Abstract
Advancements in targeted protein degradation (TPD) technologies are spearheading a new era in precision oncology, offering unprecedented avenues for tackling key oncogenic drivers such as Cyclin-dependent kinase 2 (CDK2). As a pivotal regulator of the cell cycle, CDK2’s aberrant activity is closely linked with cancer progression, making it a prime target for therapeutic intervention. This Patent Highlight delves into the innovative TPD strategies aimed at CDK2 degradation, illustrating their potential to disrupt cancer cell proliferation and reshape the therapeutic landscape significantly. By extending the focus to other critical proteins within cancer biology, the discussion emphasizes TPD technologies’ versatility and transformative potential in delivering targeted, efficacious cancer therapies.
Important Compound Classes
Titles
Bifunctional Compounds Containing 2,5-Substituted Pyrimidine Derivatives for Degrading Cyclin-Dependent Kinase 2 via Ubiquitin Proteasome Pathway; Bifunctional Compounds Containing Pyrimidine Derivatives for Degrading Cyclin-Dependent Kinase 2 via Ubiquitin Proteasome Pathway; and Bifunctional Compounds Containing Pyrido[2,3-Djpyrimidin-7(8H)-one Derivatives for Degrading Cyclin-Dependent Kinase 2 via Ubiquitin Proteasome Pathway
Patent Publication Numbers
WO 2024/102849 A1 (URL: https://patents.google.com/patent/WO2024102849A1/en?oq=WO+2024%2f102849+A1;
WO 2023/249970 A1 (URL: https://patents.google.com/patent/WO2023249970A1/en?oq=WO+2023%2f249970+A1);
WO 2023/249968 A1 (URL: https://patents.google.com/patent/WO2023249968A1/en?oq=WO+2023%2f249968+A1).
Publication Dates
May 16, 2024 (WO 2024/102849 A1); December 28, 2023 (WO 2023/249970 A1 and WO 2023/249968 A1)
Priority Applications
US 63/528,596; US 63/354,233; US 63/354,669
Priority Dates
July 24, 2023; June 21, 2022; June 22, 2022
Inventors
Yu, Z.; Lou, Y. (WO 2024/102849 A1); Lou, Y.; Yu, Z. (WO 2023/249970 A1 and WO 2023/249968 A1)
Assignee Companies
Nikang Therapeutics, Inc. [US/US], 200 Powder Mill Road, BLDG E500, Wilmington, Delaware 19803, USA
Disease Area
Cancer
Biological Target
CDK2
Summary
In the quest to improve cancer treatment outcomes, the role of Cyclin-dependent kinase 2 (CDK2) as a critical regulator of the cell cycle and a driver of cancer progression has drawn significant attention. CDK2’s involvement in cell cycle regulation makes it an attractive target for therapeutic intervention, particularly in cancers where its activity is deregulated. Traditional therapeutic strategies have aimed at inhibiting CDK2 activity; however, targeted protein degradation (TPD) technologies offer a more radical approach: the selective degradation of CDK2 itself. This article explores the innovative TPD approaches focused on CDK2 degradation, highlighting their potential to halt cancer cell proliferation and the implications for precision oncology.
Recent developments in TPD technologies have led to designing strategies specifically targeting CDK2 for degradation. These innovative approaches, documented in various patents, propose using bifunctional molecules that bridge CDK2 to E3 ubiquitin ligases, tagging it for degradation via the ubiquitin-proteasome system. This targeted degradation of CDK2 aims to directly dismantle the machinery that drives cancer cell proliferation, offering a potentially more effective and less resistance-prone treatment option than traditional kinase inhibitors.
The targeted degradation of CDK2 represents a significant leap forward in cancer therapy, providing a strategy that could effectively halt the progression of tumors dependent on CDK2’s activity for growth and survival. This approach underscores the specificity and efficacy of TPD technologies and highlights their potential to transform cancer treatment paradigms.
The application of TPD technologies extends beyond CDK2, encompassing a wide range of proteins implicated in cancer biology. By targeting various oncogenic drivers for degradation, TPD strategies offer a versatile toolkit for precision oncology, enabling the design of therapies tailored to the specific molecular profiles of individual cancers.
Exploring additional targets for TPD-based therapies has the potential to significantly diversify and enhance the arsenal of cancer treatments. This includes proteins that have been traditionally challenging to target with small molecules or antibodies, offering new hope for tackling cancers with complex genetic landscapes or those resistant to existing therapies.
Despite the promising advances, expanding the spectrum of TPD targets presents several challenges. Achieving high specificity in targeting proteins for degradation is paramount to avoid off-target effects that could lead to toxicity. Additionally, the potential for cancer cells to develop resistance to TPD-based therapies through mutations that prevent the recognition or binding of the bifunctional molecules remains a concern. The continued evolution of TPD technologies promises to play a pivotal role in advancing precision oncology. Overcoming the challenges of specificity and resistance will be essential to fully realizing the potential of TPD strategies. The ongoing research and development in this field are expected to expand the range of targetable proteins and refine the mechanisms of action, paving the way for more effective, targeted, and durable cancer therapies.
As such, the role of TPD in targeting CDK2 and beyond represents a transformative shift in the approach to cancer therapy. By leveraging the cell’s degradation mechanisms to target and eliminate key oncogenic drivers specifically, TPD technologies offer a powerful platform for developing next-generation cancer therapeutics, marking a significant stride toward achieving the goals of precision oncology.
Key Structures
Biological Assay
Phospho-Rb assay
Biological Data
The table provides IC50 of
CDK2 PROTAC exemplary compounds in pRB(S807/811) assay, where A =
< 0.1 μM; 0.1 μM < B ≤ 0.5 μM.
Recent Review Articles
The author declares no competing financial interest.
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