved in the European Union in November 2016, and it was approved in Japan in December 2017
.

In addition, clinical work on other types of breast cancer, liver cancer, brain cancer, prostate cancer, pancreatic cancer, leukemia and other malignant tumors is also underway

       Ribociclib

       The development company is Novartis, which cooperates with Astex Pharmaceuticals for research and development
.

In March 2017, Ribocinil was approved for marketing in the United States.

       This variety was approved in the European Union in August 2017
.

In addition, other types of breast cancer, teratomas, neuroendocrine tumors, endometrial cancer, liposarcoma, NSCLC, melanoma, glioma, hepatocellular carcinoma, head and neck squamous cell carcinoma and other malignant tumors Work is also in progress
.

       Abemaciclib

       The development company is Eli Lilly
.
In October 2017, Abesinil was approved for marketing in the United States, and its indications are single-agent or combined with fulvestrant for the second-line treatment of HR-positive/HER2-negative advanced metastatic breast cancer; FDA approved it again in February 2018 The drug is used in combination with aromatase inhibitors as the initial therapy of endocrine therapy for the treatment of postmenopausal women with HR-positive/HER2-negative advanced or metastatic breast cancer
.

       In September 2018, Abesini was approved for listing in the EU; in November 2018, it was approved for listing in Japan
.
In addition, other types of breast cancer, mantle cell lymphoma, MCL, liposarcoma, glioblastoma, endometrial cancer, prostate cancer, mesothelioma, head and neck squamous cell carcinoma, gastroesophageal adenocarcinoma, bile duct Clinical work on cancer, glioma, non-small cell lung cancer, pancreatic cancer and other malignant tumors is also in progress
.

       Trilaciclib

       The development company is G1 Therapeutics (formerly G-Zero Therapeutics); it was approved for marketing by the US FDA in March 2021.
It is a drug that reduces the frequency of bone marrow suppression in patients with extensive-stage small cell lung cancer when receiving certain types of chemotherapy.
The first CDK4/6 inhibitor approved for this indication
.
In addition, clinical work on TNBC, urothelial carcinoma, NSCLC and other malignant tumors is also underway
.

       Four, summary

       The success of CDK4/6 inhibitors is naturally inseparable from the location and role of the kinase in the cell cycle, which can effectively control the process from G1 phase to S phase.
At the same time, the development cycle of CDK4/6 inhibitors has been more than ten years.
Over time, the development time limit is much longer than that of other subtype inhibitors.
Moreover, the launch of 4 inhibitors has greatly consolidated the foundation of the target drug and has initially solved most of the clinical needs
.
Therefore, how to make better differences will be more worthy of attention when we are about to usher in the promotion of domestically-made new drugs
.

       Reference source:

       1.
https://finance.
sina.
com.
cn/realstock/company/sh600276/nc.
shtml

       2.
European Journal of Medicinal Chemistry.
doi.
org/10.
1016/j.
ejmech.
2020.
112531

       3.
Acta Pharmaceutica.
doi.
org/10.
1016/j.
apsb.
2020.
05.
001

       4.
FDA official website

       5.
CNKI information