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Structural analysis of PIM1 kinase complexes with ATP-competitive inhibitors
Jozefina Bogusz1,2, Karol Zrubek1,2, Krzysztof P Rembacz1,2
1Malopolska Centre of Biotechnology, Jagiellonian University, Gronostajowa 7a, 30-387, Krakow, Poland.
Abstract:
PIM1 is an oncogenic kinase overexpressed in a number of cancers where it correlates with poor prognosis. Several studies demonstrated that inhibition of PIM1 activity is an attractive strategy in fighting overexpressing cancers, while distinct structural features of ATP binding pocket make PIM1 an inviting target for the design of selective inhibitors. To facilitate development of specific PIM1 inhibitors, in this study we report three crystal structures of ATP-competitive inhibitors at the ATP binding pocket of PIM1. Two of the reported structures (CX-4945 and Ro-3306) explain the off-target effect on PIM1 of respectively casein kinase 2 and cyclin-dependent kinase 1 dedicated inhibitors. In turn, the structure with CX-6258 demonstrates a binding mode of a potent, selective inhibitor of PIM1, PIM2, PIM3 and Flt-3 kinases. The consequences of our findings for future inhibitor development are discussed.
Insights
This study reveals the crystal structures of PIM1 kinase inhibitors, aiding the development of targeted cancer therapies. Understanding these structures helps design more effective PIM1 inhibitors for cancer treatment.
Area of Science:
- Biochemistry
- Structural Biology
- Oncology
Background:
- PIM1 kinase is an oncogene overexpressed in various cancers, linked to poor patient prognosis.
- Inhibiting PIM1 kinase is a promising strategy for cancer therapy.
- The ATP binding pocket of PIM1 presents a target for selective inhibitor design.
Purpose of the Study:
- To elucidate the structural basis of PIM1 kinase inhibition.
- To understand off-target effects of existing inhibitors.
- To guide the development of novel, selective PIM1 inhibitors.
Main Methods:
- X-ray crystallography was used to determine the structures of PIM1 in complex with inhibitors.
- Analysis of inhibitor binding modes within the ATP binding pocket.
Main Results:
- Crystal structures of three ATP-competitive inhibitors (CX-4945, Ro-3306, CX-6258) bound to PIM1 were determined.
- Structures of CX-4945 and Ro-3306 explain their off-target effects on PIM1.
- The structure of CX-6258 reveals its potent and selective inhibition of PIM1, PIM2, PIM3, and Flt-3 kinases.
Conclusions:
- The determined crystal structures provide crucial insights into PIM1 inhibitor binding.
- These findings facilitate the rational design of more selective and potent PIM1-targeting cancer drugs.
- Understanding inhibitor interactions is key for advancing PIM1-based cancer therapies.