Treating Cancer by Spindle Assembly Checkpoint Abrogation: Discovery of Two Clinical Candidates, BAY 1161909 and BAY...

Area of Science:

• Oncology
• Molecular Biology
• Medicinal Chemistry

Background:

• Monopolar spindle 1 (MPS1) kinase is a key regulator of mitosis.
• Inhibition of MPS1 offers a novel cancer treatment strategy by inducing aneuploidy and cell death.
• Targeting MPS1 bypasses cell cycle arrest, irrespective of DNA damage or chromosome attachment issues.

Purpose of the Study:

• To optimize initial HTS hits from triazolopyridine and imidazopyrazine series into clinical candidates.
• To characterize the binding interactions of novel MPS1 inhibitors with the kinase's ATP site.
• To evaluate the preclinical efficacy of developed MPS1 inhibitors in vivo.

Main Methods:

• Hit-to-lead optimization of two distinct chemical series (triazolopyridines and imidazopyrazines).
• Structure-based drug design and medicinal chemistry approaches to enhance potency and metabolic stability.
• Biochemical assays to confirm binding to the MPS1 ATP site and assess inhibitory activity.
• Preclinical in vivo efficacy studies in relevant cancer models.

Main Results:

• Successful evolution of both series, addressing initial challenges of moderate potency (triazolopyridines) and poor metabolic stability (imidazopyrazines).
• Identification of clinical candidates BAY 1161909 and BAY 1217389 with distinct binding modes within the MPS1 ATP site.
• Demonstration of potent MPS1 inhibition and promising preclinical efficacy in vivo.

Conclusions:

• BAY 1161909 and BAY 1217389 represent promising clinical candidates for MPS1-targeted cancer therapy.
• The distinct binding strategies highlight the versatility of targeting the MPS1 ATP pocket.
• Further clinical development is warranted based on the preclinical data and novel mechanism of action.