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A unique hinge binder of extremely selective aminopyridine-based Mps1 (TTK) kinase inhibitors with cellular activity
Ken-ichi Kusakabe1, Nobuyuki Ide1, Yataro Daigo2
1Medicinal Research Laboratories, Shionogi Pharmaceutical Research Center, 1-1 Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan.
Abstract:
Mps1, also known as TTK, is a dual-specificity kinase that regulates the spindle assembly check point. Increased expression levels of Mps1 are observed in cancer cells, and the expression levels correlate well with tumor grade. Such evidence points to selective inhibition of Mps1 as an attractive strategy for cancer therapeutics. Starting from an aminopyridine-based lead 3a that binds to a flipped-peptide conformation at the hinge region in Mps1, elaboration of the aminopyridine scaffold at the 2- and 6-positions led to the discovery of 19c that exhibited no significant inhibition for 287 kinases as well as improved cellular Mps1 and antiproliferative activities in A549 lung carcinoma cells (cellular Mps1 IC₅₀=5.3 nM, A549 IC₅₀=26 nM). A clear correlation between cellular Mps1 and antiproliferative IC₅₀ values indicated that the antiproliferative activity observed in A549 cells would be responsible for the cellular inhibition of Mps1. The X-ray structure of 19c in complex with Mps1 revealed that this compound retains the ability to bind to the peptide flip conformation. Finally, comparative analysis of the X-ray structures of 19c, a deamino analogue 33, and a known Mps1 inhibitor bound to Mps1 provided insights into the unique binding mode at the hinge region.
Insights
Researchers developed a novel Mps1 kinase inhibitor, 19c, demonstrating potent antiproliferative effects in lung cancer cells. This targeted approach shows promise for cancer therapeutics by selectively inhibiting Mps1.
Area of Science:
- Biochemistry
- Molecular Biology
- Medicinal Chemistry
Background:
- Mps1 (TTK) is a dual-specificity kinase crucial for the spindle assembly checkpoint.
- Elevated Mps1 expression in cancer correlates with tumor grade, suggesting it as a therapeutic target.
Purpose of the Study:
- To develop selective Mps1 inhibitors for cancer therapy.
- To investigate the structure-activity relationship of novel aminopyridine-based Mps1 inhibitors.
Main Methods:
- Lead optimization of an aminopyridine scaffold.
- In vitro kinase inhibition assays and cellular assays (antiproliferative, cellular Mps1 inhibition).
- X-ray crystallography to determine the binding mode of inhibitors.
Main Results:
- Compound 19c showed potent cellular Mps1 inhibition (IC₅₀=5.3 nM) and antiproliferative activity in A549 lung carcinoma cells (IC₅₀=26 nM).
- 19c demonstrated high selectivity, with no significant inhibition against 287 other kinases.
- X-ray structures revealed 19c binds to the flipped-peptide conformation at the Mps1 hinge region.
Conclusions:
- Selective Mps1 inhibition via compounds like 19c is a viable strategy for cancer therapeutics.
- The observed antiproliferative activity is directly linked to cellular Mps1 inhibition.
- Structural insights elucidate the unique binding interactions at the Mps1 hinge region.
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