ATP-competitive inhibitors for cancer treatment – kinases and the world beyond

Jug, Ana (author), Ilaš, Janez (author)

Adenosine 5′-(tetrahydrogen triphosphate) (ATP), an essential molecule for cellular energy transfer, plays a crucial role in various biochemical processes, including protein folding, DNA repair and intracellular signalling. A promising strategy for the development of anticancer therapies is to target ATP-binding sites of proteins involved in these processes with ATP-competitive inhibitors. They either mimic ATP to block its binding or bind allosterically to induce conformational changes that prevent ATP interaction. While protein kinases are the main focus of ATP-competitive inhibitors used in cancer therapy, other non-kinase targets such as Hsp90, Topo II, p97, RNA helicases and ABC transporters are also recognized as important molecular targets. Their inhibition can overcome resistance to kinase inhibitors, which develops due to mutations in kinase domains, and at the same time alter essential properties of cancer cells. Although they target different protein families, selectivity remains a challenge due to the conserved nature of ATP binding sites. However, the structural differences between the target proteins allow the development of specific inhibitors. In addition, dual inhibitors targeting multiple ATP-dependent proteins can increase therapeutic efficacy, reduce drug resistance and minimize side effects. Several ATP-competitive kinase inhibitors are already approved for clinical use and many more are in clinical trials, demonstrating their potential in cancer therapy. In this review, we focus on ATP-competitive inhibition in cancer therapy beyond kinases, highlighting recent advances and challenges in the field while applying lessons learned from the development of kinase inhibitors.

• Language: English
• Keywords: protein kinase inhibitors, cancer treatment, pharmaceutical chemistry, cancer, medicine
• Work type: Article
• Typology: 1.02 - Review Article
• Organization: FFA - Faculty of Pharmacy
• Publication status: Published
• Publication version: Version of Record
• Year: 2025
• Number of pages: Str. 4044-4067
• Numbering: Vol. 16, iss. 9
• PID: 20.500.12556/RUL-178382
• UDC: 615.4:54:616-006
• ISSN on article: 2632-8682
• DOI: 10.1039/D5MD00235D
• COBISS.SI-ID: 250742787
• Publication date in RUL: 26.01.2026

Record is a part of a journal

• Title: RSC medicinal chemistry
• Shortened title: RSC med. chem.
• Publisher: Royal Society of Chemistry
• ISSN: 2632-8682
• COBISS.SI-ID: 304960512

Licences

• License: CC BY 3.0, Creative Commons Attribution 3.0 Unported
• Link: https://creativecommons.org/licenses/by/3.0/deed.en
• Description: You are free to reproduce and redistribute the material in any medium or format. You are free to remix, transform, and build upon the material for any purpose, even commercially. You must give appropriate credit, provide a link to the license, and indicate if changes were made. You may do so in any reasonable manner, but not in any way that suggests the licensor endorses you or your use. You may not apply legal terms or technological measures that legally restrict others from doing anything the license permits.

Secondary language

• Language: Slovenian
• Keywords: zaviralci proteinske kinaze, zdravljenje raka, farmacevtska kemija, rak, medicina