Is the target CDK2 the highest stage clinical phase III worthy of further follow-up?

Cell cycle repair is a key step for tumor cell survival.
Breaking this balance is an important means to kill tumor cells
.
The therapeutic effects of CDKs protein family inhibitors have been sufficiently clinically proven in the past 5 years.
CDK4/6 has gradually become a classic target in the field of oncology.
Then, CDK2, another key factor in the cell cycle process, is currently under development.
how? Is the track congested? Is the R&D party worthy of follow-up? Please see this manuscript
.
01 The role of CDKs in the tumor environment.
Malignant tumors usually have the following characteristics: inactivation of apoptosis program, formation of new blood vessels, escape from immune surveillance, amplification of non-physiological growth signals/inhibitory signals, abnormal adhesion function, cell immortality and so
.
Among them, the targeted regulation of tumor cell cycle to change the apoptotic state of tumor cells has been clinically proven to be effective, and the specific representative species is the CDK family inhibitor
.
CDK family targets are mainly divided into two categories.
One is involved in cell cycle regulation and related to mitosis.
The subtypes are represented by CDK1, 2, 4, and 6; the other is mainly involved in transcription regulation and regulates the phosphorylation of RNA polymerase II.
Modifications, the subtypes are represented by CDK7, 8, 9, 11; see the figure below for details
.
Schematic diagram of the main CDKs and their functions (Reference: Pharmaceutical Progress/2015) 02 CDK2 target mechanism Under the stimulation of mitotic signals, cells enter the G1 phase of mitosis from the G0 phase, and the internal activities of the cells are gradually upregulated
.
CDK4/6 binds to cyclinD to promote phosphorylation of retinoblastoma protein (Rb), and part of the activity of transcription elongation factor E2F is released, which is used to synthesize a large amount of RNA and protein to prepare for chromosome replication
.
In the late stage of G1, CDK2 combines with cyclinE to form the proteasome complex CDK2-cyclinE and activates it, which promotes further phosphorylation of Rb and induces the continuous expression of transcription factor E2F, thereby regulating the smooth passage of cells through the G1 phase.

.
After entering the S phase, CDK2 combines with cyclinA to form a complex CDK2-cyclinA that participates in the S phase of the cell cycle and completes DNA replication
.
Subsequently, cyclinA/B and CDK1 form a CDK1-cyclinA/B complex, which drives the cell cycle into the G2/M phase, and synthesizes RNA and protein to prepare for the formation of spindle filaments
.
Finally, the cell completes mitosis through all cell cycles G1-S-G2-M in an orderly manner
.
CDK2 regulates the process of mitosis (Chinese Journal of Cell Biology/2021) In terms of structure, CDK2 protein is highly conserved and consists of 298 amino acids.
Cleavage determines the specific binding of ATP or protein binding substrates to CDK2, and plays a key role in cell regulation
.
Figure 2.
1 The structure of CDK2-3D (PDB: 1HCL) 03 CDK2 clinical research drugs Since 1990s, the development of CDK2 inhibitors has entered the clinical stage, but almost all of them are multi-target inhibitors
.
Orthomorphic direction, the Ilel0, Vall8, Ala31, Lys33, Phe80, Glu81, Phe8, Leu83, His84, Gln85, Asp86, Lys89, Glnl31, Leul34, Alal44 and Aspl45 in CDK2 play a role in the process of binding ATP critical use
.
However, due to the high degree of conservation of the ATP binding pocket in the CDK protein family, it is difficult to develop selective CDK2 inhibitors for the ATP binding pocket.
Therefore, non-ATP-binding allosteric inhibitors are also under development, and two new inhibitors have been discovered.
Binding pocket: 1) It is composed of Leu55, Lys56, Phe80, Asp145, Phe146 and Lys33, located between the ATP binding site and the C-terminal helix; 2) It is composed of Leu124, Phe152, Val154-156, Glu172, Gly176, Thr182, Val184 , Val227-230, Ser232-234 and Asp270-Asn272
.
Dinaciclib (Phase III) The development company is Merck, which is a CDK1/2/5/9 inhibitor.
It is currently in clinical phase III for the treatment of refractory chronic lymphocytic leukemia
.
In 2011, the FDA granted Dinaciclib an orphan drug designation for the treatment of CLL
.
This variety has inhibitory activity on CDK2, CDK5, CDK1 and CDK9, with IC50 of 1nM, 1nM, 3nM and 4nM respectively; clinical research results show that when Dinaciclib and rituximab are used in combination to treat relapsed chronic lymphocytic leukemia, The patient is well tolerated
.
Seliciclib (Phase II) The development company is Cyclacel Pharmaceuticals.
It is the lead compound of the CYC-200 series of oral small molecule cyclin-dependent kinase (CDK1/2/5/7) inhibitors.
It has been tested in more than 100 cell lines.
The determination of anti-proliferative activity is currently in clinical phase II.
It is used for the treatment of B lymphocytic leukemia and is used in combination with gemcitabine/cisplatin as a first-line treatment for non-small cell lung cancer
.
In addition, the company is also studying the drug for the potential treatment of inflammation associated with SARS-CoV-2 infection (COVID-19)
.
PF-07104091 (Phase I/II) The development company is Pfizer, which is a selective inhibitor of CDK2.
It is orally used for the treatment of a variety of cancers, including breast cancer, small cell lung cancer, non-small cell lung cancer, and ovarian cancer
.
In September 2020, it launched Phase I/II trials of advanced SCLC, advanced epithelial ovarian/fallopian tube/primary peritoneal cancer, advanced breast cancer and advanced NSCLC; in October 2020, the company listed the drug as metastatic breast Phase I trials for cancer
.
In April 2021, the pre-clinical data was announced at the 112th AACR Annual Meeting: In the OVCAR3 model, PF-07104091 (25, 75 and 175 mg/kg, po, bid) showed a dose-dependent tumor reduction, with a maximum effect of 86 %; In the CCNE1 (high) ovarian model (OV5392), PF-07104091 (75 and 150 mg/kg, po, bid) showed tumor growth inhibition similar to that observed in OVCAR-3; NCI-H526 cells (Rb( mut)) SCLC model, PF-07104091 (25, 75, 175 or 150mg/kg, po, bid) showed single drug activity; in ER+HER2- breast cancer cell line, PF-07104091 and palbociclib showed synergistic Cell growth inhibitory effect; in the T47D model, PF-07104091 (150mg/kg, po, bid) + palbociclib (10mg/kg, po, bid) showed a combined effect
.
Ebvaciclib (Phase I/II) The development company is Pfizer, which is a CDK2/4/6 inhibitor; in November 2018, at the 30th AACR annual meeting in Dublin, Ireland, the in vitro and in vivo data of Ebvaciclib were first announced ; Ebvaciclib has higher binding affinity to CDK2, 4, 5 and 6, which is 40 times higher than off-target CDK1 and CDK9
.
In March 2018, it was initiated in refractory/relapsed patients who have received CDK4/6 inhibitor treatment and HR-positive HER2-negative breast cancer, metastatic triple-negative breast cancer, or advanced platinum-resistant epithelial ovarian cancer/fallopian tube cancer Phase I/II trials are expected to obtain trial data in 2021
.
Fadraciclib (Phase I) The development company is Cyclacel Pharmaceuticals, a CDK2/9 inhibitor, intravenously used to treat advanced cancers, including chronic lymphocytic leukemia, acute myeloid leukemia, and myelodysplastic syndrome
.
In April 2018, the preclinical data was announced at the 109th AACR Annual Meeting in Chicago; in November 2018, the clinical phase I trial for relapsed or refractory CLL was launched; in July 2019, the relapse or refractory CLL was launched Phase I clinical trials of AML and MDS
.
NUV-422 (Phase I/II) The development company is Nuvation Bio, which is a CDK2/4/6 inhibitor and is clinically developed for the treatment of glioma
.
In November 2020, a phase I/II trial for adult patients with relapsed or refractory high-grade glioma was launched; in February 2021, the company plans to initiate a phase I trial for brain metastasis, and then start brain metastasis, female A phase I trial for hormone receptor-positive metastatic breast cancer, and then a phase I trial for metastatic castration-resistant prostate cancer
.
Figure 3.
2 Partial chemical structure of CDK2 inhibitor 04 Domestic R&D follow-up status Through patent inquiry, domestic development of CDK2 inhibitors: foreign applicants mainly include Avantis Pharmaceuticals, Hoffman-La Roche Co.
, Ltd.
, etc.
; domestic applicants mainly China Pharmaceutical University, Sichuan University, Binzhou Medical College, Changzhou University, Jiangnan University, and so on
.
It is not difficult to see that at present, there is no large number of pharmaceutical companies to follow up on the target species in China, and the track is unobstructed.

.
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Targeting CDK2 in cancer: challenges and opportunities for therapy.
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2.
To control or to be controlled? Dual roles of CDK2 in DNA damage and DNA damage response.
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dnarep.
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102702.
3.
Research on the function of cyclin-dependent kinase 2 and its inhibitors.
Chinese Journal of Cell Biology/2021.
4.
CDK inhibition Progress in the research and development of anti-tumor agents.
Pharmaceutical Progress/2015.