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

Abstract

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.

Fig. 1. Different inhibition mechanisms. 1A: Active enzyme with bound ATP molecule. 1B: Competitive inhibitor binds to the ATP-binding pocket and prevents the binding of ATP to the enzyme. 1C: Allosteric inhibitor changes the conformation of the ATP-binding pocket and prevents binding.

Fig. 2. Structures of FDA approved ATP-competitive protein kinase inhibitors since 2019 (name; molecular target; year of approval).

Fig. 3. Superimposed Eg5 in complex with AMPPNP (PDB: 3HQD) and Eg5 in complex with PVZB1194 (PDB: 3WPN).

Fig. 4. p97 inhibitors – quinazoline derivatives.

Fig. 5. Design of QAP-1, the first catalytic ATP-competitive inhibitor of human topoisomerase IIα as a preclinical candidate.

Fig. 6. Chemical structures of Topo II inhibitors that act as ATP-mimetics compared to an ATP molecule.

Fig. 7. Predicted binding pose of 1,2,4-substituted N-phenylpyrrolamide inhibitor.

Fig. 8. Topo II inhibitors bearing pyrazole and pyrazoline scaffolds.

Fig. 9. Topoisomerase inhibitors derived from natural products.

Fig. 10. Optimization of SMARCA inhibitors.

Ana Jug

Janez Ilaš