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Rapid Discovery of Pyrido[3,4-d]pyrimidine Inhibitors of Monopolar Spindle Kinase 1 (MPS1) Using a Structure-Based
Paolo Innocenti1, Hannah L Woodward1, Savade Solanki1
1Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research , 15 Cotswold Road, Sutton, London, SM2 5NG, United Kingdom.
Abstract:
Monopolar spindle 1 (MPS1) plays a central role in the transition of cells from metaphase to anaphase and is one of the main components of the spindle assembly checkpoint. Chromosomally unstable cancer cells rely heavily on MPS1 to cope with the stress arising from abnormal numbers of chromosomes and centrosomes and are thus more sensitive to MPS1 inhibition than normal cells. We report the discovery and optimization of a series of new pyrido[3,4-d]pyrimidine based inhibitors via a structure-based hybridization approach from our previously reported inhibitor CCT251455 and a modestly potent screening hit. Compounds in this novel series display excellent potency and selectivity for MPS1, which translates into biomarker modulation in an in vivo human tumor xenograft model.
Insights
New pyrido[3,4-d]pyrimidine inhibitors targeting Monopolar spindle 1 (MPS1) show high potency and selectivity. These compounds effectively modulate biomarkers in vivo, offering a promising strategy against chromosomally unstable cancers.
Area of Science:
- Cell biology
- Molecular oncology
- Medicinal chemistry
Background:
- Monopolar spindle 1 (MPS1) is crucial for cell cycle progression, particularly the metaphase-to-anaphase transition.
- The spindle assembly checkpoint relies on MPS1 for proper chromosome segregation.
- Cancer cells with chromosomal instability depend on MPS1 and are sensitive to its inhibition.
Purpose of the Study:
- To discover and optimize novel MPS1 inhibitors.
- To develop pyrido[3,4-d]pyrimidine derivatives with improved potency and selectivity.
- To evaluate the in vivo efficacy of these inhibitors.
Main Methods:
- Structure-based drug design and hybridization approach.
- Synthesis and in vitro characterization of pyrido[3,4-d]pyrimidine compounds.
- In vivo evaluation in human tumor xenograft models.
Main Results:
- Discovery of a novel series of potent and selective MPS1 inhibitors.
- Optimization yielded compounds with excellent biochemical and cellular activity.
- Demonstrated in vivo biomarker modulation in a tumor xenograft model.
Conclusions:
- The novel pyrido[3,4-d]pyrimidine inhibitors represent a promising therapeutic strategy for cancers with chromosomal instability.
- Structure-based design effectively generated potent and selective MPS1 inhibitors.
- In vivo efficacy supports further development of these compounds for cancer treatment.
