ArticleJournal of medicinal chemistry2018
Introduction of a Methyl Group Curbs Metabolism of Pyrido[3,4- d]pyrimidine Monopolar Spindle 1 (MPS1) Inhibitors and Enables the Discovery of the Phase 1 Clinical Candidate N
Article in Journal of medicinal chemistry, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
What it found
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
9 citing papers in PubMed, 33 citations in OpenAlex.
- MPS1 inhibition as an anticancer strategy: where do we stand?Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology · 2026Review
- TTK Inhibition Alleviates Postinjury Neointimal Formation and Atherosclerosis.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Exploring the Therapeutic Implications of Co-Targeting the EGFR and Spindle Assembly Checkpoint Pathways in Oral Cancer.Pharmaceutics · 2024Review
- The two sides of chromosomal instability: drivers and brakes in cancer.Signal transduction and targeted therapy · 2024Review
- Computational Biology Dynamics of Mps1 Kinase Molecular Interactions with Isoflavones Reveals a Chemical Scaffold with Potential to Develop New Therapeutics for the Treatment of Cancer.International journal of molecular sciences · 2022Article
- Inhibition of Mps1 kinase enhances taxanes efficacy in castration resistant prostate cancer.Cell death & disease · 2022Article
- Review on the Synthesis and Therapeutic Potential of Pyrido[2,3-Pharmaceuticals (Basel, Switzerland) · 2022Review
- Studies of Interaction Mechanism between Pyrido [3,4-Molecules (Basel, Switzerland) · 2021Article
- Second-Generation Antimitotics in Cancer Clinical Trials.Pharmaceutics · 2021Review
Corrections and comments
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Authors and funding
25 authors at 1 institution in 1 country.
Funding
Abstract
Monopolar spindle 1 (MPS1) occupies a central role in mitosis and is one of the main components of the spindle assembly checkpoint. The MPS1 kinase is an attractive cancer target, and herein, we report the discovery of the clinical candidate BOS172722. The starting point for our work was a series of pyrido[3,4- d]pyrimidine inhibitors that demonstrated excellent potency and kinase selectivity but suffered from rapid turnover in human liver microsomes (HLM). Optimizing HLM stability proved challenging since it was not possible to identify a consistent site of metabolism and lowering lipophilicity proved unsuccessful. Key to overcoming this problem was the finding that introduction of a methyl group at the 6-position of the pyrido[3,4- d]pyrimidine core significantly improved HLM stability. Met ID studies suggested that the methyl group suppressed metabolism at the distant aniline portion of the molecule, likely by blocking the preferred pharmacophore through which P450 recognized the compound. This work ultimately led to the discovery of BOS172722 as a Phase 1 clinical candidate.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.