Small molecule DNA-PK inhibitors as potential cancer therapy: a patent review (2010–present)

ABSTRACT

Introduction: DNA-dependent protein kinase (DNA-PK) plays a crucial role in the repair of DSBs via non-homologous end joining (NHEJ). Several DNA-PK inhibitors are being investigated for potential anticancer treatment in clinical trials.

Area covered: This review aims to give an overview of patents published since 2010 by analyzing the patent space and structure features of scaffolds used in those patents. It also discusses the recent clinical developments and provides perspectives on future challenges and directions in this field.

Expert opinion: As a key component of the DNA damage response (DDR) pathway, DNA-PK appears to be a viable drug target for anticancer therapy. The clinical investigation of a DNA-PK inhibitor employs both a monotherapy and a combination strategy. In the combination strategy, a DNA-PK inhibitor is typically combined with a DSB inducer, radiation, a chemotherapy agent, or a PARP inhibitor, etc. Patent analyses suggest that diverse structures comprising different scaffolds from mono-heteroaryl to bicyclic heteroaryl to tricyclic heteroaryl are capable to achieve good DNA-PK inhibitory activity and good DNA-PK selectivity over other closely related enzymes. Several DNA-PK inhibitors are currently being evaluated in clinics, with the hope to get approval in the near future.

KEYWORDS:

• DNA double strand breaks (DSBs)
• DNA damage response (DDR)
• DNA-PK
• inhibitor
• cancer therapy
• patent review

Article highlights

• DNA-PK is an enzyme playing a crucial role in the repair of DSBs via non-homologous end joining (NHEJ). DNA-PK appears to be a viable drug target for anticancer therapy.

• DNA-PK belongs to phosphatidylinositol 3-kinase-related kinase (PIKK) family. Due to structure similarity, developing a DNA-PK inhibitor with good selectivity over PIKK family members such as ATM and ATR as well as PI3K enzymes is challenging but achievable.

• Although the minimal efficacy was seen in the monotherapy of nedisertib (M3814), the result doesn’t rule out the monotherapy of this drug target. The clinical activities involving both monotherapy and a combination strategy of a DNA-PK inhibitor are ongoing. In the clinical development, a DNA-PK inhibitor is typically used in the combination with a DSBs inducer such as radiation, a PARP inhibitor.

• Patent analysis reveals that diverse structures bearing scaffolds from monocyclic heteroaryl to bicyclic heteroaryl to tricyclic heteroaryl have good DNA-PK inhibitory activity.

• Several DNA-PK inhibitors are in advanced clinical studies. It’s hopeful that a DNA-PK inhibitor drug will be approved in the near future.

This box summarizes key points contained in the article.

Declaration of interest

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was funded by the National Natural Science Foundation of China (81730108 and 81973635), Hangzhou Normal University startup fund (4125C5021920419), the French National Research Agency under the program “Investissements d’Avenir” with reference ANR-11-LABX-0021 (LabEX LipSTIC), and the Agence Nationale de la Recherche (grant ANR-17-CE17-0023 to FL).