From "pan" to "fine", can it become another anti-cancer potential target after CDK4/6?

ArticleMedicine Guanlan

At the European Society of Medical Oncology (ESMO) conference held in September 2021, an emerging anti-cancer drug target has attracted people's attention, that is, CDK7
.
At this conference, Carrick Therapeutics and Syros Pharmaceuticals respectively announced the positive results of clinical trials of their CDK7 inhibitors

Like the well-known CDK4/6, CDK7 is also a member of the cyclin family and is closely related to the occurrence of cancer
.
In the past two decades, scientists have been exploring the development of targeted anti-cancer drugs for CDK7

CDK7 and cancer

CDK7 is called cyclin-dependent kinase 7, and it forms CDK-activated kinase (CAK) together with cyclin H and MAT1
.
CDK-activated kinase provides phosphorylation of the T-loop required to activate CDK1, CDK2, CDK4 and CDK6, thereby driving the progression of the cell cycle, in which CDK7 plays an important role

As a component of the general transcription factor complex TFIIH, CDK-activated kinase also plays a role in transcriptional regulation
.
CDK7 can not only phosphorylate the C-terminal domain of RNA polymerase II to promote transcription initiation, but also phosphorylate CDK9 to drive transcription elongation

The close relationship between CDK7 and tumorigenesis was discovered twenty years ago
.
At that time, scientists performed immunohistochemical analysis of a range of tumor types

Existing studies have shown that in estrogen receptor positive (ER+) breast cancer, the three components of CDK-activated kinase CDK7, cyclin H and MAT1 are all overexpressed
.
In addition, in gastric cancer, ovarian cancer, oral squamous cell carcinoma (OSCC), hepatocellular carcinoma and glioblastoma, the researchers also observed an association between CDK7 expression and reduced survival rates

The twists and turns of development

Due to the dual role of CDK7 in regulating cell cycle and transcription, and its close relationship with cancer, researchers have already begun to try to develop anti-cancer drugs that target CDK7
.
The early development of CDK inhibitors are mainly pan-CDK inhibitors, which have activities against a variety of CDKs, usually including CDK7

Alvocidib (flavopiridol) is the first CDK inhibitor to enter clinical trials.
It is a semi-synthetic flavonoid derivative that can inhibit the activity of CDK1, CDK2, CDK4, CDK6, CDK7 and CDK9
.
Between 2008 and 2014, researchers evaluated alvocidib in more than 60 clinical trials for multiple tumor types

Another early pan-CDK inhibitor is the purine-based compound seliciclib (roscovitine), which can inhibit CDK1, CDK2, CDK5, CDK7, and CDK9
.
Researchers have evaluated it in clinical trials of various tumor types, but like alvocidib, seliciclib has only shown limited clinical activity
.

Since then, researchers have begun to try to develop CDK inhibitors with higher selectivity to CDK1 and CDK2.
These efforts have given birth to the second generation of multi-target CDK inhibitors.
SNS-032 is an example of this, which is an amino group-based inhibitor.
Thiazole compounds can effectively inhibit CDK2, CDK7 and CDK9
.
SNS-032 has conducted phase 1 clinical trials in advanced lymphatic system and advanced solid malignancies, but has not made more progress
.

The main reason why early CDK inhibitors failed clinically was their inability to selectively target individual CDK family members
.
Because CDK protein is also vital to the function of normal tissues, pan-CDK inhibitors cannot accurately distinguish cancer cells from normal cells, which makes their treatment window very narrow, and fatigue, diarrhea, nausea, and hyperglycemia may also occur.
Toxicity
.
In addition, the lack of specificity also makes it difficult for researchers to determine which CDK activities are inhibited by pan-CDK inhibitors in vivo
.
These limitations limit the further development of pan-CDK inhibitors as targeted therapies
.

In recent years, research in the field of CDK inhibitors has mainly focused on further improving the selectivity of CDK inhibitors.
The most successful case is selective CDK4/6 inhibitors
.
Up to now, a variety of CDK4/6 inhibitors have been approved for the treatment of hormone receptor (HR) positive metastatic breast cancer worldwide, including Pfizer's Ibrance (palbociclib) and Novartis's Kisqali (ribociclib) and Lilly (Eli Lilly and company) company Verzenio (abemaciclib) and so on
.
These advances provide researchers with confidence in the development of selective inhibitors that precisely target CDK7 and other CDKs
.

From "pan" to "fine", CDK7 inhibitors welcome new progress

According to a review published in Cancer and Metastasis Reviews in 2020, the first highly selective CDK7 inhibitor developed is BS-181, which is a pyrazolopyrimidine derivative
.
Although its in vivo activity has been confirmed, its poor bioavailability and insufficient cell permeability hinder its further development as a clinical drug candidate
.
Therefore, on this basis, researchers have developed BS-181 analogs that not only retain the selectivity of CDK7, but also have improved drug properties, and thus produced the first oral bioavailable highly selective CDK7 inhibitor Agent-samuraciclib (ICEC0942, CT7001)
.

Studies have shown that samuraciclib can effectively inhibit the growth of cancer cell lines and ER+ breast cancer cells, and has good absorption, distribution, metabolism, excretion and pharmacokinetic (PK) characteristics, which makes it a potential Clinical drug candidates
.
Samuraciclib has been licensed to Carrick Therapeutics, and recently obtained fast track qualification granted by the US FDA for the treatment of CDK4/6 inhibitor-resistant HR-positive and HER2-negative advanced breast cancer in combination with fulvestrant, as well as in combination with chemotherapy Treatment of locally advanced or metastatic triple-negative breast cancer
.

At the ESMO conference in 2021, Carrick Therapeutics announced the positive phase 2a clinical data of the combination of samuraciclib and fulvestrant in the treatment of patients with advanced HR+ and HER2- breast cancer: Of the 24 patients whose efficacy can be evaluated, 17 patients have tumors Reduced, 2 cases had partial remission (PR), 13 cases (54%) had stable disease (SD); the median progression-free survival (mPFS) of the intention-to-treat (ITT) population was 16.
1 weeks (n=31), The mPFS of patients with TP53 gene mutation was 32.
0 weeks (n=18)
.
At present, Carrick Therapeutics is also evaluating samuraciclib in triple-negative breast cancer and prostate cancer, and plans to explore the therapeutic potential of the candidate drug in pancreatic, ovarian, and colorectal cancer
.

At the same time, researchers have also developed many covalent CDK7 inhibitors
.
The first is THZ1, which targets the cysteine ​​residue (Cys312) on the C-terminal extension outside the CDK7 ATP binding site and has strong activity in many cancer types
.
However, studies have shown that in addition to CDK7, the anti-transcriptional and anti-tumor activity of THZ1 also depends on the inhibition of CDK12 and CDK13
.
Therefore, the researchers developed YKL-5-124 on this basis
.
Like THZ1, YKL-5-124 is covalently linked to Cys312 of CDK7, but does not affect the activities of CDK12 and CDK13
.

Syros Pharmaceuticals has obtained the exclusive global authorization of a variety of CDK7 inhibitors including THZ1 from Dana-Farber Cancer Institute, and has developed THZ2, SY-1365 and other CDK7 inhibitors based on THZ1
.
At present, Syros Pharmaceuticals' rapid research progress is a new type of oral CDK7 inhibitor SY-5609
.
Public information shows that SY-5609 has higher selectivity and efficacy against CDK7, and therefore has become a priority development target for Syros Pharmaceuticals
.

At the ESMO conference in 2021, Syros Pharmaceuticals announced the results of a phase 1 clinical trial of SY-5609 as a single drug for the treatment of multiple cancer types
.
The study showed that among the 45 refractory patients who received an average of 4 pre-treatments, SY-5609 achieved stable disease in 13 (28.
9%) patients, and the tumor shrinkage of 6 patients reached 20%
.
The clinical activity of SY-5609 is the most obvious among patients with advanced pancreatic cancer who have received a variety of pre-treatments.
38.
5% (5/13) of the evaluable patients reached stable disease, and two of them had tumor shrinkage
.

Another CDK7 inhibitor entering the clinical stage is XL102, which is a selective, orally bioavailable covalent CDK7 inhibitor, introduced by Exelixis from Aurigene
.
In January 2021, Exelixis announced the initiation of phase 1 clinical trials of XL102 to evaluate its safety, tolerability, pharmacokinetics, and preliminary treatment of patients with advanced or metastatic solid tumors as a single agent and in combination with other anticancer drugs.
Anti-tumor activity
.
In the subsequent expansion phase of the cohort, XL102 will be evaluated in certain types of ovarian, breast, and prostate cancer patients
.

In addition, some other companies are also developing highly selective CDK7 inhibitors
.
For example, Perlon Bio is developing a series of new generation CDK inhibitors
.
According to the press release issued by Protobio in July 2021, the company has successfully designed a highly selective, non-covalent CDK7 inhibitor through cooperation
.

According to existing research findings, in addition to monotherapy, another development potential of CDK7 inhibitors is combination therapy
.
Studies have found that CDK7 inhibitors can be combined with anti-estrogen therapy, Bcl-2 inhibitors, BET inhibitors, histone deacetylase (HDAC) inhibitors, immunotherapy (such as PD-1 inhibitors, etc.
) to treat cancer.
Potential
.
Carrick Therapeutics is carrying out clinical trials of the combination of samuraciclib and fulvestrant in the treatment of breast cancer, and plans to explore the combined therapeutic potential of samuraciclib and the next generation of oral selective estrogen receptor downregulators (SERD) giredestrant and other more drugs
.
Syros Pharmaceuticals will also plan to evaluate the effect of SY-5609 in combination with chemotherapy, BTK inhibitors, or immunotherapy to treat a variety of different types of solid tumors and hematological malignancies
.

In general, as an emerging drug target, the development of selective inhibitors of CDK7 is still in the early stages
.
For those cancer patients who are congenital or acquired resistance to other drugs, CDK7 inhibitors are expected to provide them with a new treatment strategy
.
It is hoped that with the progress of research, more breakthroughs can be made in the development of selective inhibitors of CDK7, which will bring new treatment options to cancer patients as soon as possible
.

references:

[1]Sava GP, Fan H, et al.
(2020).
CDK7 inhibitors as anticancer drugs.
Cancer Metastasis Rev.
doi:10.
1007/s10555-020-09885-8

[2] Carrick Therapeutics Presents Encouraging Initial Efficacy for Samuraciclib (CT-7001) in Combination with Fulvestrant in Advanced HR+, HER2- Breast Cancer Patients at ESMO Congress 2021.
Retrieved September 16, 2021, from https:// /article/releases/carrick-therapeutics-presents-encouraging-initial-efficacy-for-samuraciclib-ct-7001-in-combination-with-fulvestrant-in-advanced-hr-her2-breast-cancer-patients-at-esmo -congress-2021/

[3] Exelixis Announces Initiation of Phase 1 Trial Evaluating XL102 as a Single Agent and in Combination with Other Anti-Cancer Agents in Patients with Advanced or Metastatic Solid Tumors.
Retrieved Jan 25, 2021, from https:// /article/releases/exelixis-announces-initiation-of-phase-1-trial-evaluating-xl102-as-a-single-agent-and-in-combination-with-other-anti-cancer-agents-in-patients -with-advanced-or-metastatic-solid-tumors/

[4]PionBio and Exscientia deepen cooperation to accelerate the development of new anti-tumor drugs.
Retrieved July 21, 2021, from http://43.
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