How to develop better CDK inhibitors behind the US$5 billion?

Continuous proliferation is an important feature of tumor cells, so blocking the tumor cell cycle has become an important means to control tumor development.

01 Introduction to the CDK family

CDK, which belongs to the serine/threonine protein kinase family, has been reported to have 20 different family subtypes, all of which contain a homologous sequence of PSTAIRE, and through this sequence and the corresponding regulatory subunit-cyclin (cyclin) Combines to form an active heterodimer, which participates in physiological processes such as transcription, metabolism, neural differentiation and development.

Classified by function:

One type of CDK is involved in cell cycle regulation, mainly including CDK1, CDK2, CDK4, CDK6, etc.

One type of CDK is involved in transcription regulation, mainly including CDK7, CDK8, CDK9, CDK10, CDK11 and so on.

Picture source: "Progress in Pharmacy"

In tumor cells, overexpression or overactivation of cyclin, inhibition of CDKI activity, continuous activation of upstream division signals, etc.

Image source: Bioorganic & Medicinal Chemistry Letters

Reference: doi.

02 CDK family inhibitor development strategy

In the past 10 years, great progress has been made in the development of CDK inhibitors.

The earliest CDK inhibitors developed were pan-CDK inhibitors, such as flavopiridol and seliciclib.

The presence of cysteine ​​and lysine residues outside the standard ATP pocket has shifted researchers' attention to the development of covalent inhibitors.

Figure 2.

Image source: Bioorganic & Medicinal Chemistry Letters

https://doi.

03 Allosteric & Covalent & Degradable & Reversible

☆ Allosteric inhibitor

Currently, it is mainly in the preclinical stage.

☆ Covalent inhibitor

Covalently bound CDK inhibitors are definitely a hot spot of development in recent years.

☆ Targeted degradation

By enhancing the ubiquitination of CDK protein, it induces its mediated degradation of the proteasome, thereby inhibiting protein function.

☆ Reversible competitive inhibitor

HTS is usually used to obtain CDK reversible competitive inhibitors, especially the most popular CDK4/6 inhibitors, and the focus of development is still on activity, selectivity and brain permeability.

04Conclusions and Prospects

In the past ten years, the drug discovery in the field of CDK inhibitors has made great progress, especially the selective dual CDK4/6 inhibitors have shown strong clinical efficacy and safety.

reference:

1.
The development of CDK inhibitors in the field of anti-tumor.
"Progress in Pharmacy"

2.
European Journal of Medicinal Chemistry.
doi.
org/10.
1016/j.
ejmech.
2019.
01.
003

3.
Bioorganic & Medicinal Chemistry Letters.
doi.
org/10.
1016/j.
ejmech.
2019.
01.
003.